Background

Over the past several decades, it has been challenging to attract meaningful investment for the development of new treatments for brain cancers. In particular, GBM or high grade gliomas (HGGs) are considered “radioactive” by many institutional and strategic investors owing to a dismal track record of clinical failures coupled with modest total addressable market size.

To be fair, GBM/HGG is one of the most challenging therapeutic areas in oncology development. One is hard pressed to find another cancer phenotype in the which the tumor microenvironment (TME) is as highly heterogeneous, invasive and immunosuppressed as one sees in GBM/HGG. Add to that an anatomical location in the brain and behind the blood brain barrier (BBB), and a very challenging situation arises.

The situation has been compounded by a research environment that has been out-of-touch with the forefront of modern molecular oncology and immuno-oncology. As a longtime Biotech entrepreneur and former Venture Partner at a large Tier 1 multi-strategy fund, the quality of the science that we have seen associated with Neuro-Oncology was substandard relative to other areas of Oncology. It is difficult to recommend a substantial Series A investment of $50-100 million when investigators or companies cannot elucidate a mechanism of action for a therapeutic candidate, and have not employed state-of-the-art molecular and cellular techniques in an effort to figure things out. Moreover, a clinician-led environment in which single agents lacking sound mechanistic rationale are thrown against the wall like therapeutic spaghetti is not a situation that raises the confidence of investors, or for that matter, patients.

A Path Forward

Given the extensive heterogeneity and immunosuppression in the human GBM/HGG TME, the most important lessons that we have learned are:

1. Single target monotherapies are not a winning strategy. The TME is too heterogeneous, and a result of atypical genetic/molecular flux (e.g. ecDNA), is too fluid to expect that a single target can be anything other than transiently useful.

2. In a combination strategy, it is essential that one element of the combination must induce immunological response. The highest frequency of clinical Objective Responses (ORs) that we see result from using a form of immunotherapy with a TME that has been converted to Hot (pro-inflammatory) instead of the baseline Cold (immunosuppressed) status. Surprisingly, one does not necessarily need a pharmacological intervention to flip the TME to Hot. Directed energy of modest power delivered by medical devices and tuned to particular resonant frequencies of key molecular nodes/processes can trigger a molecular cascade that results in a Hot TME. An added advantage is that such approaches are relatively non-invasive and circumvent the BBB.

3. The Phase 0/Window of Opportunity clinical trial framework is gaining traction. We do not know of a validated pre-clinical model of GBM/HGG that comes close to replicating the human clinical situation. As a result, brain cancer studies can produce remarkable results in animals, but utterly fail to translate into humans. This is particularly true of immunotherapy approaches. We have come to view pre-clinical models as useful for the assessment of safety margins and mechanistic rationale, but not much else. Employing Phase 0/Window of Opportunity clinical studies to quantitatively assess neuropharmacology and gain crucial evidence of mechanism translation is an idea whose time has come.

Brain Cancer is Investable

The nearby table summarizes selected investments in GBM/HGG companies and programs over the last 24 months. In order to preserve confidentiality, we have not listed the actual amounts invested nor the identities of some investors in the cases in which such information has not been otherwise publicly disclosed. Nonetheless, the aggregate amount of committed capital exceeds $350 million. If one includes other programs not featured in the table or resident within non-disclosing Biopharma companies, the figure rises to more than $400 million. Moreover, we are aware of three additional programs totaling another $200 million that are currently in fundraising or have raised funds but wish to remain in Stealth Mode. Of the seven programs in the table, five of them function via a mechanism that either directly or indirectly involves immunotherapy. In addition, four of the programs involve a novel medical device technology apart from radiotherapy.

Over the last four years, we have focused most of our time on identifying and working with investigators and companies that want to do things differently. An emphasis has been placed on those groups that are facile with modern molecular, cellular and immunological techniques and display a willingness to explore unconventional pathways in a rigorously scientific manner. We listen to hundreds of pitches each year; have provided uncompensated consulting advice to dozens of programs; have contributed Seed capital; and are delighted to socialize the best projects with our syndicate. We are not alone in this regard. Slowly, better science is emerging in Neuro-Oncology…and it is attracting meaningful investment.

We are not naïve. Nothing is more difficult than human clinical development, and it requires massive amounts of capital. Clinical setbacks are inevitable and several programs will fail to translate. Capital markets can be negatively impacted by both program-specific problems, macro trends such as geopolitical conflict and a rising cost of capital. But it is refreshing to see that a cadre of investors have stepped forward to nucleate significant investment in brain cancer based on improving science and a recognition of unmet clinical need.

Onward.

Julie passed away from GBM one year ago today (see here). The past year was the “Year of Transition” as we worked to ensure that all the nuts-and-bolts of family affairs were completed, and that our children were moving forward within their professional and personal lives. There were weddings, engagements, graduations and all the joyous things that one hopes for in life. Julie is undoubtedly happy. We miss her.

Onward! Investment in Brain Cancer is Having a Moment.

It was also an intense year of activity within Project Jubilie and Mission GBM to build several new companies and investments in the brain cancer space. We wanted to remain in Stealth Mode over the past year because company formation is best done below the radar, especially in a therapeutic area as historically challenged as brain cancer.

But now, it’s time to pull back the curtain in stages. Over the next few months, readers can expect a series of posts outlining the investments that have been made. Suffice it to say, brain cancer investment is having a moment. Over the last 15 months, there has been more aggregate investment in promising new therapies from Tier 1 capital sources than at any previous point that we can identify. The amount of committed capital so far exceeds $200 million (exclusive of a couple of M&A transactions) with all four of our Project Jubilie investment finalists from my time as a Venture Partner at RA Capital Ventures (aka “RAVen”) now funded and operating. And there are a couple more investments that are about to close or are actively being considered. Watch this space.

What do the funded companies have in common, and how were they able to attract significant capital in an area historically unencumbered by success? Damn good translational science carefully conducted by teams of committed and rigorous researchers who were hand-selected from worldwide institutions, often apart from the “Usual Suspects” in historical Neuro-Oncology. While the approach is no guarantee of ultimate clinical success, in our view it is absolutely the right way to enhance the probability of success, and to convince Tier 1 institutional and strategic investors that the time is right to back such efforts. Let’s be frank, the historical approach was not working over more than four decades.

Fresh Content for the “Brain Cancer Science Talk” and “Investing in Brain Cancer” Series

Mission GBM readers overwhelmingly enjoyed the opportunity to meet the Mission GBM Team and to hear what innovative science they were pursuing to generate new treatment options. Expect more video chats in this regard. In addition, we are planning to post some video interviews in which our leading institutional and strategic investor colleagues talk with Mission GBM about what they look for when contemplating an investment in brain cancer, and why they have chosen to put capital to work now in brain cancer. Check out the “Brain Cancer Science Talk” and “Investing in Brain Cancer” navigation tabs at the top of the website to see previous interviews, and to catch the new content when it is posted.

Some Other Interesting Project Jubilie Initiatives

In addition to the company building and investment activities, we are working on some projects that have been suggested by Mission GBM readers.

Fireside Chat with Mission GBM families – Talking about how they interacted with Mission GBM, and what sort of support and connections were helpful to patients, caregivers and families.

Support for Brain Cancer Advocacy and Patient Groups – While non-profit patient support and advocacy activities are not our focus, we do recognize the importance of such organizations…and we want to help. Fun things ranging from a series of Jubilie Jam live concerts (we do like our live music, and have sponsored many artists over the years) to meet-ups and a particularly intriguing art project are in the planning stages. Please let us hear from you if your organization has ideas or wants to partner. The Mission GBM community is large, active and encompasses many leading worldwide brain cancer centers, researchers and families.

Onward – Let’s Go!

However, a reader of the press release issued by Imvax would be challenged to understand that the trial missed its PEP. Instead, the company decided to put a positive spin on the results by noting that the trial data showed an extension in median Overall Survival (mOS), which was the Secondary Endpoint (SEP). No supporting #Data was provided to bolster the claim. Perhaps, the company will present such data at a future medical conference or in a reputable journal.

The company’s PR also indicated that Imvax would meet with the FDA in an attempt to somehow gain approval for IGV-001 despite the clinical trial miss. In the days prior to Jan-2025, there have been a few recent precedents for jawboning (bludgeoning?) the FDA into granting approval for candidates that miss pre-specified PEPs in indications that are severe and lack any good therapeutic options. In particular, we note the controversial approvals of Sarepta’s Elevidys® (Delandistrogene moxeparvovec; see here) for Duchenne’s Muscular Dystrophyand the initial approval of Biogen’s Aduhelm® (aducanumab; see here and here) for Alzheimer’s disease. In both cases, the aggressive and vocal actions of patient advocacy groups played a significant role in backing the FDA into an uncomfortable corner, and even over-ruling the recommendations of the Advisory Committees that reviewed the NDAs.

Always Let the Facts Get in the Way of a Good Story

We refer to this unfortunate Spin Doctor practice in Biopharma as “never letting the facts get in the way of a good story”. In contrast, we tell all the CEOs of our portfolio companies to do the exact opposite: ALWAYS let the facts get in the way of a good story. Those who listen get the support of our syndicates; those who do not generally become unemployed rather quickly.

Why, Dear Reader, would Imvax choose to pursue such a strategy…especially in a field that has been historically unencumbered by success and plagued by poor science and questionable clinical trial practices? Well, as my father told me decades ago, “When you don’t know the answer, follow the money”. Imvax has raised substantial amounts of investment capital in the last 6 years (see here), and the investors would understandably like to enjoy an ROI. The pressure to deliver an ROI has been known to tempt CEOs to suspend disbelief; issue a Spin-a-Palooza press release; and beat a hasty path to the FDA with vocal patient advocacy groups in tow. While we cannot predict the response of the FDA to the Imvax strategy (particularly in light of the #Chaos happening at the FDA following 20-Jan-2025; see here and here), we would advise that you get your popcorn ready as this will be a jolly good show.

The Bigger Picture

The questionable Imvax regulatory strategy in the face of its PEP miss in the Phase 2b trial may have a much larger spillover effect on the entire field of clinical development for GBM/HGG. Why?

Imvax was one of the first companies with a therapeutics candidate for GBM/HGG in late stage clinical development to get the FDA to consider PFS as an approvable PEP versus the Agency’s historically dogmatic insistence on mOS as the only approval PEP (in the wake of the bevacizumab (Avastin®) approval debacle for GBM). In the last 18 months we have become aware of at least four other companies also pursuing the PFS regulatory strategy for GBM after meeting with FDA. PFS as an approvable PEP is common in other forms of cancer apart from GBM/HGG, but has not been permissible for the past 15 years in GBM/HGG on account of the Agency’s embarrassment regarding the misguided bevacizumab approval. Thus, the Imvax #Data and regulatory strategy runs the risk of pushing the FDA back into its “mOS only for GBM approval” bunker.

Trials with mOS PEPs are longer, more expensive and more difficult to conduct relative to trials with a PFS endpoint, especially as new therapies advance which extend mOS. Moreover, one needs to consider the clinical situation and patient Quality of Life when using mOS as the PEP. Very few patients want to be bedridden, wearing an adult diaper and suffering frequent seizures or dense aphasia just because mOS statistics have to be obtained.

The Road Ahead for IGV-001

The FDA may eventually approve IGV-001 for GBM despite the Phase 2b clinical trial miss. Predicting what will happen at the FDA these days is a parlor game that those of us in the Biopharma industry conduct on almost a daily basis because the New Look FDA seems to be driven by forces other than rigorous evaluation of #Data and scientific evidence. Ugh!

Assuming that IGV-001 gains approval, the battle is only partially won. Imvax will still have to get acceptance from both the Neuro-Oncology community to write for the therapy and the Payers to underwrite the cost. Judging from the dozens of phone calls that we have received from NOs and Payers over the last 48 hours, this will be an uphill battle.

Maybe the facts will ultimately get in the way of a good story after all.

The Real World Difference Between PFS and mOS

On this score and offering my own personal note, Julie had an OS of 38 months which is extraordinary for a GBM patient with her clinical presentation, and is a testament to the power and innovative thinking of Team Julie. She lost her durable Complete Response in Mar-2024 when we had to suspend the use of pembrolizumab (Keytruda®; Thank You, Merck for being an enormously supportive partner for MissionGBM patients over the last 3+ years) due to a Grade 4 irSAE that perforated her colon (see here). We knew she would convert to rGBM status as soon as the CD8+ T-cells in the TME became exhausted. Right on cue at 2.5 half-lives after the last pembrolizumab infusion, we got the first Bad Scan in more than two years. The tumor grew rapidly and she was presented with the option of an awake craniotomy in Aug-2024 in order to debulk the tumor and provide runway for Team Julie to initiate an even more advanced immunotherapy with additional prophylaxis against irAEs.

While the awake crani was successful and expertly perfomed by one of the best neurosurgeons on the planet (Dr. Nduka Amankulor; Hospital of the University of Pennsylvania), Julie exhibited dense expressive aphasia and advancing neuromotor deficit in the post-surgical period. Because we had conducted detailed Goals of Care planning sessions early in Julie’s ndGBM period (see here), she made it clear that she did not want to live as a non-ambulatory aphasic who was completely dependent on her caregivers (principally me) to keep her alive. So we made the tough decision to suspend therapy and transition her to home hospice care despite the belief that the new therapeutic protocol could keep her alive for a significant additional period of time. Julie died peacefully in bed with me lying next to her in Jan-2025.

That, Dear Reader, is the Real World difference between PFS and mOS.

Onward!

Note about the future of Mission GBM. We had not intended to publish any new content until the one year anniversary of Julie’s death (Jan-2026); however, the Imvax PR and the strident response that it generated prompted us to publish this post. Life is what happens while we are busy making other plans. While we have not been writing and speaking much over the past year, we have been very active. Stay tuned for our emergence from stealth mode in 1H2026 with news regarding what we have been doing, and the multiple investments and Board memberships that we have undertaken to advance new therapies for GBM and HGGs. The battle continues.

Julie passed away peacefully in her sleep on 21-Jan with me by her side.

She lived with GBM for 1141 days (37.5 months), and for most of that Bonus Time she enjoyed a remarkable quality of life.

A brief remembrance of Julie, written by our son Alex, can be found here.

After a while, I will return to this forum with some additional thoughts. But for now, thanks to everyone in the MissionGBM community for all of the support and encouragement during Julie’s journey.

UPDATE: A few hours after we originally posted, Servier updated its Home page and issued a press release about the Vorasidenib approval. See here for further information.

We have had 20-Aug-2024 circled on our calendar for months because it was the PDUFA date for vorasidenib.  Just over one hour ago, FDA delivered an upside surprise and issued an approval two weeks early for vorasidenib (Voranigo®; see here) for low grade Astrocytoma and Oligodendroglioma patients with IDH1/IDH2 mutations based on compelling results from the pivotal INDIGO clinical trials (see here).

Warmest Congratulations to the Servier and Agios teams that discovered and developed vorasidenib over many years.  Many thanks to the patients and investigators whose participation in clinical trials made today’s approval possible.

Onward!

It is the dog days of summer, but the cases just keep coming.  We don’t mind – this is what we do.

Green Shoots

We are beginning to see higher quality programs with improved scientific content.  Huzzah!  We like to think that the constant messaging that we publish regarding an Investable Profile (see our five part “Investing in Brain Cancer” series) is helping to shift the conversation onto a more actionable footing.

The Highlights:

DNA Damage Response/Repair.  We have always been supportive of therapeutic agents that target DNA Damage Response/Repair (“DDR”) mechanisms.  Current research has ventured far beyond older agents to emphasize much more brain-penetrant and targeted agents.  When combined with complementary medicines like brain-penetrant PARP-1 inhibitors, the story and #Data become quite interesting.  There are multiple validated targets available, so careful prioritization based on the full spectrum of #Data will be necessary to optimize progress and prevent premature clinical trials failures for the usual reasons (e.g. no neuropharmacology data; inadequate PK/PD).  Even more heartening is the clear increase in activity and interest that we see from organizations across the expanse of brain cancer research and strategic investing ranging from the DNA Damage Response Consortium at NBTS to several Big Pharmas.  Confidentiality obligations prevent us from commenting more specifically at this time, but watch this space.

Immunotherapy.  We believe that immunotherapy must be a necessary part of a combination regimen in order to significantly alter the treatment prognoses for brain cancer patients.  At the moment, we are active with more than a dozen companies and research efforts focused on innovating immunotherapies across the range of modalities – Immuno-Oncology, Cell Therapies (CAR-T, CAR-NK, TCR-T, Gamma-Delta T, Antibody-Targeted T-cells), Tumor-Infiltrating Lymphocytes, Gene Therapies, Vaccines, Oncolytic Viruses and some really “out there” approaches.  Given our perspective, we see increasing evidence of the convergence of a handful of mechanistic pathways that these approaches have in common.  This is good thing because it signals that cross-pollination of the data sets will allow the field to more rapidly understand those targets and pathways that deserve increased attention and development.  It should also make it clear that some approaches are going to struggle to move forward (e.g. low valency CAR-T without TME stimulation and checkpoint inhibition; No, lymphodepletion is not the answer). Confidentiality obligations prevent us from commenting more specifically at this time, but watch this space.

Ancillary Targets and Mechanisms.  We have previously written about the attractiveness of certain, well-chosen ancillary (not directly oncogenic) targets and mechanisms to be included in combination treatment protocols (see here).  One Seed program in particular is looking rather promising, and has generated a #Data package of sufficient quality to merit exploring a range of strategic investing options.  We are directly involved, and believe that this program will yield compelling translational evidence as well as a visible example of a model for investing in brain cancer.  Confidentiality obligations prevent us from commenting more specifically at this time, but watch this space.

Certain Device-based Approaches.  We continue to think that medical devices will have an important role to play in brain cancer treatment regimens.  Of the four opportunities that we advanced in our Brain Cancer group at a major institutional investor, all involved a medical device to either (i) enhance trans-BBB drug delivery; or (ii) affect a biophysical mechanism that could be exploited as part of an overall treatment protocol.  The challenge is consistently that device companies do not generally “speak molecular language” or have a staff that has experience with the Research and Regulatory methods and processes that one uses in the Biopharma world*.  We have seen several protracted clinical holds imposed on device companies when they have attempted to advance drug-device combination programs into clinical and Regulatory stages because they have not incorporated the necessary pre-clinical studies to generate the required data.  This is a solvable problem, and we encourage device companies to seek out expertise in the molecular world as part of their strategic planning.

*We had one Investor/Director of a device company (a computer engineer by background) confidently tell us that the mechanistic rationale for the device was that “cancer cells do not use mitochondria while normal cells do”.  You can imagine our reaction.

Expanding Investor Interest.  Institutional and Strategic investor interest in brain cancer has been measurably expanding over the last 18 months.  There are syndicates forming.  We are involved in multiple discussions on a weekly basis with several of them evolving into Seed investments ($2-5M) designed to generate #Data sets that seek to bridge the translational research gap between early stage discoveries and #Data packages that support opening early stage, well-conceived clinical trials.  This is real progress because, over time, the investor conversation needs to shift from that of “Uninvestable Space” (historical situation) to “The Data Support It” (based on rigorous science- and evidence-based programs).  We are not naïve.  The transformation of investor interest in brain cancer will take time and will absolutely be built on high quality science.  However, we also are confident that several programs will advance from the Seed stage to the point that typical Series A and B rounds with Tier 1 syndicates will be possible ($40-100M).

It's a Rough Neighborhood

We recently began working with our 300^th MissionGBM case.  Our motivation for founding MissionGBM in 2022 was to scale the resources (science, clinical, investing) at our disposal to assist other brain cancer patients and families worldwide in a way that we did not see operating in the space.  Each case is a personal story, and we get to know the patient and patient’s family as part of the Journey.  While we know that we have been able to help many families, no one bats 1.000 in brain cancer.  A few patients have lost their fight, and that just makes us want to go even harder at our objectives.  On the other hand, we have many cases that are out beyond three years post-diagnosis…and counting…and most of these cases have unfavorable clinical and tumor molecular profiles.  The tenacity and never-give-up spirit of some of the families buoys us.  We hope to have a few of them join us for a “Community” video chat this year.

We Get By With a Lot of Help from the Team

We owe a debt of gratitude to the MissionGBM Team, a group of individuals hand-selected for their leadership in brain cancer research and clinical practice.  The reader can see many of the of these people featured under the “Meet the Team” and “Brain Cancer Science Talk” tabs on the MissionGBM homepage, and we expect that others will be added in the future.  Not a single person in the Team believes SoC is an acceptable goal for brain cancer patients.  Everyone is open-minded and constantly pushes the envelope to redefine the state-of-the-art.  We frequently cross-pollinate ideas, and a few of the Team members are co-authoring grants and investment proposals together.  This is how we change the field, and advance it based on a foundation of rigorous science.  Moreover, the clinicians on the Team have been beyond generous with their time.  They have agreed to see MissionGBM patients without hesitation; have jumped on peer-to-peer consults with fellow clinicians; and have continuously come up with ideas around the clock (they all know that I will likely respond in real time at 2am).  Sometimes this means a Zoom call from their car in the parking lot of a child’s lacrosse game (at half time); a quick consult during a break in a daughter’s graduation party; or locating WiFi to send a message while on safari in Africa.  Recently, one Neuro-Oncologist at a leading Center commented that the MissionGBM Team is “the best virtual Tumor Board around”.  We do what we can.

Onward!

For these reasons, one of the most promising avenues of brain tumor research involves immunotherapies designed to harness the human immune system, and focus its unique cytotoxic weaponry on selectively eliminating cancer cells.  One of the laboratories leading the development of immunotherapies for brain tumors is that of Michael Lim, MD (Professor and Chair of the Department of Neurosurgery at Stanford University; see here and here).

We first met Mike a few years ago at a reception during the Society for Neuro-Oncology Annual Meeting.  The talk quickly turned to the science of designing and developing immunotherapies for brain tumors, and the significant barriers to implementing such immunotherapies in the clinic.  For Episode 7 of the Brain Cancer Science Talk series, Mike and I decided to share some of our thoughts with the MissionGBM audience regarding:

• Characteristics of effective immunotherapies regardless of modality

• Discovering and developing actionable biomarkers for patient selection and enhanced Objective Response outcomes

• Encouraging tumor-specific cytotoxic T lymphocytes and other anti-cancer immune cells to activate and traffic to the tumor site in the brain; and

• Sustaining specific anti-cancer immune responses in a highly immunosuppressive TME.

In addition, we touch on a few fundamental scientific limitations that have plagued more rapid advancement of promising immunotherapies into the clinic, including:

• Lack of high quality pre-clinical models that translate to the human clinical environment; and

• Neuro-Oncology’s historical neglect of rigorous neuropharmacology studies for therapeutic candidates, thus often leading to an inability to interpret clinical trial data.

We conclude by focusing on accelerating the clinical development of immunotherapies (i) by deploying Window of Opportunity trial designs to directly obtain the missing neuropharmacology and treatment response data in the best model system possible (the actual human); (ii) by highlighting the promise of adaptive platform trial designs using rigorously vetted clinical candidates; and (iii) by emphasizing the need for modernization of the Regulatory framework to permit clinical trial designs that will be necessary to register effective new therapeutic agents in a rare disease area such as brain cancers.

Onward!

Frustrating Aspects of Cancer Clinical Trials

In our original “The Reality of Clinical Trials – Part 1” post (see here), we featured some eloquent and poignant writing from Bess Stillman, MD whose husband has been battling recurrent squamous cell cancer of the Head & Neck.  Dr. Stillman is better positioned than most to understand and navigate the vicissitudes of modern clinical trials, as she writes in a very recent public post (see here).

The same is true of the MissionGBM team, and yet we all struggle with a common set of frustrations:

• Most (>80%) of the registered clinical trials in brain cancers should not be open and recruiting patients due to the poor quality of pre-clinical science used as justification for the trial.  Continuing to subject patients, particularly rGBM/HGG patients, to low quality trials with no scientific basis only guarantees that the trial will fail, and perpetuate the perception among investors and other stakeholders that clinical development in brain cancer is “radioactive”.

• Clinical trial sites at the major Brain Tumor Centers (“BTC”) are incentivized to recruit and enroll patients for trials open at their BTC, which means that patients will frequently meet a Clinical Trial Coordinator on their first post-neurosurgery visit and prior to a discussion of the overall treatment plan with the Neuro-Oncologist.  This behavior is confusing and often perceived by the patients as self-serving and disingenuous. In some cases, it can also be harmful. We have had to coordinate rescue plans for more than a dozen cases in which the patient should never have been enrolled in the trial due to (i) ineligibility according to the published Inclusion or Exclusion criteria; or (ii) a prior medical history that clearly indicated the patient would very likely experience a Serious Adverse Event (SAE).

• Clinical trial records on ClinicalTrials.gov tend to be out-of-date, incomplete, difficult to navigate, and in many cases, contain misleading information.

• Individual clinical trial sites and the associated Investigators often apply a set of patient selection criteria that is somewhat different than the published Inclusion and Exclusion criteria, which is terribly frustrating to potential trial enrollees.

• Both the Investigators and the Sponsor know that the best scientifically rational course of treatment for the patient involves a combination therapy, but they are prevented from doing so because the Regulatory agencies insist on a series of monotherapy RCTs, each with its own SoC Control arm.

For brain cancer patients with aggressive clinical timelines, every day counts so the above complications serve as unnecessary roadblocks to clinical trial participation.

Look, we get it.  The embarrassment of approving bevacizumab (Avastin®) for GBM based on data from a single arm trial in which the readout criteria for the Primary Endpoint was poorly understood (once again, poor quality science in NO) at the time has haunted the FDA for years.  But that cannot be an excuse for a reluctance to work with the Neuro-Oncology community and Sponsors to design a more flexible clinical trial environment that has a fair chance of identifying and approving therapies, including combination protocols, that can actually make a difference for brain cancer patients.

Towards Better Trials for Brain Cancers

We have a few thoughts on the matter, and we know that we are not alone in supporting some of the following proposals.  Numerous Sponsors, investors, and Neuro-Oncologists have spoken to us extensively about the following topics.

Allow Trials to Incorporate External or Historical SoC Controls.  There are simply not enough patients to insist on an active Control arm utilizing SoC for each pivotal clinical trial.  The SoC treatment regimens have been around long enough to have yielded consistent mOS and other trial parameter data over many trials.  Further, no prospective patient wants to be randomized into the SoC Control arm as they are very aware that SoC is not a winning strategy.

Permit Combination Trials That Do Not Require a Factorial Design.  By factorial design, we mean the Regulatory requirement that necessitates multiple arms designed to evaluate Combination-versus-the Parts data.  Again, there are simply not enough patients to meet this requirement in a fair number of brain cancers.  Brain cancers tend to be heterogenous, aggressive and invasive, and we believe the #Data indicates that combination protocols will be required to make progress towards effective treatments.  Instead, Regulatory agencies should consider (i) demanding rigorous, pre-clinical #Data in the IND/IDE package that establishes the MoA biology, pharmacokinetics and safety pharmacology of the Combination-versus-the Parts in suitable pre-clinical models; and (ii) incorporating sophisticated statistical and data analysis techniques capable of determining if the proposed combination protocol is valid and working.  A Regulatory insistence on IND/IDE packages that emphasize Point (i) would eliminate a fair number of the poor quality protocols that currently lead to open trials, and thus, siphon away the very limited number of patients into trials that have no chance of providing any benefit other than clinical trial revenue to the BTC and yet another published paper describing a failed trial.

Encourage Cooperative Platform Trials, but Be Rigorous About the Candidates Selected for the Trial.  Platform trials are an idea that has been around in rare disease communities for a long time, and we are generally supportive.  When the number of patients is small, it seems reasonable to encourage patient coordination amongst potentially competing clinical sites in order to ensure that promising clinical development candidates are efficiently tested with an adequate number of trial enrollees.  For platform trials to work, some key criteria must be met:

1. Investigators and trial sites must agree to the cooperative framework established by the Platform Trial Organization (PTO).

2. Regulatory agencies must approve a Master Trial Protocol that they agree can result in an approved therapeutic agent, if the trial data is supportive.

3. Sponsors must be sufficiently attracted to the Master Trial Protocol and the professional capabilities of the PTO that they become willing to cede trial execution and reporting responsibility to the PTO.

4. The Candidate Selection Committee for the platform trial must demand rigorous pre-clinical data from the Sponsor before a Candidate is allowed to enroll patients.

5. Patients must feel that they are willing to be enrolled in a trial that is based on sound science and clinical trial design.

In practice, it has historically been challenging to execute platform trials because one or more of the preceding criteria is compromised, usually Criteria #3 and #4.  Criteria #3 can be difficult to satisfy because every Sponsor is nervous about giving up control of a clinical trial to a PTO that does not “own” the Candidate, and may be a rather inexperienced, academic organization that is prone to poor communication and quality control.  But the real Achilles heel is Criteria #4 owing to the strong incentive that a PTO’s Candidate Selection Committee has to “feed the beast” by allowing lower quality Candidates to be included in the platform trial in order to help pay for the expensive infrastructure that the PTO has established.

The Global Coalition for Adaptive Research (GCAR, see here) was established as a non-profit organization to encourage and facilitate adaptive clinical platform trials in a variety of disease areas including GBM.  GBM-AGILE was launched and has been operating for about five years (see here and here).  Unfortunately, GBM-AGILE has yet to achieve its promise.  For many in the brain tumor community, the effort has suffered from admitting Candidates of questionable scientific justification into the GBM-AGILE framework, often from thinly-funded Sponsors who do not have sufficient resources to prosecute well-designed pre-clinical and early clinical studies (we have seen the pre-clinical and Phase 1/2 data packages).  In addition, the GBM-AGILE protocol was not designed to readily accommodate combination trials, which are vitally important in high grade brain cancers like GBM.  We remain hopeful about the platform trial approach, but only if the Candidate Selection Committee is (a) able to upgrade its disciplined analysis of potential Candidates based on scientific #Data; and (b) design a Master Trial Protocol that can handle combination trials.

Discourage the Publication of “Science Lite” Clinical Trials.  Academic science and medicine is a “publish or perish” business.  Careers are built upon a publication record that can emphasize quantity over quality, particularly in a field like Neuro-Oncology in which little advancement has occurred over decades.  If the IRB at an institution is willing to green light a study without first demanding reasonable scientific justification, and often desperate patients at that BTC can be convinced to enroll, it is possible to generate a significant volume of work.  However, publication of low quality work should be another matter.  Not every study is of the quality or impact to be reported in Nature, Science, Cell, New England Journal of Medicine, or even Journal of Neuro-Oncology.  But all journals should nonetheless demand strong scientific rationale before publishing a clinical study.  Doing so would send a clear message that publication will only be granted to those studies that are thoughtful, scientifically rigorous and focused on the patients. No science; no ink.

Onward!

Each year in early June the American Society of Clinical Oncology (ASCO) holds its annual meeting in Chicago.  If you have not attended, imagine a combination of the Super Bowl and a Taylor Swift concert all rolled up into one very intense week focused on “All Things Cancer”.  It can be both overwhelming and physically exhausting as meetings, presentations and receptions often run from 6am to well after midnight.  Whenever I attend, there is very little sleep, irregular meals and a backpack full of energy bars to get me through the day.

Usually brain cancer presentations and #Data at ASCO get lost in the enormity of the highlighted news releases associated with the larger oncology indications (lung, prostate, breast, melanoma, etc.). This year was not significantly different, but since MissionGBM is focused on brain cancer, we offer the below summaries and commentary regarding some of the more noteworthy brain cancer presentations.

Niraparib Makes a Splash in ndGBM

Niraparib (Zejula®) is a PARP inhibitor (PARPi) that has previously been approved for a number of non-brain cancer indications.  PARP (Poly (ADP-ribose) polymerase) is a category of native enzymes that have evolved to repair DNA that becomes damaged by normal cell division processes or external treatment perturbations (e.g. radiation, chemotherapy).  The PARP class has two principal subvariants (PARP1 and PARP2), and niraparib inhibits both.  However, what makes niraparib interesting and differentiated for brain cancers is that it displays reasonable brain penetrance and pharmacology at oral dosing levels that can be tolerated by patients.  Previous attempts to use PARPi’s to treat brain cancers have not been successful because (1) most PARPi are not sufficiently brain penetrant at tolerable doses; and (2) the therapeutic benefit of PARPi is really only obtainable when it is paired with a DNA damage agent (i.e. it does not well work as a monotherapy).

The Ivy Brain Tumor Center and the Barrow Neurological Institute (Phoenix) presented clinical data at ASCO that showed real promise for the combination of niraparib and RT for the treatment of ndGBM in uMGMT patients (see here and here).  There are two key points that we would like to emphasize:

• As we have written many times and which we validated in a thorough analysis of dozens of failed GBM trials with the brain cancer group at RA Capital, if the drug cannot get to the site of the brain tumor in sufficient concentration and dwell time to affect the targeted pharmacodynamic MoA, then the drug has ZERO chance of providing therapeutic benefit.  Every serious biopharmaceutical drug developer knows this, and we can tell you from personal experience that no Development Committee at a Biopharma will advance a Development Candidate into IND-enabling studies or clinical development if the neuropharmacology #Data is absent, or is not supportive of obtaining adequate drug levels at the target.  And yet, the field of clinical Neuro-Oncology, being Clinical Heavy and Science Lite, has repeatedly put drugs into patients without first doing the PK and neuropharmacology scientific work to rationally advance the drugs into patients. Uggggh!

• Congratulations to Nader Sanai and the Ivy Brain Tumor Center team for designing the niraparib Phase 0/2 “trigger” trial and doing the rigorous non-clinical scientific work to understand the neuropharmacology of niraparib in the brain BEFORE blindly dosing GBM patients with yet another drug that is not very brain penetrant.

Bottom Line.  Niraparib + RT should be advanced into a Phase 3 pivotal trial against an SoC Control group.  Of course, making the investment decision to do so is a complicated mix of scientific, market and financial analysis conducted by the Sponsor, and is not as straightforward as the brain cancer community would like.

Shout out to the Ivy Brain Tumor Center for promoting and executing Phase 0 “Window of Opportunity” studies to quantitatively assess the PK and neuropharmacology of niraparib and other drugs for brain cancers.  In the eyes of MissionGBM and experienced drug developers everywhere, you are doing things right, and providing much needed scientific leadership in a long neglected area of brain cancer science that has held back clinical development for decades.

METIS (EF-25) Phase 3 Trial of TTF in NSCLC Patients with Brain Metastases

Novocure presented the full clinical results from the Phase 3 METIS trial (see here).  As we previously commented when the top line data was released, the results are intriguing (see here).  Full Disclosure: We are fans of TTF when it is used in combination with therapeutic agents that catalyze and sustain TTF-induced in situ “vaccination” of the TME (see here and here).  Going forward, we are hopeful that the company will (i) recognize and emphasize the true power of TTF to unlock synergistic combination MoAs (instead of purely emphasizing the historical cytodyskinesis monotherapy theory); (ii) conduct high quality scientific investigations that incorporate leading edge molecular biology to rigorously describe the most effective TTF-driven MoAs, and thereby, overcome the significant “pseudo-science” overhang that is holding back adoption of TTF by many brain cancer centers; and (iii) design future clinical trials and partnerships to accelerate the most effective TTF-driven MoAs even it means that the company has to share development control with other organizations that have a proven track record of efficient combination drug/device clinical development.

Interim report of a Phase 2 study of sonodynamic therapy (SDT) using SONALA-001 together with MR-guided low-intensity focused ultrasound (MRgFUS) in children with diffuse intrinsic pontine glioma (DIPG) (see here)

We continue to be intrigued by the promise of Sonodynamic Therapy (SDT); albeit the non-clinical and clinical #Data that we have reviewed to date as part of our syndicated investment activities have not been compelling enough to write a check.  Nonetheless, we remain open-minded about the approach, and have periodically considered it as potential rGBM treatment for Julie when she eventually progresses.  It is worth noting that the most compelling clinical #Data that we have seen to date has come from H3-mutant HGGs such as DIPG and DMG, which was the subject of the linked ASCO presentation.  The #Data for non-H3-mutant HGGs (GBM, Grade 3/4 Astrocytomas) has not yet been as convincing.  We think regularly about how to construct a viable investment case for SDT (or other therapeutic agents) in H3-mutant gliomas despite the very small number of affected patients.  There has to be a way forward, if we work together to construct it.

We should point out that we have a deep background from our MIT/MGH days with related photodynamic therapy (PDT) using pulsed micro- and nanosecond lasers as well as picosecond time-resolved laser spectroscopy to quantitatively measure delta singlet oxygen and other reactive oxygen species induced by laser light in the presence of photosensitizers (see here, here and here). So hand-waving explanations of the SDT MoA do not cut it with us. We remain hopeful that companies working in the SDT space will conduct the rigorous science to elucidate the cytotoxic MoA of SDT and its potential synergistic linkage to immune system response.

A Phase 1 study of the protein arginine methyltransferase 5 (PRMT5) brain-penetrant inhibitor PRT811 in patients with recurrent high-grade glioma or uveal melanoma (UM) (see here)

The MissionGBM cohort has several MTAP dual-deletion GBM patients, who could potentially benefit from treatment with a brain-penetrant PRMT5 inhibitor, particularly in combination with a brain-penetrant CDK4/6 inhibitor.  We have invested lots of time talking with a few (Bio)Pharma Chief Scientific Officers on behalf of MGBM patients in order to assess the possibility of conducting such a combination clinical study, or gaining use via Expanded Access (aka Compassionate Use) programs.  It has been frustratingly slow because the current Regulatory framework virtually demands a single agent RCT prior to the design and conduct of a combination study.  Sponsors simply cannot risk the ire of the FDA or the complication of a mandated and expensive factorial combo-vs-the-parts trial as their first clinical campaign.  Thus, we wait – Uggggh!

While development of PRT811 has been discontinued by Prelude Therapeutics, we would advise that readers keep and eye on the development programs for Amgen’s AMG193 (see here and here) and TNG908 and TNG462 (Tango Therapeutics; see here).

Outcomes and immune response after peptide vaccination targeting human cytomegalovirus (CMV) antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma (see here)

It has been observed for a long time that the TME in brain tumors often stains positive for CMV-associated proteins.  A spirited “chicken-versus-egg” debate continues apace regarding whether CMV plays a role in glioma initiation/progression -versus- CMV shows up later in the TME because the high degree of immunosuppression enables CMV to set up residence (just about all adults have been exposed to CMV).  We all know that correlation does not equal causation, but there has not been definitive #Data reported to date to resolve the argument.

Nonetheless, there is no dispute regarding the potent immuno-inflammatory action of CMV antigen pp65, which is a known “Danger Signal” to the human innate immune system.  Immunizing and subsequently boosting a human subject with a pp65 “vaccine” causes rapid and significant immune responses, which can often spiral out of control into high grade AEs requiring ICU admission, pressor support and a near-death experience.  We have a couple of adult MissionGBM members who have come to us after receiving pp65 vaccines within Phase 1 clinical studies resulting in severe irAEs requiring months of recovery/salvage therapy (again – Where is the rigorous pre-clinical #Science, Neuro-Oncology community?).  Thus, we read with interest the linked ASCO presentation in HGG and medulloblastoma.  Of interest, the patient cohort was comprised of children and young adults, who typically have not had as much native exposure to CMV, and thus, tend to have less severe immunological reactions to CMV pp65 vaccines, which renders such an approach potentially safe enough to deploy clinically in younger patients after much more careful development.

On a related matter, the broader MissionGBM team has been involved in detailed conversations to determine whether a quite promising pp65 mRNA GBM vaccine approach (see here and here) can be developed to the point at which it can be safely tested in human clinical studies for adult HGG patients.  It has been gratifying to connect our network of experts in mRNA cancer vaccines and the elucidation/mitigation of irAEs with the Sponsors in order to catalyze discussion and potential collaboration in the service of brain cancer patients.  Stay tuned.

A Phase 0/1 trigger trial of BDTX-1535 in patients with recurrent high-grade glioma (HGG) with EGFR alterations or fusions (see here)

While we support the Phase 0/1 study designs that the Ivy Brain Tumor Center team is conducting, one simply cannot make a silk purse out of a sow’s ear.  BDTX-1535 targets EGFR in HGG patients, which means that it will (i) show a transient depletion of EGFR-positive cells in HGG patients; and (ii) do nothing to alter the ultimate clinical course and mOS of the patients.  Why?  Because EGFR in HGG cells is principally resident on ecDNA, which will disappear quickly under therapeutic pressure, and confer a competitive advantage to the non-EGFR-positive cancer cells in the TME.  We are growing weary of repeatedly advising against EGFR-targeted monotherapies in HGGs (see here and here…and just about every other post on MissionGBM).  Doing the same thing over-and-over-again and expecting a different outcome is a sure path to bankruptcy.  Dear Sponsor:  Please suspend clinical development of BDTX-1535 for GBM right away, and reallocate the precious capital and patients to other programs until a brain-penetrant ecDNA pathway inhibitor can be advanced into the clinical to be used in combination protocols with a brain-penetrant EGFRi.

Onward!

When a family learns that a member has been diagnosed with an aggressive brain cancer, the first reaction is inevitably one of despair.  Internet search engines return depressing statistics regarding the average duration and quality of life.  There are a lot of tears and quite a few sleepless nights.  You realize that any future plans that have been made are now suddenly and irreversibly altered.

But like every day, the sun will rise again tomorrow.

Today marks the twin milestones of our 35^th wedding anniversary and 918 days (30 months) since Julie was diagnosed with GBM.

To commemorate the occasion, we decided to post a few photos taken over the years from our first meeting at MIT in the 1980s (Oh, the #BigHair!); through the early days of starting careers and a family; up through graduations, family events and some silliness; and finally, to very recent photos taken over the past 30 months after Julie’s diagnosis.  If a single picture is worth a thousand words, then the following collection speaks volumes.

As the children grow, every parent knows that there is a narrow window in which they can still be considered only slightly uncool before the kids are consumed by the Teenager Vortex.  I was bestowed the title of “Coolest Dad Ever” for 15 minutes by virtue of winning the Boston Celtics Dance Contest…in front of the family…and a couple hundred of our Biotech company employees in attendance at the Garden.  Completely Punked! by good friends in the Boston Biotech community that night.

The first year after Julie’s diagnosis brought about many enormous changes as we had to establish our personal rhythm in order to navigate the Journey.  Despite busy young adult lives lived in locations far away from our home, the children make time to visit with Mom as often as possible.

The Holidays are always a highlight of the year, and in 2023 they served as a backdrop for an hilarious neighborhood “Ugly Holiday Sweater + Formal Attire” dinner party (Oh, the food, wines and gag gifts!) plus the engagement of son Alex to fiancee Katy.

The past 30 months have allowed many great memories to be made.  We highly recommend that each MissionGBM family find a way to capture the moments that are important to them.  For us, Julie wanted to record herself reading the children’s favorite Holiday board books by the fire as a way of preserving both her voice and the good memories of our family.

Onward!

Click here for David Tran’s “Meet the Team” profile on MissionGBM

Ever since the MissionGBM “Brain Cancer Science Talk” video interview series was announced, readers have been asking, “When is David Tran’s interview going to post?”

We are pleased to reply, “The wait is over”.

Formally, David D. Tran, MD, PhD is Chief of Neuro-Oncology and Co-Director of the Brain Tumor Center at the University of Southern California in Los Angeles.  To the MissionGBM community, however, David is much more.  For the past 2.5 years, David has been a valued partner and member of a global Team that has relentlessly sought to advance brain cancer research and clinical translation in a manner that we typically do not see within the Neuro-Oncology field.  He is a rigorous and careful scientist, who never accepts mediocrity and always insists on letting the #Data speak.

David is also a genuinely good person, who will find a way to rearrange his busy schedule in order to speak with a patient, or engage in peer-to-peer consulting with other Neuro-Oncologists wrestling with challenging cases for which there are few treatment options.

Results That Matter: 2-THE-TOP…And Beyond

Dr. Tran is a soft-spoken person, who prefers to let his work do the talking.  Over several years, he patiently put together the 2-THE-TOP protocol (2TT) that was tested in a Phase 2 clinical study (see here and here).  Moreover, David and his colleagues did the hard work of elucidating the underlying molecular biology and immunology that serves as the elegant scientific foundation for the 2TT protocol (see here).  All of the work occurred against a backdrop of significant skepticism within the Neuro-Oncology field regarding the utility of the Tumor Treating Fields (TTF) technology that is integral to the 2TT regimen.  Unlike most of his peers, Dr. Tran did not simply dismiss TTF as “pseudo-science”, but instead, he chose to follow the #Data to uncover a powerful mechanism of action that linked TTF-driven disruption of the mitotic process in cancer cells to the uniquely effective anti-cancer capabilities of the activated human immune system.

Dr. Tran’s #Data revealed that the 2TT technique invoked three vitally important biological actions that are key to effective solid tumor immuno-oncology therapies:

• Present the full spectrum of Tumor-Associated Antigens (TAAs) to the antigen processing cells of the immune system.

• Cause the Tumor Micro-Environment (TME) to flip from immunologically “Cold” (immunosuppressed) to “Hot” (inflamed); thereby, providing an attractive target for immune system engagement.  Further, ensure that the immune system activation is focused on the tumor so as to minimize spillover into systemic immune-related toxicities.

• Prevent the responding anti-cancer, cytotoxic immune cells from becoming exhausted within the TME, and losing their ability to kills cancer cells expressing TAA.

The Planned Serendipity of Good Science, Its Clinical Translation and the Power of Working on a Multi-Functional Team

In the linked video interview with Dr. Tran, David and I describe how we first met, and our collective initial skepticism regarding the prevailing official explanation of the mechanism behind the TTF-driven Objective Responses that were occasionally observed. We discuss the multi-year path that David followed to design the 2TT protocol, and then carefully work out the underlying science to validate his original scientific hypotheses.  We talk about what has been learned over the past few years regarding clinical translation for GBM/HGG cases both within the formal 2TT Phase 2 trial as well as the dozens of MissionGBM cases that have employed the core 2TT protocol in community practice.  We consider findings that begin to sketch out potential biomarkers for patient selection and Objective Response prediction.  We go on to chat about the reality of irAEs in any protocol that employs immune checkpoint inhibitor medicines like pembrolizumab (Keytruda®), and how the Team was expanded to involve experts like Michael L. Dougan, MD, PhD (see here and here) in order to mitigate irAEs and keep patients safely on protocol.  Finally, we show actual #Data for Julie’s Journey from her original GBM diagnosis in Dec-2021; to her initial setback upon first utilization of the baseline 2TT protocol (Mar-2022); through the months of careful work to add prophylactic infliximab to the core 2TT regimen in order to allow safe rechallenge with pembrolizumab (Jun-2022); and ultimately all the way to a Complete Response (Dec-2022), which has proven to be durable for more than one year.

Onward!

N-of-1 on Behalf of All

UPDATED: 21-Jun-2024

Life Science researchers and clinicians share a couple of things in common with the military – namely, that we love our abbreviations and acronyms for words and phrases that are often used.  But sometimes we get so wound up in our work that we forget that our shorthand is not familiar to the broader audience.  Many thanks to the MissionGBM readership for requesting a Glossary of Terms.

So, without further ado, we humbly post the MissionGBM “Jubilie” Glossary.  You might want to bookmark this evergreen page for future reference.  Please send us any additional items that you would like to see added to this Glossary.

ADL – Activities of Daily Living. Activities that an independent adult typically performs on a daily basis – shopping, preparing meals, personal hygiene, dressing, taking medications, managing money, using the telephone, email or computer, for example.

AE – Adverse Event.  Adverse Event is the term that we use in therapeutics development to describe unwanted side effects of treatment.  AEs come in five (5) Grades:

Grade 1 – Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.

Grade 2 – Moderate; minimal or local, non-invasive intervention likely necessary an can be delivered on an out-patient basis; May interfere with some ADL.

Grade 3 – Severe or medically significant, but not immediately life-threatening; Hospitalization required and significant limitation of ADL.

Grade 4 – Life-threatening consequences; urgent intervention in a skilled medical facility is necessary.

Grade 5 – Death

BBB – Blood-Brain Barrier.  The Blood-Brain Barrier is a selective semi-permeable membrane between the blood and the interstitium of the brain, allowing cerebral blood vessels to regulate molecule and ion movement between the blood and the brain.

Bx – Biopsy.  A procedure whereby biological material from a tumor is sampled for subsequent tumor biological analysis and profiling.  Biopsies can take the form of either a direct tissue retrieval or liquid biopsy (LBx) of circulating tumor fragments/cells.

“Cold” Tumor.  A tumor that is not likely to trigger a strong immune response and respond to immunotherapy because the degree of immunosuppression in the TME is elevated. Most often the case with brain tumors.  Opposite of a “Hot” tumor.

CR – Complete Response.  As defined by RANO Criteria for brain cancers:  Disappearance of all enhancing disease, which is stable for at least four (4) weeks.  Stable or improved T2-FLAIR on MRI.  No new lesions detected.  Clinically, discontinued or reduced corticosteroid use with documented clinical stability or improvement.

DIPG - Diffuse Intrinsic Pontine’s Glioma. A rare, fast-growing tumor that forms in cells called glial cells in a part of the brain stem called the pons. DIPGs tend to spread to nearby tissue and other parts of the brain stem, are hard to treat, and have a poor prognosis. They usually occur in children. See here for further information.

DMG - Diffuse Midline Glioma. A primary central nervous system (CNS) tumor that forms in the brain or spinal column, and is typically found in the central area of the brain (see here). DMGs are very challenging to treat because they often involve or are proximal to critical brain executive function areas rendering the tumors difficult or impossible to address with conventional therapies (e.g. RT, surgery).

ecDNA – Extrachromosmal DNA.  Small circles of DNA that do not reside on chromosomes, and do not follow the normal rules of Mendelian inheritance.  ecDNA is increasingly being recognized as critically important to the neoplastic transformation process in early cancer cells.  In addition, many of the most pathological oncogenes and immunosuppressive genes have been recently been discovered to reside on ecDNA (see here and here).

Furball.  Otherwise known as a dogfight both in aerial combat (see here)…and when you realize that you must stare down brain cancer in the biggest fight of your life.  Fight’s On!

FUS – Focused Ultrasound.  A broad set of biophysical techniques that harness ultrasonic energy of varying frequency, power and energy to affect a therapeutic objective, including tissue ablation, transient opening of the BBB to permit enhanced drug delivery, or retrieval of circulating biomolecules for analysis (see here).

GoC – Goals of Care.  A super-important plan for the things that each individual patient wants to achieve from brain cancer therapy (see here).  We cannot stress three things enough: (1) GoC discussions must involve the entire Care Team, and should be considered as evergreen; (2) it is not realistic to have a goal of curing cancer; and (3) failure to soberly consider GoC is a sure fire way create unnecessary strife in your family and Care Team.  As we say, “Denial is not just a river in Africa”.

HGG – High Grade Glioma.  Primary brain tumors of glial cells pathologically graded at Grade 3 or 4 according to the 2021 World Health Organization Classification of Tumors of the Central Nervous System (see here).  If a lowercase “p” precedes HGG (e.g. pHGG), then the tumor has been found in a pediatric patient.

“Hot” Tumor.  A tumor that is likely to trigger a strong immune response and respond to immunotherapy. Opposite of a “Cold” tumor, which is most often the natural state in brain tumors.

IDH – Isocitrate Dehydrogenase.  IDH is a naturally occurring enzyme found in a cell’s metabolic pathways.  When IDH becomes mutated, it alters its biochemical reaction products in a manner that can lead to cancer neogenesis.  IDH is the most frequently mutated metabolic gene in human malignant cancer (see here).

Incurious.  Not interested in knowing the current research or best available #Data, or not wanting to discover or try anything new (see here).  A word frequently attached to the patient experience at some large brain tumor centers.

irAE – Immune-Related Adverse Event.  An AE resulting from undesirable action of the immune system on otherwise healthy tissue in a patient, usually as a result of an immunotherapy protocol.  Examples include, dermatitis, thyroiditis, colitis, pneumonitis, pancreatitis, hepatitis or hypophysitis.

irEC – Immune-Related Enterocolitis.  An irAE occurring in the colon and manifesting as confirmed colitis.

KPS – Karnofsky Performance Status.  A standardized scale used to measure the ability of cancer patients to perform ordinary tasks.  See here for further information.

LGG – Low Grade Glioma.  Primary brain tumors of glial cells pathologically graded at Grade 1 or 2 according to the 2021 World Health Organization Classification of Tumors of the Central Nervous System (see here).  If a lowercase “p” precedes LGG (e.g. pLGG), then the tumor has been found in a pediatric patient.

LITT – Laser Interstitial Thermal Therapy.  A minimally invasive neuro-surgical procedure employing heat from laser pulses to destroy selected abnormal tissue.

Metastases or Mets.  Cancer originating outside the brain that has spread (metastasized) to the brain.  Brain metastases tend to have very different molecular and genetic profiles than those observed for primary brain cancers.  Some cancers (e.g. non-small cell lung cancer) have up to a 20% probability of metastasizing to the brain.

MGBM – MissionGBM.  Self-explanatory.

MGMT.  A naturally-occurring enzyme that is designed to repair DNA damage created by the action of alkylating agents (like temozolomide) by removing the appended alkyl moieties.  The activity level of MGMT is influenced by the methylation status of its genetic promoter sequence.  uMGMT – means that the promoter is unmethylated, and therefore, MGMT actively removes appended alkyl moieties largely rendering ineffective the action of drugs such as TMZ. mMGMT – means that the promoter is methylated, and therefore, MGMT is relatively inactive at removing appended alkyl moieties largely rendering effective the action of drugs such as TMZ.  In HGGs, about two-thirds of cases have a uMGMT status while roughly one-third of cases display a mMGMT status.

MoA – Mechanism of Action.  The biological or biophysical sequence of steps by which a drug or medical device renders its therapeutic activity.

ndGBM. Newly diagnosed GBM

NO – Neuro-Oncology or Neuro-Oncologist.  Self-explanatory.  In the case of a physician, someone who has likely been trained in medical residency as a Neurologist, and then receives 1-2 years of Neuro-Oncology indoctrination during a post-residency fellowship.

NSGY – Neurosurgery.  Self-explanatory.

OR – Objective Response.  A documented Partial or Complete Response resulting from a defined treatment protocol.

ORR – Objective Response Rate.  The percentage of people in a treatment group or study who obtain a documented Objective Response.

OS – Overall Survival.  The length of time from either the date of diagnosis or the start of treatment for a disease that patients diagnosed with the disease are still alive. mOS refers to the median OS for a group of patients under observation in a study.

PD – Progressive Disease.  As defined by RANO Criteria for brain cancers: Twenty-five percent (25%) or more increase in enhancing lesions despite stable or increasing steroid dose.  Increase in T2-FLAIR on MRI not attributable to non-tumor causes.  Any new lesions detected.  Deterioration of clinical conditions not attributable to non-tumor causes, and not due to decreased steroid utilization.

PFS – Progression Free Survival.  The length of time during and after the treatment of a disease that a patient lives with the disease, but it does not get worse.  mPFS refers to the median PFS for a group of patients under observation in a study.

PR – Partial Response.  As defined by RANO Criteria for brain cancers: Fifty percent (50%) or more decrease of all measurable enhancing lesions, which is stable for at least four (4) weeks.  Stable or improved T2-FLAIR on MRI.  No new lesions detected.  Clinically, discontinued or reduced corticosteroid use with documented clinical stability or improvement.

Pseudo-Progression.  Pseudo-progression is a phenomenon in which an initial increase in tumor size is observed or new lesions appear, followed by a decrease in tumor burden; this phenomenon can benefit patients receiving immunotherapy but often leads to premature discontinuation of treatment owing to the false judgment of progression.  Can be tricky to diagnose even for the most experienced neuro-radiologists in the absence of a biopsy of the lesions noted on MRI.

Pseudo-Response.  Pseudo-response is marked by an apparent significant decrease in radiological presentation of the tumor after initiation of a therapeutic intervention, which is subsequently found to result from radiological influences unrelated to true therapeutic effect on the tumor.  Pseudo-response is often seen after administration of bevacizumab (Avastin®) or certain corticosteroids.

QoL – Quality of Life.  Each individual patient defines her/his path through life, including the acceptable level of inconveniences, AEs and neurological compromise.

Quackfoolery.  Medical treatment based on unsupported beliefs instead of actual science- or evidence-based information.  Beware! - A source of widespread pollution on cable TV channels and social media.  See here for further information.

RANO Criteria.  The Response Assessment in Neuro-Oncology (RANO) criteria was created to permit standardization of imaging interpretation used to assess brain tumors and the response to treatments thereof (see here).

RCT - Randomized Control Trial. A clinical trial design that randomly assigns patients, who have met the study Inclusion and Exclusion criteria, to either the Treatment or Control arms without regard to individual patient characteristics. Going further, RCTs can be designed such that all parties involved with the trial do not know the assignment and treatment status of the patient. A well-designed RCT is considered the Gold Standard of modern clinical development.

rGBM. Recurrent GBM

RT – Radiation Therapy.  A set of therapeutic procedures that uses energetic external beams or loco-regional radioisotopes to damage target tissue, and force them to die or generate a strong immunological response.

SAE – Serious Adverse Event.  An AE that is assessed at Grade 3 and above.

SD – Stable Disease.  As defined by RANO Criteria for brain cancers: Does not qualify for Complete Response, Partial Response or Progression.  Stable, non-enhancing T2-FLAIR on MRI.  Stable or reduced corticosteroid use compared to baseline.  Clinically stable.

SoC – Standard of Care.  The baseline treatment regimen that almost all brain cancer patients initially receive following diagnosis.  For newly diagnosed High Grade Glioma patients (GBM; Grade 3-4 Astrocytomas, Diffuse Midline Gliomas), SoC is typically some form of chemo-radiation therapy following neuro-surgical resection.

TME – Tumor Micro-Environment.  The biological conditions found within a tumor at the cellular or molecular level.

TMZ – Temozolomide.  An old, modestly brain-penetrant DNA alkylating agent that is the workhorse of most SoC treatment regimens in many brain cancer cases.

TTF - Tumor Treating Fields.  A novel anti-cancer therapeutic technique that uses low power alternating electrical fields to disrupt cellular biophysical processes, resulting in dyskinesis and a whole host of sequelae that can be harnessed to produce some rather compelling clinical results under the proper circumstances (see here).

Tx – Therapeutic or Therapeutic Regimen.  Shorthand for the specific therapeutic protocol used to treat disease.

WTF – Whiskey Tango Foxtrot.  Useful phrase/question that can be uttered in a variety of situations such as (1) when dealing with your health insurance plan; (2) when one realizes that your NO is not willing to discuss alternative treatments, and will not say why; or (3) what you might say on the radio when you begin to “gray out” because you are pulling 5Gs trying to break lag and get a clear shot on the Six of your opponent in a multi-circle furball.

Onward!

N-of-1 on Behalf of All

Click here for Paul Mischel’s “Meet the Team” profile on MissionGBM

It is our pleasure to share one of the most eagerly anticipated MissionGBM “Brain Cancer Science Talk” video interviews.  Dr. Mischel is the Fortinet Founders Professor and Professor, by courtesy, of Neurosurgery, Stanford University School of Medicine

Paul and I have spent countless hours together over more than 2 years reviewing #Data, talking about innovative, evidence-based treatment strategies for brain cancer, and catalyzing translational research to create such treatment options.

We begin by talking about the discovery of ecDNA, its role in oncogenesis, and potential strategies for clamping ecDNA to limit its cancer-promoting characteristics.  Next, we move on to a discussion of Paul’s work to identify fluoxetine (Prozac®) as a molecularly-targeted treatment for GBM/HGGs that are dependent on specific lipid structures in the cellular membrane to grow rapidly (see here).  We discuss the role of the outstanding Innovative Medicines Accelerator at Stanford University (see here) as a leading example of a model focused on translating basic academic research into promising and well-developed clinical candidates.

Finally, we chat about the pressing need to upgrade rigorous science in the field of Neuro-Oncology, and we suggest a new model for training Neuro-Oncologists that we believe will improve the probability of success of drug development, patient care, and more importantly, spare brain cancer patients from enrollment in clinical trials that have little scientific basis to recommend them.

Onward!

N-of-1 on Behalf of All

UPDATE: Paul Mischel’s “Brain Cancer Science Talk” video interview with MissionGBM can be found here.

Where is the Science?

In early 2022, we were frustrated and a bit desperate.  We knew that we had to quickly design a customized treatment protocol to give Julie a fighting chance to live more than just a few months following her GBM diagnosis.  Her tumor size (5cm; 8mm midline shift; incipient brain herniation), location (in the insula and lenticulostriate regions proximal to the middle cerebral artery) and molecular profile (uMGMT, low TMB, no actionable targets) were very unfavorable.  Quite simply, there were few viable options available once one realizes that SoC was not going to be a winning strategy.

Consultations with the world’s leading Neuro-Oncologists were uniformly disappointing.  We heard little beyond repeated recommendation of a rubber-stamped SoC approach and symptom management. We experienced difficulty generating any meaningful discussion regarding the molecular biology of GBM or the innovative use of immunotherapies in state-of-the-art treatment regimens.  How incurious!

In addition, the clinical trials that were (prematurely) pitched to us were largely of poor quality and often lacked basic scientific rationale (which we refer to as the “Clinical Heavy, but Science Lite” philosophy that has damaged the brand equity of Neuro-Oncology for decades).  Many were Investigator Sponsored Trials (ISTs) or poorly capitalized Sponsor trials at leading brain tumor Centers, and were plagued by (i) lack of basic mechanistic data to support the scientific hypothesis; (ii) missing PK and PD data that any serious private sector Biopharma company would require in order to advance a Development Candidate into the clinic; and (iii) no effort to understand the neuro-pharmacology of the therapeutic agent being tested.  If one does not bother to understand the PK and neuro-pharmacology of the drug under evaluation, then how can one know if the trial failed as a result of simply not getting enough drug to the target(s) -versus- an inadequate understanding of the underlying biological mechanisms.

We began to put together Team Julie, and leveraged our extensive biopharmaceutical and medical network to ask for help.  Longtime colleagues in the Life Sciences scientific, clinical and investing worlds began to respond right away, and to recommend additional peers who were active in brain cancer research.  From the beginning the unifying theme was: Where can we find the highest quality science and #Data in the field of brain cancer?

Designing an Effective Treatment Protocol for Julie

As is the usually the case with GBM, Julie’s tumor was heterogeneous, aggressive and invasive, which meant that a monotherapy strategy was going to be ineffective, particularly one focused on a single oncogenic target.  A combination treatment protocol was a “Must Have”, and given the tumor heterogeneity, we felt strongly that one element of the strategy had to involve the immune system.

Paging Dr. Mischel: STAT!

Enter Paul S. Mischel, MD, the Fortinet Founders Professor and Professor, by courtesy, of Neurosurgery, Stanford University School of Medicine.  Our very first call with Paul in early 2022 was conducted from a car in the parking lot of a coffee house (Julie likes her coffee).  We had reviewed Paul’s publications and research, including his many years of work regarding the molecular biology of brain cancers, but were flummoxed by the quality of the scientific discourse that spontaneously erupted that day only a few minutes after first introducing ourselves on the call.

We started with a discussion of Paul’s recently published Cell paper describing the intriguing potential role of the repurposed SMPD1 inhibitor fluoxetine (Prozac®) in a combination protocol to treat GBM (see here).  We ran through the #Data (including some that was unpublished), and I complemented him regarding the rarely-seen-in-academia technique of utilizing computational analysis of Big Data sets from anonymized healthcare claims databases to provide an additional means of scientific hypothesis testing.

And then things got really interesting.

ecDNA and Neoplastic Transformation

The conversation turned to GBM/HGG tumor heterogeneity and the potential mechanisms for it.  HGGs are significantly more heterogeneous and immunosuppressed that most solid tumors, and they do not typically display high tumor mutational burden (TMB) or micro-satellite instability.  These features make GBM/HGGs even more difficult to treat as a heterogeneous tumor defeats single target monotherapies, and the low TMB makes it easier for the tumor to evade immune surveillance.  What could be the reasons that HGGs are so heterogenous and immunosuppressed despite having low TMB?  Paul suggested that it could be ecDNA based on work emerging from his lab (see here, here, here,  here and here and references cited therein).

Paul outlined the findings from his group working in concert with other leading researchers such as Howard Y. Chang, MD, PhD (see here and here).  While still evolving, the #Data was compelling and supported by multiple, independent lines of scientific inquiry.  We were aware of the blossoming field of ecDNA  research via our Biotech professional and investing activities (see here and here), but had not yet recognized the prevalence of ecDNA in HGG tumors, nor made the leap to the potential role of ecDNA in HGG heterogeneity.  Paul reviewed #Data from as-yet-unpublished Nature and Cell papers that his lab had submitted as well as the scientific discussions under the Cancer Grand Challenge (eDyNAmiC) and Cancer Research UK working groups.

Paul went on to describe the #Data regarding the dynamic nature and rapid fungibility of ecDNA constructs within a cell under selective treatment pressure.  The inheritance patterns of ecDNA do not follow conventional chromosomal inheritance mechanisms, and thus, can significantly alter the genetic profile of a cell within only 1-2 cell cycles.  If validated, this would imply that attempting to drug an amplified oncogenic target resident on ecDNA (e.g. EGFR, CDK4/6, MDM2/4, etc.) without a concomitant method of interdicting the ecDNA mechanistic pathways would be either extraordinarily difficult, or perhaps, a Fool’s Errand.

Ok then, that clarifies matters.  We need to design a combination strategy that avoids a primary dependence on drugging highly dynamic oncogenic targets found on ecDNA. But what would such a strategy look like?

Towards a “Picket Fence” Combination Treatment Strategy

We have written and spoken extensively about our evidence-based view of the most productive combination treatment strategies as part of our “Investing in Brain Cancer” series (see here), so we will not rehash all of that discussion in this post.  In summary, one should seek to design combination brain cancer treatment strategies by employing a “menu” of treatment options that are selected from at least two of the following mechanistic categories:

• Engage the Immune System.  The single most effective anti-cancer modality is to enable the immune system to sustain an attack on the tumor.  Immunization (vaccination) is only the first step in generating a tumor-specific immune response, but it alone is not sufficient.  Making sure that the TME is immunologically “Hot” and producing a durable immune response are the more challenging pieces.  Finally, any effective immunotherapy strategy MUST have a component that keeps responding anti-tumor immune cells from becoming exhausted within the TME.

• Hit an Ancillary (Indirect) Target.  There are several biomolecular structures and mechanisms in brain cancers that support the cancer’s rapid growth without being necessarily mutated or directly oncogenic.  For example, ecDNA pathways, DNA damage response pathways and cholesterol/lipid/metabolic pathways are all fertile hunting grounds.

• Hit a Direct Oncogenic Target.  Blocking or inhibiting a direct oncogenic target is the preferred approach in the treatment protocols for many cancers including LGGs (mutant IDH-1/2, select kinases), but has not yielded compelling results in HGGs.  The lack of success appears to be related to the heterogeneity of HGG tumors, which seems to be primarily driven by ecDNA.  Bottom Line:  Any single oncogenic target approach in GBM/HGGs is more hope than strategy, which is why such monotherapy approaches repeatedly fail.

In the countless hours of phone and Zoom calls between Paul Mischel and MissionGBM, we have collected and reviewed #Data that leads us to believe that the above framework is the most promising.  Accordingly, our scientific and investing work is focused on developing such strategies and translating them into human clinical use as fast as we can. This is how we attempt to advance the field, and it would simply not be possible without top shelf scientists like Paul and his colleagues.

Paul S. Mischel – Complete Mensch

His world-leading scientific acumen aside, the thing that totally differentiates Paul from everyone else is his generosity and incredible selflessness with respect to helping cancer patients worldwide.  Over dozens of calls and hundreds of hours of interaction, we have gotten to know Paul beyond the purely scientific and medical domains.  Thus, we were not surprised when Paul revealed one of the primary reasons why he relentlessly pushes the envelope in his research.  It is his story to tell, and perhaps it will come up during his “Brain Cancer Science Talk” video interview.  When cancer touches the lives of someone close to you, your work is transformed from a professional livelihood to a personal Mission.  Paul has been beyond invaluable to the MissionGBM community, and we know for a fact that he has jumped on calls and answered emails from many MissionGBM families over the past two years.

Onward!

N-of-1 on Behalf of All

This sort of move happens all the time in small Biopharma companies that have a modest Balance Sheet, and thus, must continuously review investment allocation decisions as new data becomes available.  However, the deprioritization of ERAS-801 is noteworthy for the brain cancer community.

MissionGBM View:  As we have written/spoken/shouted many times both on this website and during our speaking engagements at public brain cancer conferences (see here and here and the reference linked therein), a monotherapy targeted at EGFR in GBM/HGGs is not a winning strategy.  Yes, a fair number of HGGs display copy number amplification of EGFR (as well as other oncogenes), but the gene tends to be resident on ecDNA cassettes.  When one introduces an EGFR blocker, the cancer cells rapidly react by modulating the expression of EGFR from ecDNA, thus removing the target and abolishing the mode of therapeutic action.  Because HGGs are heterogenous, the net result is that the cancer cells that do not display EGFR gain a competitive advantage, and the tumor progresses with little overall impact from the therapy.

Stayed Tuned:  In an upcoming episode of “Brain Cancer Science Talk”, we will be speaking with Paul Mischel, MD (Stanford) about ecDNA, its role in cancer neoplastic transformation and some potential strategies for how to more effectively treat cancers that are driven by oncogenes resident on ecDNA.

IMPORTANT NOTE FOR NEURO-ONCOLOGISTS:  Please carefully consider administering osimertinib (Tagrisso®) to your patients who have previously been receiving anti-PD(L)-1 immunotherapy.  Some of the worst irSAEs that we have ever seen occurred when the published clinical literature in this regard has been ignored (see here).  It is bad enough that an EGFRi is not going to provide much therapeutic benefit in GBM/HGG, but to subject a patient to horrendous and unnecessary irSAEs as a consequence of treatment must be avoided.

Onward!

Sam recently posted a video on social media (see here and here), which is a personal and emotional essay of what it means to a career Biopharma researcher to finally hold a drug Approval Letter in one’s hands after a lifetime of effort.  The video should be required viewing for every graduate level student on the planet (e.g. science, medicine, business, law and especially public policy).  It should also be shown on endless loop in Washington and other political centers, all too frequently characterized by performative political theater designed more to bash the Biopharma industry in pursuit of votes than to actually do the hard work of formulating policies that improve healthcare delivery and affordability.

For Episode 4 of Brain Cancer Science Talk, we chat with Sam about the long and tortuous journey of tovorafenib from its discovery through strategic deprioritization by its original Sponsors, and finally, to its successful development and recent approval for pLGG by Day One Biopharmaceuticals.  We discuss key lessons learned during the tovorafenib development, and how such lessons can be applied to additional oncology and rare disease medicines under development.  This is actually how the sausage gets made.

In addition, we spend some time talking about the importance of #Data and #Science, and the overwhelming need to always let facts get in the way of a good story.  Sam expands even further by relating his experience as a pediatric oncologist, during which he was careful to consistently emphasize the scientific and clinical evidence associated with a case, and to work relentlessly to identify evidence-based treatment options for the children under his care.  We call this concept: “N-of-1 on Behalf of All”, and Sam Blackman is a living embodiment of the approach.

To conclude, we briefly discuss the critical importance of harnessing the human immune system to specifically attack cancer cells in high grade gliomas (HGGs) and brain metastases.  Both of us believe that targeted, and perhaps cell-based, immunotherapies will be central to real progress in battling brain cancers.

Onward!

N-of-1 on Behalf of All

Warning!  The following post contains aviation analogies stretched beyond any reasonable limits and videos clips of hi-G aerobatic flight solely for the purpose of emphasizing key points about battling brain cancer.  We are happiest when we are helping brain cancer patients “fly”, and carving up airspace with the throttle pushed to the firewall.

Travel is a joyous experience for a lot of people.  But traveling is also one of the most stressful things that we regularly encounter in life.  Whether it is the morning commute or a vacation halfway around the world, unexpected events can alter a journey.  The same can be true when life is disrupted by a brain cancer diagnosis.  Everything is instantly turned upside down.  Taking a deep breath and regaining control of the Journey tests a family’s resolve and cohesion like nothing else.

Why Are Goals of Care Discussions So Important?

When we board a commercial flight, we hope for a smooth and uneventful hop.  Sometimes turbulence does occur, and it can be frightening.  The same is true of brain cancer Journeys.  They will be bumpy from time-to-time.  All oncology treatment plans have Adverse Events (AEs; aka “side effects”) associated with them.  It is unavoidable, and the treatments can occasionally be worse than the disease (see here).  When setbacks inevitably occur, it is useful or even comforting to refer back to a GoC discussion and plan to guide decision-making during a stressful period.

Create a GoC Flight Plan and Update It as New Data Presents

GoC plans need not be complex.  We advise that families start with the basics, which is typically a clear and unambiguous statement of one’s personalized Priority Objectives:

• I want to live as long as possible, but with a Quality of Life (QoL) that is acceptable to me and my family.

• I define QoL as being able to (check all that apply): (i) Communicate (speak or write); (ii) Move about with reasonable independence (walk, use a cane/walker, use a wheelchair);  (iii) Engage in adult activities and conversations requiring cognitive skills; (iv) Travel;  (v) Experience Joy with my family; (vi) Help my family understand that I may elect to terminate my treatments at some point; (vii) Make it clear to my family that they need to respect my decisions; and (viii) any other objectives that one may consider important.

• I understand that neurosurgery (NSGY) is likely, but there is a limit to how many procedures that I will endure.

• I am willing to accommodate only certain inconveniences in order to extend my life.  For example, (a) I will (not) shave my head for treatments; (b) I do (not) accept hospitalizations if necessary to mitigate any treatment-induced AEs that may arise; (c) I am (un)comfortable using adult incontinence products; and (d) I can(not) tolerate significant bouts of treatment-related nausea and vomiting.

• I do/do not have an interest in exploring clinical trial participation, and I understand that I may be randomized to the Control (SoC) arm of a study.

• I understand that my family members have lives apart from my brain cancer care, and I want them to live their lives as much as possible, even it means that I may not see them as often as I or they may like.

• When hospice becomes necessary, I prefer to move to a facility outside of my home versus remain in my home with in-home hospice care.

• I want my family to make rational financial decisions surrounding my care.

With the Primary Objectives in place, one is now ready to contact the tower and begin the takeoff roll for one’s Journey.  Be advised – Once aloft, unexpected situations will be encountered requiring periodic adjustments to the flight plan.

Caption: After a thorough pre-flight inspection and sortie planning meeting, we roll out for a two-ship sectional takeoff in a World War II vintage P-51D “Mustang” alongside our buddy in a P-40 Warhawk “Flying Tiger”. Revs Up! It’s a beautiful day to fly. (Source: Scott Rakestraw)

What to Do When Things Go Upside Down

When we are planning an aerial combat sortie (with laser designators instead of air-to-air cannons), everyone in the flight group participates in a detailed pre-flight discussion of what may go wrong, and how we plan to recover if “Stuff Happens”.  We talk about the Rules of Engagement; how to safely enter and exit an aerial furball (aka “dogfight”); radio communications and backup hand signals; and bailout procedures should something catastrophic happen (we wear parachutes and practice bailing out).  We also chat about quickly locating the “Party Bag” in the event that a “Reversal of Fortune” occurs in the middle of a hi-G maneuver (Ewww! It can be hard to see the instrument panel or out of the canopy if one’s lunch suddenly exits).

By analogy, we strongly advise that a brain cancer patient and his/her family do the same regarding the Journey.  Some common planning examples are: (i) what should we do if a seizure occurs; (ii) when to call 9-1-1 for emergency help; (iii) to which ER do we want the ambulance to transport us; (iv) how will we quickly communicate an emergent problem to the Neuro-Oncologist and care team; and (v) what is the plan to provide coverage for any children, pets or dependents if an emergency hospitalization is required.

Make a plan and a backup plan.  Pack your parachute.  As Smokey the Bear says, “Only You can prevent forest fires.”

Caption: A clip from our very first Basic Fighter Combat lesson in July 2001. The warbird is a North American AT-6 “Texan”, which was the advanced fighter trainer for the P-51D “Mustang” during World War II. Video quality is typical for 2001 as opposed to the GoPro HD video files that we create now. (Source: Scott Rakestraw)

Never Leave Your Wingman (Caregiver)

A brain cancer diagnosis affects the whole family.  For most families, a primary caregiver will emerge – usually a spouse, partner, parent or adult child.  The stress that caregivers experience can be very intense because he/she is both caring for the patient as well as trying to simultaneously manage a whole spectrum of challenging daily tasks (job, household finances, child care, food shopping and prep, cleaning, medical appointments, dealing with insurance companies, etc.).  We constantly talk with caregivers and emphasize the critical importance of making time for themselves and continuing to do activities which bring them joy.  Easier said than done, we know.

We also advise patients that they must be sensitive to the unique stresses experienced by a caregiver.  It is important to recognize and talk about these stresses, and to continually endeavor to maintain psychological balance and personal relationships despite the swings of emotion and treatment setbacks.  The worst situations that we see arise when the patient-caregiver relationship deteriorates to the point of being adversarial.  Please do not let this happen.

Caption: Never leave your Wingman! Having spent an hour ripping it up in an exciting furball, we bring our flight group back for a high speed low pass over the airfield in tight formation. The tower cleared the pattern and advised waiting aircraft on the ramp to “get your phone’s video camera rolling as you’re going to see a rare treat”. The video is recorded from my head-mounted GoPro camera as I fly the P-51D. Do NOT try this without lots of practice. (Source: Scott Rakestraw)

Putting It All Together – Fight’s On!

You have been unexpectedly thrust into the fight of your life.  You certainly did NOT want to be in this position, but you are…so now you must take the fight to your brain cancer.  Set up your battle plan; assemble your squadron; make sure that your aircraft are fueled and armed with evidence-based weapons.  Let your Wingman know that you are all in this together no matter how Hot the furball may get.

You’re ready for this: Bogey on my nose; Angels 8; Four clicks to the Merge; Closing at 400 knots; Master Arm Hot.  Fight’s ON!

Onward!

Next, we consider the Blood Brain Barrier (BBB) and the unique challenges that it creates for the development of therapeutic agents for brain cancer (see here for a recent review from Dr. de Groot’s UCSF group).  Dr. de Groot is an acknowledged leader in the advancement of Focused Ultrasound (FUS) methods for transiently opening the BBB to enhance drug delivery into various regions of the brain as well as to access tumor-associated molecular material for liquid biopsy.  We continue with an overview of the need to upgrade clinical trial design to incorporate much more scientific rationale, and to attract more brain cancer patients as enrollees.

Finally, we ponder necessary improvements to the historical Regulatory framework to better enable the efficient conduct of the combination protocol designs that will be required to yield better treatment outcomes for heterogeneous brain cancers with aggressive clinical timelines.

Dr. de Groot has been an invaluable resource for the entire MissionGBM family, and has been quick to see patients in his practice as well as do peer-to-peer consulting with other care teams.  Some of the most challenging MissionGBM cases (e.g. Lynch Syndrome, other genetic anomalies) have been taken up by Dr. de Groot and his colleagues in the UCSF Division of Neuro-Oncology.  We thank him for his leadership in the clinic and the lab.

Onward!

N-of-1 on Behalf of All

To hear Graeme Woodworth, MD talk to MissionGBM about his work with brain cancer patients and research, please click here.

When we first met Graeme Woodworth, MD (Chair of Neurosurgery; Director of the Brain Tumor Program, University of Maryland) in Feb-2023, we knew right away that we had to build a strong relationship with him.  Top talent just has a way of creating a good first impression.  Over the past 15 months, Graeme has been a frequent thought partner and a wonderful resource for many MissionGBM cases, especially the most challenging ones.  We cannot thank him enough.

Dr. Woodworth’s day job is that of a practicing neurosurgeon.  As such, he sees a lot of brain tumor cases for which he and his team must carefully plan and execute delicate surgeries in a manner that removes as much tumor as possible while also preserving brain executive function.  No one wants to clear PACU with aphasia, memory loss, neuromotor or significant cognitive deficits.

Neurosurgery for Brain Tumors:  Best to be a Careful and Unhurried Customer

Of the roughly 4000 Board-certified neurosurgeons in the US (see here and here), there are probably only about 250 that we would want operating on us.  Why?  Because we see a lot of MissionGBM cases in which the initial brain tumor resection was inadequately planned or executed resulting in post-surgical complications and problematic neurological deficits (usually spine surgeons in community hospitals, who may do only a few craniotomies and brain tumor resections each year; however, we have seen occasional poor outcomes from major academic medical centers).  It is heartbreaking to review a case in which the patient never has a fighting chance to prosper during his/her brain cancer Journey due to poor neurosurgical intervention at the outset of the case.

We tell MissionGBM families repeatedly that they often have time to research and select a top neurosurgeon for their case instead of merely signing the consent form offered by the first neurosurgeon to show up in the ED.

While we wanted Julie’s tumor resected yesterday when she presented in the ED of a local community hospital with rapid onset aphasia, we decided to stabilize her and then transfer her to a skilled hospital of neuroscience for the craniotomy and tumor resection.  Her operation occurred a week later after detailed planning was completed by her neurosurgical team (see here).

Bottom Line:  You want a top neurosurgeon like Graeme Woodworth, MD working your brain tumor case.  Take your time.  Make an informed choice.

Innovation in Neurosurgery

Like all neurosurgeons, Dr. Woodworth knows that there are significant limitations to the adage “nothing heals like cold steel” (or “hot lasers”, if you prefer).  Contemporary imaging and surgical visualization technologies simply do have enough resolution to “see” every cancer cell in the operative field.  Moreover, the tumor often has invaded areas of the brain that cannot be safely resected.  Finally, any surgical procedure carries multiple levels of risk, which requires that the neurosurgical team carefully plan the operation and also have contingency plans to rapidly address the spectrum of potential complications that can arise.

To address some of the limitations of brain tumor resection, Dr. Woodworth has established neurosurgical programs that extend current MR-guided tractography techniques into the realm of state-of-the-art “Connectomics” mapping (see here and here).  Using these technologies allows the neurosurgical team to understand and track the critical neural circuits that define brain executive function in both the surgical planning as well as intra-operative settings.  Performing neurosurgery in the absence of such neural mapping could result in cerebrovascular complications, or utterance of the infamous punchline, “Oops, there go the piano lessons!”

Dr. Woodworth is also active in the area of neurosurgical research regarding the use of Laser Interstitial Thermal Therapy (LITT; see here) in combination with other stereotactic methods to improve outcomes in brain tumor resections.  Given the thermal cytoreductive nature of LITT, there is significant risk that the patient will experience post-operative cerebral edema as a result of laser-induced thermal injury.  By combining MR-guided Connectomics with LITT, Dr. Woodworth’s team is able to create a de facto “awake LITT” procedure that is designed to ablate the tumor tissue with minimal thermal damage to the surrounding healthy neuronal tissue.  Going further, Dr. Woodworth and colleagues are currently exploring the combined use of LITT + Proton Beam Therapy to improve clinical outcomes for both ndGBM and rGBM patients (see clinical trials NCT04699773 and NCT04181684).

Transiently Opening the BBB to Enable Better Drug Delivery

Perhaps, one of Dr. Woodworth’s most intense interests is understanding the science behind the BBB, and developing techniques to permit enhanced drug delivery across the BBB.  He is a leader in the growing community of researchers focused on the application of Focused Ultrasound (FUS; see here) with microbubbles to transiently open the BBB so that therapeutically meaningful quantities of active pharmaceutical agents can gain access to the site of a brain tumor (see here, here, and here).  Under normal circumstances, the intact BBB serves as stiff barrier to the transport of therapeutic agents into the brain (see here).  In brain tumor cases, the BBB can act as an impediment to drug delivery into the tumor bed, thus limiting the efficacy of the treatment due to delivery of sub-therapeutic doses into the TME.

One of the many things that attracted us to Dr. Woodworth’s research is his insistence on developing techniques to quantitatively understand and document the neuropharmacology of FUS-enabled brain tumor drug delivery.  His work is differentiated from the majority of efforts in the area by an insistence on actually measuring the concentration of the drug as opposed to simply showing qualitative images of enhanced permeability of contrast agent after FUS application.  This is what is known as “rigorous neuropharmacology”, and there is just no substitute for it, if one is dedicated to translating research into successful human clinical trials instead of just curing cancer in mice.

Speaking of translational research, Dr. Woodworth has advanced his programs into multiple clinical studies (see here, here and here) with some of the early efforts beginning to yield Results That Matter (see here and here).

Onward!

In this Episode of the Brain Cancer Science Talk series, we speak with Graeme Woodworth, MD (Chair of Neurosurgery; Director of the Brain Tumor Program, University of Maryland; see here) about his promising work in developing and clinically deploying new techniques for transiently opening the BBB in brain cancer diagnostic and treatment protocols.

Dr. Woodworth has been an invaluable resource for the entire MissionGBM family, and has been quick to see patients in his practice as well as do peer-to-peer consulting with other care teams.

Whether you are interviewing neurosurgeons for a brain tumor resection or working with your Neuro-Oncology care team to develop treatment options, we highly recommend getting in touch with Graeme Woodworth, MD.

Onward!