Meet the Team – Paul S. Mischel, MD
World Class Molecular Oncologist, Invaluable Thought Partner and Complete Mensch
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.
Our Conclusion: A different strategy had to be deployed, and it had to be developed with people who were conversant at the leading edge of molecular oncology and comfortable with the conduct of rigorous scientific inquiry.
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.
What should be the individual “pickets” in a “Picket Fence” combination strategy to attack the tumor simultaneously on multiple fronts, thus maximizing the probability of treatment success? This question kept us awake around-the-clock for two months while Julie was advancing through Neurosurgery, recovery and the chemo-radiation portion of SoC.
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.
If that call were a scene in a Hollywood movie, there would be dramatic lighting and sound building to a crescendo as Paul and I sprinted rapid-fire through molecular oncology #Data, treatment strategies and potential experiments based on leading edge science. Bazinga! Now we’re finally cooking with gas.
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.
The proverbial light bulb switched ON in our head, and we asked the Billion Dollar Question: “Does your #Data indicate that the most frequently occurring amplified oncogenes in GBM/HGGs reside on ecDNA?”
Paul’s Answer: “Yes, we think so. Furthermore, we are now seeing evidence of immunosuppressive genes occurring on ecDNA in certain tumor types. Taken together, these results suggest a potential explanation for the observed heterogeneity of GBM tumors and the high degree of immunosuppression.”
[Cue dramatic music and thunderclap emoji]
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.
Our time on earth is relatively short, and we would all like to make a real difference in the lives of others. Paul Mischel is one of those rare individuals who has made the world a better place for countless people globally through his best-in-class science and his unwavering enthusiasm for helping cancer patients.