Investing in Brain Cancer - Part 2
Therapeutic Strategy…with some Business & Investment Strategy sprinkled in
In a series of posts on MissionGBM over the next two months, we will examine the issues surrounding “Investing in Brain Cancer”. In Part 1 of the Series, we looked at the Scope of the Challenge. In Part 2 of the Series below we take a look at Therapeutic Strategy and how it can be used to build investable profiles.
We invite the reader to follow the Series, and to ponder the challenges and opportunities that exist. The ability to craft a solution begins with understanding the problem.
Executive Summary – Core Concepts for Evaluating Brain Cancer Investments
As we outlined in Part 1 – Scope of the Challenge, brain cancers present a rather challenging environment for both therapeutics development and investing. However, there are some Core Concepts that do provide a rational basis for evaluating promising therapies and investments:
1. Combination Treatment Protocols are a “Must Have”. HGGs are heterogeneous, aggressive and invasive. Monotherapies do not represent a winning strategy. In contrast, LGGs and some brain mets tend to be more homogeneous, and sometimes can be attacked with well-designed monotherapies…until the inevitable escape mutations develop.
2. Treatment Protocols Must Have a Method for Transiting the BBB…or Bypassing It. The goal of any therapeutic protocol is to deliver the therapeutic agent to the site of the brain tumor, which means that either (i) the BBB must be transited; or (ii) the BBB must be bypassed altogether.
3. Crossover (or Pan-Cancer) Approaches Offer the Highest Probability of Attracting Significant Investment. While brain cancers do have somewhat unique genetic and molecular profiles, they can also share some oncogenic targets or mechanisms in common with non-brain cancers. Thus, it makes sense to leverage research done over the full spectrum of all cancers whenever possible. From a business and investment perspective, capital is more likely to support a bolt-on brain cancer study, if the pipeline also includes non-brain cancer studies utilizing some of the same therapeutic agents.
4. In God We Trust; Everyone Else Must Bring Data. Should be obvious, and yet, we see dozens of research and investment proposals each year with little data or scientifically inadequate data (Hint: heterotopic flank studies; studies done with a single genetically-manipulated brain cancer clone; or studies in which there is no data regarding neuro-pharmacology; studies conducted with no Control group).
5. Adverse Events are Unavoidable, but Can Be Managed. If a therapeutic agent could be perfectly targeted to only the cancer cells, then adverse events (AEs) would be minimized or eliminated. We do not live in that Utopia. All therapeutic agents have companion AEs, and when one stacks multiple therapeutic agents in a combination protocol, the AEs stack up as well. Quality of Life (QoL) matters! Carefully designed treatment protocols consider the AEs, and incorporate methods to minimize or manage the AEs.
The remainder of this post will examine Core Concepts #1 - #3 above in more detail from the perspective of building investable therapeutic strategies. Topics #4 and #5 are self-explanatory, and will not be further developed below. Lastly, the market, financial and investment analyses also need to be considered.
Building Investable Therapeutics Strategies
The most elegant mouse trap imaginable must be able to attract adequate capital if it is to make a difference in the world. With that in mind, what constitutes an investable therapeutics strategy? Here we go…
Core Concept #1 - Combination Treatment Protocols are a “Must Have”
After years of parsing pre-clinical, clinical and investment data/opportunities, our syndicate has arrived at the following menu for an attractive brain cancer therapeutics strategy.
The most effective and investable therapeutic strategies incorporate at least two of below categories in a combination protocol. Conversely, those approaches that utilize agents from only one category have been unencumbered by success…and significant investment.
· Engage the Immune System. The single most effective anti-cancer modality is to enable the immune system to sustain an attack on the tumor. Working against an immune attack is a broad spectrum of immune-suppressive mechanisms as well as the ever-present BBB. This entire space is a white hot topic in cancer research overall with new discoveries emerging weekly. We have written about the power of immune-engaging protocols in HGGs, and believe in the general approach so much that we selected a particular embodiment of it as the cornerstone of Julie’s successful GBM therapeutic protocol (see here). There are many other immunological approaches encompassing Vaccines, CAR-Ts, Tumor Infiltrating Lymphocytes and even Oncolytic Viruses.
· Hit an Ancillary (Indirect) Target. There are several biomolecular structures and mechanisms in brain cancers that support the cancer without being necessarily mutated or directly oncogenic. For example…
Extra-Chromosomal DNA (ecDNA) and Replication Stress. Recent discoveries have begun to elucidate the role of ecDNA in the genesis, amplification and heterogenous differentiation of neoplastic cell states in many types of cancers (see here, here and here). In brain cancers, we frequently see amplified copy number oncogenes residing on ecDNA (e.g. EGFR, CDK4/6, MDM2/4, etc.), which is highly dynamic and fungible within 1-2 cell cycles. There is a strong argument for the role of ecDNA as a driver of (i) HGG heterogeneity; (ii) immunosuppression in the TME; and (iii) rapid depletion of both intra- and extracellular drug targets when the cancer cells are subjected to pressure from a therapeutic agent. Thus, finding ways to target and interdict pathways involved in ecDNA replication and maintenance has become a high priority approach to potentially treating multiple types of cancer. The approach checks many of the investable profile boxes, and is considered so promising that several of the world’s leading healthcare investors have invested more than $250 million to date into Boundless Bio (see here, here and here). We at MissionGBM feel the same, and are doing everything we can to support work on ecDNA for brain cancers. Now, if only there were a combination protocol of a brain-penetrant ecDNA inhibitor and a brain-penetrant HGG oncogene inhibitor (e.g. EGFRi, CDK4/6i, etc)…watch this space.
DNA Damage Repair. The SoC workhorse temozolomide (TMZ) is a modestly brain-penetrant DNA akylating agent designed to damage DNA in replicating cells and promote cell death. However, DNA does not like to be damaged, and nature has evolved methods for repairing DNA damage (for example, MGMT). Much promising work is currently being done by several groups of top scientists to understand and selectively interdict DNA Damage Repair pathways as a means of enhancing anti-cancer effects (see here and here – kudos to the NBTS for putting the DDRC together).
Cholesterol and Lipids. Brain cancers are addicted to cholesterol for maintenance and growth, but cholesterol does not significantly cross the BBB and is largely synthesized de novo in the brain by astrocytes. Interdicting a cholesterol synthesis or transport pathway target in the brain with a brain-penetrant agent is a rational approach (see here). Same logic and data applies to other select pathways that generate lipids destined for the cell membrane (see here and here).
There are other interesting Ancillary Targets as well in brain cancers, but we offer the above as examples of the most promising.
· 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 is primarily driven by ecDNA. If one puts selective therapeutic pressure on a direct oncogenic target residing on ecDNA, the target tends to rapidly disappear while the tumor goes about its business with nearby cells that do not contain the target. The textbook example of this phenomenon is the failure of multiple therapeutic approaches to blocking or inhibiting amplified EGFR (wt or vIII) in GBM. Comparison of pre-treatment and post-treatment tumor tissue samples has repeatedly shown that the EGFR target disappears from cells displaying it without much impact on tumor viability and growth regardless of treatment modality (see here, here and here).
Core Concept #2 - Treatment Protocols Must Have a Method for Transiting the BBB…or Bypassing It
The best therapeutic agent in the world is not going to be effective if it cannot get to the desired site of therapeutic action in a sufficient amount and with enough dwell time to affect its therapeutic benefit. The BBB is very efficient at rejecting molecular agents, particularly macromolecules (see here for Alzheimer’s Disease, and here and here for a failed Phase 3 GBM trial with an Antibody-Drug Conjugate).
In view of the difficulty of getting therapeutic molecules across the BBB, one must consider:
A. Using directed energy therapies that eliminate the need to transit the BBB. Examples include radiation therapy (RT), Tumor Treating Fields (TTF), various electro-magnetic directed energy technologies (EM) and perhaps even sonodynamic therapy (SDT) when combined with a brain-penetrant sensitizing agent.
B. Enhancing trans-BBB delivery of therapeutic agent via temporarily opening the BBB. Pioneering approaches employing Focused Ultrasound (FUS) with microbubbles have shown promising results both in brain cancers and neurodegenerative diseases (see here, here and here).
C. Building molecules that have enhanced BBB permeability. Several approaches in this category ranging from standard brain-penetrant medicinal chemistry of small molecules to sophisticated protein engineering to enhance trans-BBB macromolecular delivery (see here).
D. Implantable devices for delivery of a therapeutic agent to the brain behind the BBB. Technologies in this space have significantly advanced since the approval of the implantable and bioerodible depot chemotherapeutic agent Gliadel® (1996 for rGBM; 2003 for ndHGG). Current approaches employ implantable hydrogels (see here and here) and Convection Enhanced Deliverywith in-dwelling catheters behind the BBB. Since these techniques require neurosurgical procedures to initially insert the reservoir, and may require subsequent neurosurgical procedures to recharge the reservoir or implant additional reservoirs, the jury is still out on the overall feasibility and clinical utility. Let the clinical data speak (aka Core Concept #4)!
While all of these approaches are technically feasible, our analysis has favored Directed Energy Therapies and Enhanced Delivery via Transient BBB Opening in combination with therapeutics agents.
In fact, of the four investment theses that we developed over the past year (ranging in size from $10 million to nearly $100 million), (i) all featured technologies in one of these two categories; and (ii) combined a medical device with a molecular therapeutic agent. However, none of these deals ultimately got done: two fell apart in late stage due diligence (please do NOT hide the fact that you are co-administering high dose bevacizumab and dexamethasone! We will find out); one failed because the right molecule to deliver could not be identified; and the largest deal crashed because the company controlling the technology rejected our deal proposal.
We expect medicinal chemistry directed at developing brain-penetrant LMW therapeutic agents to also play a significant role, particularly with respect to Ancillary Targets.
Core Concept #3 - Crossover (or Pan-Cancer) Approaches Offer the Highest Probability of Attracting Significant Investment
In view of all the significant challenges outlined in Part 1 of this Series, investors view brain cancer as an extraordinarily risky area, even more risky than Oncology in general (Oncology programs have the lowest overall probability of regulatory approval). Thus, brain cancer therapeutics developers need to exploit every advantage available in order to attract significant investment. One strategy that we favor is to leverage the large amount of research and capital that is devoted to non-brain cancers and neurodegenerative diseases when possible. For example, we believe that advances in understanding ecDNA mechanisms and drugging them has the potential to fundamentally change Oncology therapeutics development across multiple cancers. This type of opportunity does not present very often, and when it does, it attracts enormous amounts of innovation and investment. Another promising area is technology that can enhance trans-BBB therapeutic agent delivery. Keep an eye on Focused Ultrasound (FUS) developers (see here, here, here and here) as they advance FUS in both neurodegenerative diseases and brain cancers.
Final Thought
Developing effective therapies for brain cancers is darn hard, but it is not impossible. Success will be incremental and will require patient research and investment over an extended period of time. We suggest that developers and investors should consider the Core Concepts raised in this post as they design, evaluate and select programs worthy of their efforts and capital.