The Resistance Bio Investment Thesis
APRIL 20TH, 2021
Drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer. The problem of drug resistance in cancer has strong similarities to the field of infectious disease, in that both disciplines are challenged by highly proliferating intrinsic or extrinsic aggressors. As with antimicrobial therapy, the excitement that was brought about by initial successes of early chemotherapeutics was quickly tempered by evidence showing that although tumors went into remission quickly, they developed resistance, resulting in disease relapse.
New therapeutic strategies directed at targeting the key enabling characteristics and acquired capabilities that transform normal cells into malignancies began to emerge in the early-mid 2010s. The introduction of these targeted therapies, was an important leap forward and has resulted in highly efficacious therapies against tyrosine kinases, nuclear receptors and other molecular targets. The initial successes of estrogen receptor (ER) and androgen receptor (AR) antagonists, as well as BCR-ABL, HER2 and EGFR inhibitors, led to a massive effort to develop molecules that target oncogenes and other key cellular vulnerabilities. More recently, oncological therapy has advanced again by using immunological approaches to recognize and attack cancer. Anti-CTLA412 and anti-PD-1/PD-L113 monoclonal antibodies that disable negative regulators, or checkpoints, of the adaptive immune system have resulted in remarkable anti-tumour activity—and even cures—in a few tumor types. And yet, similarly to what was previously observed with conventional chemotherapy, eventual resistance to targeted and immunological therapies remains the norm. Resistance development to oncological therapies is responsible for up to 90% of cancer deaths each year.
Enter resistanceBio.
The resistanceBio team, led by Nicholas Goldner and Christopher Bulow, initially amassed expertise in the world of antibiotic resistance. The team proved their ability to rapidly simulate and map antibiotic resistance and subsequently sequence therapies in a manner that produced a MRSA treatment many times more effective than the current MRSA standard of care. It was this foundational knowledge and platform proof of concept that allowed the team to ask- can we apply our technology to cancer?
With this mindset and approach, resistanceBio has built its ResCu platform, which mimics clinically reported cancer resistance mechanisms in a dish, generating a proprietary biobank of resistant cancer cell populations. Leveraging multi-omics measurements, resistanceBio defines the cause of resistance and identifies novel biomarkers, drug targets, and drug candidates. Screening these drugs against the biobank, resistanceBio generates a new therapy class—Resistance Therapy—that can attack a complex intractable tumor and drive it to a simpler, more susceptible state.
The first scientific breakthrough in that equation is afforded by ResCu- which allows resistanceBio researchers to very accurately model the kinds of resistances that pharma actually sees in clinical trials or worse when the drug is in market. This is not information that pharma companies currently have at their disposal while they’re developing new cancer drugs. An oncological therapy typically takes months or even years to fail in the face of evolved resistance. The ResCu system allows resistanceBio to model and identify the same resistance evolution in a single week. Suddenly, pharma companies have access to highly accurate resistance failure data on compounds at the preclinical stage, as opposed to finding out that a compound fails in the face of resistance evolution during a late stage clinical trial or when the drug is already on the market.
The resistanceBio breakthroughs don’t stop there. Once evolved resistance has been modeled, researchers perform a multi-omics measurement to analyze the genome and transcriptome to learn where the tumor has become vulnerable as a result of its evolution to the original therapy. This is the exact moment when the table has been turned- an evolutionary adaptability mechanism that was once a superpower of the cancer has suddenly become its kryptonite. Combinations of drugs are identified that have a high probability of exploiting the newfound weakness—Resistance Therapies—and are applied to the ResCu model to evaluate efficacy. Utilizing the insights provided by ResCu, these therapies can be predesigned to overcome the cancer’s future resistance evolution mechanisms.
Thus, we arrive at a new cancer treatment paradigm where patients who relapse to an existing standard of care therapy are no longer in dire straits, but rather have a new therapy option tailored to use the evolutionary mechanisms of their specific cancer’s biology against it, and likely achieve a curative outcome. In addition, the resitanceBio team will work with pharma companies to develop new standard of care options, so patients don’t have to wait for first line of defense failure but rather, are given a first line therapy designed with all possible resistance evolution taken into account.
The combination of the speed of the ResCu system and the ability of the multi-omics platform to identify tumor vulnerabilities has the potential to ensure we will soon live in a world where cancer resistance is a thing of the past, and as a result, 90% of cancer deaths are avoided altogether.
In short, and stated without hyperbole, resistanceBio is one of humanity’s best shots at a developing a cure for cancer, and I couldn’t be more proud to support them. The significance of resistanceBio achieving its goals cannot be overstated and doing so would (deservedly) result in a multi-billion dollar revenue line. This is the type of investment I’m here for.
