At some point in their lifetimes, about half of all Americans will hear the terrifying words, “You have cancer.” For these individuals and their relatives, the burden of cancer can be staggering. Although research aimed at discovering new cancer treatments has intensified in recent years, both scientific and medical communities recognize the limitations of current therapies which, overall, are able to cure only about half of all individuals who receive this diagnosis. Recent excitement in the field has focused on “precision medicine”—the deployment of targeted drugs to counter specific “driver” mutations in tumors, in combination with “immune checkpoint” therapies that stimulate the body’s immune system to fight cancer cells. Currently the standard-of-care for many types of cancer, these approaches have produced some genuine success stories, but not enough cancer patients—especially those with advanced breast, lung, colon, brain, prostate, and pancreatic cancer—are achieving the kind of lasting remissions that were anticipated. Even more discouraging is the fact that most tumors cannot be treated successfully using drugs that are targeted solely against mutations.
Although cancer researchers are constantly refining these targeted treatments, new complementary approaches are urgently required. Here, as in many other fields, more definitive answers may be forthcoming by asking questions in an entirely different and more analytical way. In this case, by attempting to solve the following conundrum: “What does it take to be, or not to be a cancer cell?—that is the question.” As part of this quest to pinpoint the operational nexus of cancer dysregulation, leaders in the field are increasingly asking: Is there some secret code running inside cancer cells? And can we crack it by applying mathematics and using computational approaches rooted in systems biology?
Quantitative modeling has been remarkably successful in disciplines as diverse as astronomy, economics, physics, and computer science. More recently, “cancer quants”—scientists implementing quantitative analyses to the landscape of cancer biology—have begun to use novel, big data and AI technologies to illuminate some of the greatest—and, up to now, elusive--mysteries of cancer biology, among them: What are the hidden molecular codes and logic—i.e., the oncotecture- -that underpin a cancer cell? Why does a cancer cell stay a cancer cell? How are discoveries in this space helpful in identifying definitive, precision-based drugs to kill cancer cells in patients? And what does Charles Darwin have to do with all this? In short, we are witnessing the emergence of a sweeping new definition and taxonomization of cancer—an evolution in the precision-based alignment of drugs and tumor subtypes that has been dissected by the most advanced computational and experimental technologies in the bioresearch space.
This bold strategy has been in the works for almost 15 years at Columbia University and the technology emanating from this world class research has found a home at DarwinHealth, which has exclusively licensed the technology from Columbia for commercial development in the fiercely competitive world of cancer drug discovery. The idea is to incorporate robotics and supercomputers—in combination with other experimental biology platforms—to map more universal tumor vulnerabilities and, by extension, to identify novel or already FDA-approved drugs to target them, individually or in combination.
DarwinHealth, a New York City- and San Diegobased biotechnology company focused on precision oncology, co-founded in 2015 by CEO Gideon Bosker, MD, and Professor Andrea Califano, Clyde and Helen Wu Professor of Chemical Systems Biology and Chair, Department of Systems Biology at Columbia University—is applying precisely this new way of thinking about cancer. Its unconventional and highly innovative technology has been developed to identify biomarker-based, patient-drug alignments by leveraging the discovery of Master Regulator proteins, the biological “foot soldiers” that regulate key cellular functions. These proteins represent a new class of mechanistic tumor drivers—and thus vulnerabilities— that are organized into modular structures known as “tumor checkpoints” that are capable of initiating and maintaining the “cancer cell state.” By allowing direct identification of tumor checkpoints, upon which the cancer cell depends for its survival, DarwinHealth’s proprietary technology is positioned to accelerate the development and validation of pipeline compounds currently being evaluated by the biopharmaceutical industry.
Utilizing the Proprietary VIPER Algorithm
To achieve its drug discovery goals, DarwinHealth utilizes proprietary, systems biology algorithms to match virtually every cancer patient with the drugs and drug combinations that are most likely to produce a successful treatment outcome. “Conversely, these same algorithms also can prioritize investigational drugs and compound combinations of unknown potential against a full spectrum of human malignancies, as well as identify novel cancer vulnerabilities for targeted drug development,” explains Dr. Bosker. “This makes them invaluable for pharmaceutical companies seeking to both optimize their compound pipelines and to discover novel, mechanistically actionable cancer targets and compound-tumor alignments.”
Armed with such analytical assets, DarwinHealth’s mission statement is to deploy novel technologies, rooted in systems biology—a new discipline that fuses experimental biology with the power of supercomputing—to improve clinical outcomes of cancer treatment. Its core technology, the VIPER algorithm, can identify tightly knit modules of Master Regulator proteins providing an entirely new class of therapeutically actionable cancer targets. “The methodology is applied along two complementary axes,” explains Dr. Califano. “First, DarwinHealth’s technologies support the systematic identification and validation of novel druggable targets by interrogating the cancer cell’s regulatory logic, rather than its mutational landscape. This allows us and our scientific partners to exploit a new generation of pharmacological actionability, rooted in more fundamental and universal tumor dependencies. Second, from a drug development and discovery perspective, the same technologies can leverage master regulator analysis to repurpose existing drugs and compounds towards cancers most likely to respond to them.” This is where the DarwinHealth oncotectural approach, with its emphasis on elucidating and targeting tumor checkpoints, provides its most important solutions and repositioning roadmaps for advancing precision-focused cancer drug discovery and therapeutics.
The proprietary precision medicine algorithms employed by DarwinHealth are supported by a broad body of literature in high impact journals, authored by its scientific leadership, including DarwinHealth CSO, Mariano Alvarez, PhD, who co-developed the company’s critical computational infrastructure, the VIPER algorithm. These proprietary strategies leverage the ability to reverse-engineer and analyze the genome-wide regulatory and signaling logic of the cancer cell, by integrating data from in silico, in vitro, and in vivo assays. This provides a fully integrated drug characterization and discovery platform designed to elucidate, accelerate, and validate precise developmental trajectories for pharmaceutical assets, so their full clinical and commercial potential can be realized.
Oncotectural Basis of DarwinHealth Technology
What, exactly, has made DarwinHealth’s technology unique and so successful in the cancer drug discovery space? Perhaps, the simplest answer is: its oncotectural approach to dissecting the critical mediators—the Master Regulators that make up the tumor checkpoint—of cancer cell behavior. Validation of what can be achieved from this powerful marriage of computational and experimental biology was recently covered by feature articles in Science and Nature and its application to The Cancer Genome Atlas, one of the largest repositories of tumor samples, was published in January, 2021 in the journal, Cell, co-authored by DarwinHealth principals and researchers from Columbia.
“The data published in this manuscript strongly support the Oncotecture Hypothesis. They suggest that a much larger and finer-grained mutational repertoire than previously suspected may be causally responsible for inducing and maintaining aberrant activity of the handful of master regulator proteins that underpin the molecular identity of a tumor,” explains Dr. Califano. He adds that, “fortunately, only 24 master regulator modules emerged from the study of almost 10,000 different tumors, which could dramatically simplify the quest for novel therapeutics.” If these research findings are confirmed, the planned follow-up studies may change the trajectory of drug discovery for precision cancer medicine in a number of important ways.
The methodologies and results reported in Cell introduce an entirely novel approach for taxonomizing cancer subtypes—essentially, categorizing them according to their targetable tumor dependencies, instead of their tissue or mutational state. This would represent a paradigmatic shift, opening up multiple avenues of inquiry and applications that have translational impact at the front lines of clinical care for cancer patients. Dr. Gideon Bosker, DarwinHealth CEO, notes, “The new molecular classification reported in Cell sets the stage for identifying and testing drugs that can negate the regulatory anomaly responsible for implementing and perpetuating the cancer cell state.”
Research, Licensing and Scientific Collaborations
One of its principle products, DarwinOncoTreat, which has received Clinical Laboratory Improvement Amendments (CLIA) certification by the New York State and California Departments of Health, is now the foundation of multiple clinical trials, including an RNA-based “N of 1” study at Columbia University. The study focuses on patients who have rapidly progressed after failing to respond to multiple conventional or targeted therapies. The goal of the study is to identify cancer patients who may benefit from more effective and personalized therapies.
The technologies introduced and developed by DarwinHealth have quickly led to a number of landscape-changing collaborations between the company and international biopharmaceutical companies. In 2016, Daiichi Sankyo partnered to use DarwinHealth’s oncotecture-based technology to help prioritize investigational compounds in the Daiichi Sankyo Cancer Enterprise pipeline for clinical development. In 2018, the Encheng Group, based in China, acquired the exclusive commercial rights to the DarwinOncoTarget and DarwinOncoTreat tests in the Greater China region, including Hong Kong, Macao, and Taiwan. The tests will be used in Chinabased clinical trials focused on gastrointestinal tumors, particularly gastric and esophageal cancer.
In 2018, Hookipa Pharma partnered with DarwinHealth to identify shared self-antigens for multiple tumor subtypes. The collaboration is expected to yield antigens with validated immunogenicity that Hookipa can use as the basis for immunotherapies. In 2019, DarwinHealth entered a multi-year collaboration with Celgene Corporation (acquired by Bristol-Myers Squibb on November 20, 2019) to support clinical development initiatives. The research collaboration, known as the C2C (Compound-2-Clinic) initiative, will implement VIPER and DarwinOncoTreat algorithms to provide a comprehensive readout of the potential clinical value of BMS compounds in specific cancers, helping to accelerate the development of drugs across the pan-cancer continuum.
In 2019, the VIPER algorithm was evaluated retrospectively based on tumor samples from a clinical study funded by Karyopharm evaluating the use of oral selinexor–dexamethasone for triple-class refractory multiple myeloma. A predictive biomarker of response to selinexor was sought in patients with myeloma by using the algorithm, which transformed gene-expression profiles from tumor samples into accurate predictions of protein activity for approximately 6000 regulatory proteins. Four of five patients who had a response and six of seven who did not respond to selinexor were correctly identified by the marker, yielding a prediction accuracy of 83% (95% CI, 55 to 95).
More recently, in 2020, Curis and DarwinHealth announced a multi-year scientific research collaboration to apply DarwinHealth’s algorithms to understand better and articulate the role of MYC in the mechanism of action of the Curis compound, fimepinostat; and explore additional potential novel biomarkers that may help patient selection in hematologic and solid tumors clinical studies evaluating fimepinostat. The collaboration will deploy DarwinHealth’s compound-checkpoint-tumor subtype matching platform, its VIPER algorithm, and its high-throughput drug perturbation and Plate-Seq discovery platform to analyze the potential therapeutic efficacy of fimepinostat (a synthetic, orally available, small molecule that inhibits the activity of histone deacetylase, or HDAC, and phosphatidyl-inositol three kinase, or PI3 kinase enzymes) across several tumor subtypes.
Finally, beginning in 2021, the DarwinOncotarget and DarwinOncotreat tests from DarwinHealth— in combination with more traditional mutational profiling—will be used to inform the therapeutic choices of a molecular tumor board evaluating thousands of patients at Columbia, across eight aggressive tumor types.
In nearly of these scientific partnerships, the Master Regulator-based technology and associated biomarkers help identify much tighter alignments between the drugs developed by DarwinHealth’s biopharmaceutical partners and the specific patient sub-populations who tumors are most likely to respond to these investigational agents. From a drug discovery—and cost of discovery— perspective, this means that DarwinHealth’s technologies can help oncology-focused companies significantly increase the efficiency of their discovery and development pipelines, by targeting more universal tumor vulnerabilities and by conducting smaller—and thus faster and less costly—clinical trials with a higher likelihood of producing a successful outcome leading to regulatory approval.
The Future of Cancer Drug Discovery
Based on its successes thus far, DarwinHealth’s oncotecture-based, “digging deeper than genes” discovery framework and associated technologies will continue to exploit a complementary combination of experimental and computation-based, inferential methods to identify novel cancer targets, effective drugs and biomarkers on a fully mechanistic, rather than empirical basis. In addition, the company’s drug and novel cancer target discovery programs, including the DarwinOncoMarker, Compound-2-Clinic (C2C), and novel cancer target initiative (NCTI) platforms will allow its scientific teams, working either independently or in collaboration with biopharmaceutical partners, to target cancer at its most vulnerable and universal spots; more specifically, at the regulatory bottlenecks implemented by tumor checkpoints.
By using Master Regulator-based analyses and leveraging their capacity for dissecting more universal cancer targets DarwinHealth hopes to discover more effective therapies than could be achieved by geneticbased approaches alone, thus addressing the unexpected precision deficit shortfall of targeted therapy and its partial failure to fully deliver on the initial promise.