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DarwinHealth Scientists Publish Foundational Research Identifying Regulatory Mechanisms Controlling Cancer Cell States and Drug Response

·9 min read

NEW YORK, Jan. 11, 2021 /PRNewswire/ -- DarwinHealth, Inc., a New York-based biotechnology and cancer drug discovery company announces the January 11, 2021 online publication in Cell of a landmark paper, "A Modular Master Regulator Landscape Controls Cancer Transcriptional Identity,"1,2 in which scientists from Columbia University and DarwinHealth apply the VIPER (Virtual Inference of Protein activity by Enriched Regulon) analysis algorithm to identify recurrent regulatory networks—"tumor checkpoints"—operative across the pancancer subtype continuum.

This research paper, with lead author Dr. Evan Paull, from the Department of Systems Biology at Columbia University, in conjunction with DarwinHealth Co-Founder, Professor Andrea Califano and Chief Scientific Officer, Dr. Mariano Alvarez and other investigators, presents results and analyses, using a novel Multi-Omics Master-Regulator Analysis framework (MOMA), that validates the foundational paradigm informing DarwinHealth technologies.

The study, funded by the U.S. National Institutes of Health and the Instituto de Salud Carlos III/Ministerio de Asuntos Economicos y Transformacion Digital (Spain), demonstrates that different genetic alterations in individual patients within the same tumor subtype induce aberrant activation of the same Master Regulator proteins, which maintain the subtype's transcriptional identity. Moreover, it shows that Master Regulators operate within small, hyperconnected modules (Master Regulator Blocks [MRBs]) that mechanistically control key cancer hallmarks necessary for the survival of the cancer cell.

The results reported in Cell provide one of the most comprehensive confirmations to date of the value of proprietary, network-based approaches for the identification of therapeutic targets in cancer using VIPER technology. The latter has been exclusively licensed, for commercial use, to DarwinHealth by Columbia University. The Cell publication concludes that, "Taken together, these data suggest that MRBs may provide complementary 'molecular recipes' for implementing the same cancer hallmarks in different tumor contexts."

"These data support the Oncotecture Hypothesis, which suggests that a much larger and finer grain mutational repertoire than previously suspected may be responsible for inducing aberrant MR activity and implementing transcriptional tumor identities," explains Dr. Califano. "The results presented by this multi-disciplinary team also confirm that Tumor Checkpoint-based Master Regulators implement regulatory bottlenecks in cancer that are responsible for canalizing the effect of multiple functional mutations." He adds that, "Importantly, the Tumor Checkpoints that define each subtype can thus be deconstructed into highly specific combinations of a handful of activated and inactivated Master Regulator-Blocks—specifically, 24 identified in this study. The MRBs can potentially regulate complementary genetic programs required to implement and maintain a tumor cell's transcriptional identity, which undergirds key aspects of cancer cell behavior and determines susceptibility to specific drugs and therapeutic interventions."

The study provides a data-driven roadmap for identifying potential therapeutic targets that may benefit a large subset of cancer patients within each one of 112 tumor subtypes, independent of their mutational state, characterized by the analysis. Accordingly, the authors note that, "Consistent with the notion that transcriptional cell states have emerged as more accurate predictors of drug-sensitivity compared to genetics, this suggests that MR-based analyses may produce a more tractable landscape of potential therapeutic targets than what could be achieved by genetic-based approaches."

These research findings and planned follow-up studies are likely to change the trajectory of classification schemes for cancer and evolving approaches to precision-based drug discovery in a number of important ways. The methodologies and results reported in Cell introduce to the cancer research and clinical community an entirely new approach for taxonomizing cancer subtypes—essentially, categorizing them according to the composition of downstream regulatory bottlenecks with unique compositions of MRBs representing targetable tumor dependencies, independent of canonical mutational signatures. In fact, ongoing studies suggest these MR-based, tumor checkpoints are more reliable off-on switches for cancer cell governance than mutations themselves. Accordingly, this novel, data-driven taxonomization of molecular species (i.e., MR proteins comprising tumor checkpoints) responsible for cancer cell behavior—and susceptibility to therapeutic targeting—represents 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 induce a state of 'regulatory network contraception,' that is, disable or disrupt formation of checkpoint-governed programs that maintain and perpetuate the cancer cell state."

Importantly, the identification of Master Regulators has been made possible by the VIPER technology, developed by Califano and Alvarez at Columbia and licensed exclusively to DarwinHealth. VIPER allows precise measurement of protein activity from inexpensive and easily-accessible gene expression profiles—as measured by mRNA sequencing. Much like thermostats maintain a constant room temperature, the VIPER-inferred Master Regulators coalesce into complex auto-regulated modules—the tumor checkpoints—that are necessary and sufficient to maintain a consistently programmed malignant state of the cancer cell over time.

"The coordinated activity of Master Regulator proteins comprising the tumor checkpoint activates key hallmark programs needed by the cancer cell," explains Dr. Alvarez, DarwinHealth CSO. "Among them are those controlling unchecked proliferation, migration, and metastatic progression—while suppressing other hallmark functions controlling programmed cell death (or apoptosis) and immune system detection; as well as others, which would otherwise prevent tumor formation. Essentially, by channeling genetic and mutational information into a discrete downstream regulatory nexus, the Master Regulators in a tumor checkpoint initiate and maintain the biological and behavioral hallmarks of a cancer cell."

"At DarwinHealth, we use the full spectrum of proprietary, patented VIPER-based technologies developed by our scientists and co-founders to accurately and reproducibly quantify the activity of Master Regulators," explained Dr. Bosker. "From an actionable and real world precision oncology perspective, we have developed specific VIPER-based diagnostic tests, including DarwinOncoTreat and DarwinOncoTarget, to pinpoint drugs that can invert the activity of an entire tumor checkpoint or of specific master regulators. These algorithms have received New York and California CLIA certification and are being used clinically, including in several ongoing clinical trials." The first clinical trial based on this technology, which employed the combination of the HDAC6 inhibitor ricolinostat and NAB-paclitaxel, has shown virtually 100% accuracy in the prediction of responders and non-responders as reported in a recent manuscript currently under review and available on MedRxiv (medRxiv 2020.04.23.20066928).

DarwinHealth's oncotecture-based, "digging deeper than genes" discovery framework and associated technologies described in the Cell paper 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 line with the strategies reported Cell.

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 allow its scientific teams, working either independently or in collaboration with biopharmaceutical partners, to target cancer at its most vulnerable and stable spots; more specifically, at the regulatory interfaces implemented by tumor checkpoints.

These DarwinHealth technologies and methods, already widely published in leading scientific and medical journals, are currently being evaluated in numerous clinical trials across the globe. By using Master Regulator-based analyses and leveraging their capacity for dissecting more actionable therapeutic targets—and by extension, discovering more effective drugs—than could be achieved by genetic-based approaches alone, these validated approaches are expected to address the precision deficit shortfalls associated with more traditional, mutation-centric approaches to precision oncology, many of which have failed to fully deliver on their initial promise.

About DarwinHealth

DarwinHealth: Precision Therapeutics for Cancer Medicine is a "frontiers of cancer," biotechnology-focused company, co-founded 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. The company's technology was developed by the Califano lab over the past 15 years and is exclusively licensed from Columbia University.

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 novel cancer targets," explained Dr. Bosker, "which make them invaluable for pharmaceutical companies seeking to both optimize their compound pipelines and discover mechanistically actionable, novel cancer targets and compound-tumor alignments."

DarwinHealth's mission statement is to deploy novel technologies rooted in systems biology to improve clinical outcomes of cancer treatment. Its core technology, the VIPER algorithm, can identify tightly knit modules of master regulator proteins that represent a new class of actionable therapeutic targets in cancer. The methodology is applied along two complementary axes: First, DarwinHealth's technologies support the systematic identification and validation of druggable targets at a more foundational, deep state of the cancer cell's regulatory logic so we and our scientific partners can exploit next generation actionability based on fundamental and more universal tumor dependencies and mechanisms. Second, from a drug development and discovery perspective, the same technologies are capable of identifying potentially druggable novel targets based on master regulators, and upstream modulators of those targets. 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-based methods employed by DarwinHealth are supported by a deep body of scientific literature authored by its scientific leadership, including DarwinHealth CSO, Mariano Alvarez, PhD, who co-developed the company's critical computational infrastructure. 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. For more information, please visit: www.DarwinHealth.com.

1Cell 184, 1–18, January 21, 2021 (print version)
2Cell (online pub, January 11, 2021),
https://www.sciencedirect.com/science/article/pii/S0092867420316172?dgcid=author

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