DarwinHealth Publication Reports Step-by-Step Protocol for its Tumor Checkpoint-Based, Compound-to-Clinic (C2C) Cancer Drug Discovery Pipeline: Elucidates a Patient-to-Model-to-Patient (PMP) Roadmap for Precision- and Mechanism-Based Identification and Clinical Validation of Novel, Investigational and FDA-Approved Therapeutic Agents Targeting Tumor Regulatory Architecture
Link to the article provided herein: https://currentprotocols.onlinelibrary.wiley.com/doi/10.1002/cpz1.544
As the scientists note in their publication, the Patient-to-Model-to-Patient (PMP) protocol, which represents DarwinHealth’s foundational drug, biomarker, and novel cancer target discovery pipeline/technology, addresses directly the current Achilles heel of cancer drug development, i.e., the inability to forge precise and predictive connections among three critical elements required for successful drug discovery and validation in human trials, including: (a) identifying the mechanistic -biological drivers and determinants of the cancer cell state; (b) characterizing and targeting therapeutically significant molecular targets governing the transcriptional state of cancer cells; and (c) generating validated biomarkers that are accurate predictors of clinical response in trial settings.
These barriers to precision-based cancer treatment and drug discovery are made even more complex by the heterogeneous nature of cancer, a challenge that the DarwinHealth group addresses by employing single cell analysis in combination with proprietary algorithmic tools, thereby making it possible to taxonomize tumor subtypes based on their transcriptional identity state.
Leveraging an oncotecture-based framework for cancer biology, the PMP approach reported by DarwinHealth employs computational algorithms and experimental methodologies to reconstruct and interrogate the regulatory logic of human cancer cells for identifying and therapeutically targeting a “tumor checkpoint” with novel, as well as existing pharmacological agents. Importantly, the PMP protocol systematically identifies, from specific patient tumor samples, the Master Regulator (MR) proteins that comprise the tumor checkpoint. Then, using gene expression profiles (RNA sequencing), it identifies in vitro and in vivo models that, by recapitulating the patient’s tumor checkpoint, constitute appropriate cell line and animal models to further elucidate tissue context-specific drug mechanism of action.
Use of these matched models permits precise, biomarker-based pre-clinical validations of drug efficacy, the results of which can then be translated for use in more advanced PDX validations and human trials, which are currently in progress using this technology. Specifically, the combination of drug context-specific mechanism of action and the precise identification of patients’ tumor checkpoints provides a personalized, mechanism-based biomarker for enrichment of prospective clinical trials with patients most likely to respond to the pharmacologic therapy under investigation.
Explaining the scientific and commercial implications of DarwinHealth’s PMP drug and biomarker discovery platform, science journalist Forest Ray, PhD, reports on the paper and its technology in an article published online for genomeweb. Link is provided herein:
“PMP is a patient-centered, systems biology-driven, protocol that integrates highly sophisticated computational methods and experimental approaches—incorporating the precision of single-cell analysis—to optimize and accelerate drug discovery,” noted lead author, Dr. Pasquale Laise, Senior Director of Computational Biology at DarwinHealth. “While the protocol is fully generalizable and can be applied to any cancer type or subtype, each step of the PMP discovery pipeline is tailored to the molecular profiles of tumors from individual patient samples and, therefore, is also able to identify large cohorts of patients representing distinct pharmacotypes linked to mechanistic biomarkers, an alignment that maximizes the chances of success in biomarker-directed clinical trials.”
The identification and drug-based targeting of tumor checkpoints is a hallmark of DarwinHealth’s proprietary methodology focused on cancer drug development. “The PMP protocol constitutes a systematic approach for identifying and targeting the core set of regulatory proteins (or master regulators) controlling the transcriptional identity [phenotypic state] of cancer cells, which distinguishes this Compound-2-Clinic (C2C) developmental roadmap from all other available strategies,” explained DarwinHealth CSO, Dr. Mariano Alvarez. “Importantly, it expands the concept of oncogene addiction to the transcriptional regulators of the cancer cell state, which are universally present and, therefore, can be dissected for every tumor. The protocol closes the circle by dissecting such Master Regulators directly from the patient’s tumor tissue, and then by using a drug’s context-specific mechanism of action—empirically elucidated in cognate in vitro models—the pipeline predicts the therapeutic response of drugs under evaluation in the setting that matters most: clinical trials.”
The PMP protocol is designed to address shortfalls and limitations in current approaches to cancer therapy and biomarker development. “Much like a building stands on multiple pillars—with the caveat that compromising any single pillar would not cause the entire structure to collapse—optimal, enduring approaches to cancer therapy require targeting multiple tumor dependencies simultaneously,” explains Dr. Andrea Califano, Professor and Chair, Department of Systems Biology, Columbia University (https://news.columbia.edu/news/deciphering-cancer-messy-and-complex-were-here-it), and Co-Founder of DarwinHealth. “The technology and approach to cancer drug discovery highlighted in this manuscript provides significant complementarity to oncogene therapy by targeting an entire repertoire of tumor vulnerabilities, as represented by Master Regulator proteins that are responsible for maintaining the aberrant state and regulatory programs of the tumor cell.”
DarwinHealth’s PMP platform and drug discovery pipeline undergird the foundational technology the company has deployed for many scientific collaborations and partnerships focused on identification of novel cancer targets, generation of novel biomarkers, and drug development. “The Patient-to-Model-to-Patient protocol (PMP) we report is a patient tumor sample-centered, systems biology-based pipeline for cancer drug discovery with broad applications in the precision oncology and immuno-oncology space,” explained Dr. Gideon Bosker, DarwinHealth Co-Founder and CEO. “Each step of the compound-to-clinic drug development and validation pipeline reported in Current Protocols is leveraged by the integration of computational algorithms and experimental data to ensure the targeted regulatory architecture—the ‘tumor checkpoint’—and the mechanism-of action (MOA) of drugs being evaluated are consistently and actionably linked as the protocol progresses from cell lines to animal models and finally, into patients for clinical translation. Its universality in the context of cancer biology permits the PMP model to be applied across a broad spectrum of hematological and solid tumors, where numerous clinical trials based on this drug discovery technology are currently in progress. Moreover, the application of PMP technology to optimize immune response and diminish immunosuppressive effects among cell subtypes—including Tregs, fibroblasts, and macrophages—in the tumor microenvironment represents one of the most promising trajectories for developing drugs that can rescue response of immune checkpoint inhibitors by reprogramming phenotypic states of immunosuppressing cells.”
When deployed in a systematic fashion, as it is at DarwinHealth where the commercial applications of the PMP protocol are under continual refinement and expansion, the PMP-based cancer target, biomarker, and drug discovery pipeline provides a roadmap for precision- and MOA-based identification of investigational, proprietary, and FDA-approved therapeutic agents targeting both tumor regulatory architecture, as well as the regulatory architecture of immune-centric cells.
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 oncotecture-based 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.
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