On January 13, 2020 Curis, Inc (NASDAQ: CRIS) and DarwinHealth, Inc. reported a multi-year scientific research collaboration to use quantitative, systems biology-based algorithms, CLIA-approved technologies, and novel, validated approaches focused on Master Regulator (MR) proteins and tumor checkpoints to: (a) better understand and articulate the role of MYC in fimepinostat’s mechanism of action; and (b) explore additional potential novel biomarkers that may help patient selection in hematologic and solid tumors clinical studies (Press release, Curis, JAN 13, 2020, View Source [SID1234553071]).
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The collaboration will deploy DarwinHealth’s proprietary compound-checkpoint-tumor subtype matching platform, its VIPER algorithm to characterize protein activity signatures that are the hallmark of regulatory network dysfunction in cancer cells, 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 3 kinase, or PI3 kinase enzymes) across a number of tumor subtypes.
"The aim of this exciting collaboration," explained Professor Andrea Califano, Clyde and Helen Wu Professor and Chair, Department of Systems Biology, Columbia University and co-founder of DarwinHealth, "is to assess and characterize the role of MYC as a critical effector of fimepinostat activity in DLBCL, as well as its overall, tumor-specific Mechanism of Action (MoA), considering that both HDAC and PI3K inhibitors have been independently characterized among the strongest regulators of tumorigenic MYC activity. Additionally, the collaboration will mechanistically characterize additional therapeutic opportunities for fimepinostat across multiple hematopoietic and solid tumor subtypes, as selected by Curis for this scientific collaboration. The study will leverage the VIPER algorithm to characterize fimepinostat’s activity against key Master Regulator (MR) protein modules (tumor checkpoints) necessary for subtype-specific tumor viability."
As part of this initiative, DarwinHealth will provide a comprehensive readout of fimepinostat’s potential clinical value across a number of cancer tissue-specific contexts, including its genome-wide mechanism of action, its tumor-specific biomarkers of sensitivity and resistance, and its ability to synergize with venetoclax for combination therapy applications in DLBCL and solid tumors. Through quantitative modeling, mechanism-driven and biomarker-driven developmental trajectories for fimepinostat will be predicted to help Curis design in vivo validation studies and focused clinical studies to leverage key opportunities for this dual HDAC/PI3 kinase inhibitor that would not be apparent using conventional technologies.
"In light of promising clinical data already reported for fimepinostat, and its unique MOA, our Compound-2-Clinic (C2C) collaboration with Curis promises to be one of our most productive scientific collaborations," noted Dr. Gideon Bosker, CEO and co-founder of DarwinHealth. "Our C2C technologies are ideally suited to identify mechanistic alignment between compounds and cancer patients, based on their ability to inactivate the patient-specific master regulator proteins that are necessary for tumor state maintenance. Compounds and compound combinations prioritized by this technology can be efficiently validated, first in PDX models and subsequently in the clinic, using our NYS State, CLIA-certified DarwinOncoTreat/Target tests. In addition to achieving a more mechanistic characterization of MYC as a critical effector of fimepinostat activity in DLBCL, our goal is to delineate the range of additional tumor subtypes—many of which may be entirely unanticipated—where fimepinostat may consistently and predictably collapse tumor checkpoint activity, thus abrogating tumor growth. These discoveries can be quickly matured to precision, biomarker-driven, clinical human testing and commercial development."
"This scientific collaboration aligns with our development path for fimepinostat by deepening our understanding of the MYC mechanism of action and potentially identifying additional, novel trajectories, indications, mechanisms, and precision-focused drug-tumor alignments that can produce a more inclusive developmental roadmap for our lead compound," said James Dentzer, President and Chief Executive Officer of Curis. "The DarwinHealth team led by Drs. Andrea Califano and Mariano Alvarez, who co-developed VIPER technology in the Califano Lab at Columbia University, bring world-class expertise that will be invaluable for identifying the full commercialization pathway for fimepinostat."
"DarwinHealth’s approach to tumor checkpoint elucidation, linked to MR proteins, will help support fimepinostat’s MYC-driven mechanism of action," said Dr. Robert Martell, Head of R&D at Curis. "This approach is also ideally suited for identifying additional biomarkers in our DLBCL program and illuminating additional tumor subtypes in which fimepinostat, alone or in combination with venetoclax, may have therapeutic potential. These mechanistically relevant insights will help us to focus on, test, and prioritize with a higher likelihood of success, the comprehensive translational roadmap for fimepinostat in targeted clinical contexts."
As part of this collaboration, DarwinHealth will be eligible for milestone payments and royalties for applications that directly result from their analyses.