PR87559

NEW YORK, Jan. 12, 2021 /PRNewswire=KYODO JBN/ --

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.

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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.

(1)Cell 184, 1–18, January 21, 2021 (print version)

(2)Cell (online pub, January 11, 2021),

https://www.sciencedirect.com/science/article/pii/S0092867420316172?dgcid=author

SOURCE DarwinHealth

CONTACT: Gideon Bosker, MD, CEO, DarwinHealth, Inc., Email:

GBosker@DarwinHealth.com, Phone: (1) 503-880-2207