ASCO 2021 : Cellworks CBM Clinical Study Identifies Novel Biomarkers for ATRA Benefit and Failure in AML Patients
Personalized Therapy Biosimulation Predicts with 100% Accuracy ATRA Non-Response in AML Patients with Favorable Genomic Features
SOUTH SAN FRANCISCO, Calif., June 4, 2021 – Cellworks Group, Inc., a world leader in Personalized Medicine in the key therapeutic areas of Oncology and Immunology, today announced results from a Cellworks Clinical Trial, in which the Cellworks Computational Omics Biology Model (CBM) accurately predicted that All-Trans Retinoic Acid (ATRA) combined with cytarabine, etoposide, idarubicin (ATRA-CEI) benefits a subset of non-APL (Acute Promyelocytic Leukemia) Acute Myeloid Leukemia (AML) patients. The study also revealed novel biomarkers and key mechanisms of resistance to ATRA-CEI benefit and failure in adults with AML.
The results from this Cellworks clinical trial will be featured in a poster session with comments from Dr. Scott Howard, MD, MSc, University of Tennessee, Health Science Center, as part of the 2021 ASCO Annual Meeting June 4-8th during the Hematologic Malignancies-Leukemia, Myelodysplastic Syndromes, Allotransplant Track and available online as abstract 7027.
ATRA has revolutionized the treatment of APL, and subsequent in vitro data studies showed that some non-APL AML patients may benefit from addition of ATRA to standard therapy. This study aimed to predict ATRA response a priori to determine the optimal treatment for each patient. Cellworks CBM was used to predict and evaluate the impact of initial therapy with ATRA combined with cytarabine, etoposide, idarubicin (ATRA-CEI) to access the biomarkers responsible in adults with AML. The Cellworks CBM biosimulated the downstream molecular effects of cell signaling, drugs and combination therapies on patient-specific in silico cancer cells.
“ATRA plus arsenic trioxide is the standard of care for APL. ATRA also has activity against a subset of non-APL AMLs, so identifying sensitive patients ahead of time allows addition of an additional effective agent whose toxicities are non-overlapping with cytarabine, anthracyclines, and etoposide. Furthermore, understanding the biologic basis of ATRA sensitivity paves the way for even more progress in AML in future studies,” said Dr. Scott Howard, MD, MSc, University of Tennessee, Health Science Center and Co-Principal Investigator for the Cellworks CBM ATRA AML study. “In this study, we aimed to more deeply understand the response to ATRA-CEI in individual non-APL AML patients at the molecular level. Cellworks results were impressive– particularly in uncovering novel biomarkers for ATRA failure/benefit and identifying patient responders who have monosomy 7, where non-response is the norm.”
“Cellworks CBM provides oncologists with an artificial intelligence tool in the clinic capable of revealing oncogenic and transcriptional mechanisms underlying unsuspected drug vulnerabilities and sources of drug resistance,” said Dr. Michael Castro, MD, neuro-oncologist and medical oncologist specializing in molecular oncology, precision medicine, and immunotherapy of cancer at Beverly Hills Cancer Center; Chief Medical Officer for Cellworks Group, Inc.; and Co-Principal Investigator for the Cellworks CBM ATRA AML study. “Cellworks CBM can identify non-APL patients who derive benefit ATRA and avoid its unnecessary use in patients unlikely to respond, thus improving efficacy while reducing toxicity and cost.”
Clinical Study Methods and Results
AML patients in clinical trial NCT00151242 had their leukemia sequenced as part of the trial. Their genomic profiles were used for computational modeling by the Cellworks CBM, which uses curated data about genomic aberrations from PubMed as input to generate disease-specific protein network maps and predict drug responses. Disease biomarkers unique to each patient were identified using the Cellworks therapy biosimulation platform. Digital drug simulations were conducted by measuring the effect of ATRA-CEI on a composite cell growth score of cell proliferation, apoptosis and other hallmarks for cancer. ATRA-CEI was mapped to the patient genome along with a mechanism of action and validated based on the genomic profile and its biological consequences.
Of 171 patients treated with ATRA-CEI, 107 responded (R) and 64 did not respond (NR). Of the 64 NRs, there was a subset of 18 patients with favorable genomic features who did not respond and their non-response was correctly predicted by Cellworks CBM in all 18 cases. Mutations of DNMT3A, EZH2, ASXL, FLT-3 and GART amplification emerged as novel biomarkers of ATRA-CEI failure.
In general, monosomy 7 is expected to confer ATRA resistance due to the presence of EZH2 and KMT2E gene deletions. In this study, 18 of the 32 patients with monosomy 7 did not respond. However, 14 patients with monosomy 7 did respond, and Cellworks identified these patients had co-occurrence of deletions involving IGFBP3, PMS2, HUS1, CDK5, XRCC2/4, AKR1B10 and others that overcame ATRA resistance associated with monosomy 7.
“In this study Cellworks CBM was able to identify non-responders among patients considered likely to respond, and responders among patients considered unlikely to respond,” said Khush F. Mehta, CEO of Cellworks Group, Inc. “By using computational modeling of all genetic biomarkers, we are able to take a holistic view of a patient’s response to drugs, which explains this study’s success versus traditional one-mutation, one drug approaches.”
About Cellworks Group
Cellworks Group, Inc. is a world leader in Personalized Medicine in the key therapeutic areas of Oncology and Immunology. Using innovative multi-omics modeling, computational biosimulation and Artificial Intelligence heuristics, Cellworks predicts the most efficacious therapies for patients. The Cellworks unique biosimulation platform is a unified representation of biological knowledge curated from heterogeneous datasets and applied to finding cures. Backed by UnitedHealth Group, Sequoia Capital, Agilent and Artiman, Cellworks has the world’s strongest trans-disciplinary team of molecular biologists, cellular pathway modelers and software technologists working toward a common goal – attacking serious diseases to improve the lives of patients. The company is based in South San Francisco, California and has a research and development facility in Bangalore, India. For more information, visit www.cellworks.life and follow us on Twitter @cellworkslife.
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