Data suggest rigosertib stimulates an anti-cancer immune response via NLRP3 activation, providing mechanistic support for clinical trials of rigosertib-checkpoint inhibitor combinations
Data reveal potential targets engaged by rigosertib to inhibit the RAS-MAPK pathway, the overactivation of which is implicated in a range of cancers
NEWTOWN, Pa., March 07, 2023 (GLOBE NEWSWIRE) -- Onconova Therapeutics Inc. (NASDAQ: ONTX), (“Onconova”), a clinical-stage biopharmaceutical company focused on discovering and developing novel products for patients with cancer, announced new preclinical data characterizing rigosertib’s mechanisms of action in a poster at the American Association for Cancer Research Special Conference on Targeting RAS (AACR Targeting RAS Conference).
“The preclinical results presented at the Targeting RAS Conference increase our understanding of rigosertib’s anti-cancer effects and thereby represent a valuable tool to inform its continued clinical development,” said Mark Gelder, M.D., Chief Medical Officer of Onconova. “I am particularly encouraged by data showing rigosertib-induced activation of the NLRP3 inflammasome. These data provide additional support for previously reported clinical results in KRAS-mutated non-small cell lung cancer that suggest rigosertib can synergize with checkpoint inhibition to drive clinical response in patients with various KRAS mutations that failed prior checkpoint inhibitor therapy. Data identifying potential targets through which rigosertib inhibits RAS-MAPK signaling are also compelling, as this pathway plays a key role in the formation and growth of a variety of cancers. Collectively, these data provide a mechanistic rationale for the differentiated potential of rigosertib when compared to the FDA approved agents that target only the KRAS G12C mutation.”
Preclinical studies featured in the poster evaluated mechanisms by which rigosertib may activate an anti-cancer immune response and inhibit the RAS-MAPK pathway. Results indicate that rigosertib stimulates an immune response via activation of the NLRP3 inflammasome, which leads to the secretion of the pro-inflammatory cytokines IL-1β and IL-18. Additional data identified the proteins NQO2, ERO1A, and NEK7 as potential novel targets that may be modulated by rigosertib. Activation of NQO2 and/or ERO1A leads to reactive oxygen species (ROS)-induced activation of JNK signaling, which in-turn leads to RAS-MAPK pathway inhibition. Rigosertib interaction with NEK7 could possibly cause the destabilization of microtubules and cell cycle arrest in mitosis, which are critical for cell division.
A copy of the poster, titled “CETSA Profiling Unveils Novel Targets Engaged by Anti-tumor Drug Rigosertib to Inhibit RAS-MAPK Signaling and Trigger NLRP3 Inflammasome Activation,” is available on the “Scientific Presentations” section of the Onconova website.
About Onconova Therapeutics, Inc.
Onconova Therapeutics is a clinical-stage biopharmaceutical company focused on discovering and developing novel products for patients with cancer. The Company has proprietary targeted anti-cancer agents designed to disrupt specific cellular pathways that are important for cancer cell proliferation.
Onconova’s novel, proprietary multi-kinase inhibitor narazaciclib (formerly ON 123300) is being evaluated in two separate and complementary Phase 1 dose escalation and expansion studies. These trials are currently underway in the United States and China. Based on preclinical and clinical studies of CDK 4/6 inhibitors, Onconova is also planning a combination trial of narazaciclib with estrogen blockade in advanced endometrial cancer, as well as its clinical study in additional indications.
Onconova’s product candidate rigosertib is being studied in multiple investigator-sponsored studies, including a dose-escalation and expansion Phase 1/2a study of oral rigosertib in combination with nivolumab in patients with KRAS+ non-small cell lung cancer, and a Phase 2 program evaluating rigosertib monotherapy in advanced squamous cell carcinoma complicating recessive dystrophic epidermolysis bullosa.
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Company Contact:
Mark Guerin
Onconova Therapeutics, Inc.
267-759-3680
ir@onconova.us
Investor Contact:
Bruce Mackle
LifeSci Advisors, LLC
646-889-1200
bmackle@lifesciadvisors.com
