SAN DIEGO, April 27, 2020 (GLOBE NEWSWIRE) — eFFECTOR Therapeutics, Inc., a leader in the development of selective translation regulator inhibitors (STRIs) for the treatment of cancer, announced that data presented today in a virtual session at the AACR Annual Meeting, showed the anti-tumor activity of the company’s product candidate, zotatifin, in preclinical models of FGFR1, FGFR2 and HER2 driven cancers, demonstrating the potential of zotatifin in receptor tyrosine kinase (RTK)-driven cancers.
Peggy A. Thompson, Ph.D., executive director, translational medicine at eFFECTOR, gave a presentation entitled, “Preclinical evaluation of eFT226, a potent and selective eIF4A inhibitor with anti-tumor activity in FGFR1, FGFR2 and HER2 driven cancers” which showed that zotatifin significantly inhibited tumor growth and caused tumor regression across diverse RTK-driven tumor types. Zotatifin has been shown to downregulate RTK protein levels and associated AKT and MAPK signaling, resulting in anti-tumor activity in FGFR1, FGFR2 and HER2 driven models. In a HER2+ breast cancer model, tumor regression was sustained long after cessation of therapy. Further evaluation of predictive markers of sensitivity or resistance showed that RTK tumor models with mTOR mediated activation of eIF4A are most sensitive to zotatifin.
“These promising preclinical studies demonstrated that the association of zotatifin activity in RTK tumor models with mTOR pathway activation provides an opportunity to further enrich for sensitive patient subsets during clinical development,” said Steve Worland, Ph.D., president and chief executive officer of eFFECTOR. “This selection strategy will complement our selection of KRAS-mutant tumors based on zotatifin’s down-regulation of KRAS protein in preclinical studies.”
A Phase 1/2 clinical trial of zotatifin in patients with KRAS- or RTK-mutant solid tumors is ongoing [NCT04092673]. The trial is enrolling patients with activating mutations, amplifications or fusions in HER2, ERBB3, FGFR1, or FGFR2 receptor tyrosine kinases, or any KRAS mutation subtype. The primary objectives of the trial include safety and tolerability of zotatifin as monotherapy. Secondary objectives include antitumor activity and survival, as well as pharmacokinetics of the drug. Exploratory objectives include pharmacodynamics of zotatifin.
Zotatifin is a potent and sequence selective inhibitor of eukaryotic translation initiation factor 4A (eIF4A) mediated translation. Zotatifin is designed to inhibit the translation of mRNAs encoding several important oncogenes and survival factors, including several RTKS, KRAS, Cyclin D, CDK4/6, MYC, MCL1 and BCL-2 resulting in potent in vivo tumor regression in multiple tumor models dependent on these factors, including colorectal cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma and B cell lymphomas. Since zotatifin inhibits the translation of mRNA encoding KRAS and RTK, it is not limited to any mutation subtypes. The product candidate is currently being evaluated in a Phase 1/2 clinical trial in patients with solid tumors.
eIF4A is an RNA helicase that catalyzes the ATP-dependent translation of highly structured mRNA. eIF4A helicase activity is tightly controlled by the PI3K and RAS signaling pathways. Activation of eIF4A results in the selective upregulation of oncogenes with highly structured 5’-UTRs (untranslated regions) that are involved in cell proliferation, survival and metastasis. Inhibition of eIF4A selectively regulates the translation of a set of target mRNAs distinct from those regulated by MNK1/2 and eIF4E. Targeting these selective translational regulators may expand the potential patient population that benefits from translation regulation therapy.
eFFECTOR is a next-generation oncology company developing a new class of targeted therapies that restore control of the processes that cancer cells manipulate for survival. The company’s pipeline of product candidates targets different, complementary systems cancer harnesses for its growth and proliferation, creating the potential for combination use with each other or existing therapeutics. Tomivosertib, an inhibitor of MNK1/2, works at multiple points in the cancer immunity cycle, and has demonstrated efficacy in a Phase 2 clinical trial in patients who progressed on check point inhibitors. Zotatifin, which targets eIF4A, an enzyme responsible for unwinding complex RNA structures to facilitate transcription initiation, is being evaluated in an ongoing Phase 1/2 clinical trial in patients with solid tumors.