On October 16, 2020 Kitov Pharma Ltd. ("Kitov") (NASDAQ/TASE: KTOV), a clinical-stage company advancing first-in-class therapies to overcome tumor immune evasion and drug resistance, reported new data supporting the mechanism of action of NT219, a dual inhibitor, novel small molecule targeting IRS1/2 and STAT3 is being presented in a video recorded presentation at the Epigenetics and Metabolism AACR (Free AACR Whitepaper) Special Virtual Conference by researchers at Tel-Aviv University (Press release, Kitov Pharmaceuticals , OCT 16, 2020, View Source [SID1234568556]). The data was generated as part of the Company’s collaboration with Professor Ido Wolf, Head of the Oncology Division, Tel Aviv Sourasky Medical Center.
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The new data demonstrates IRS2-amplified colorectal cancer (CRC) cells upregulate β-catenin expression, and treatment with NT219 significantly decreased the β-catenin transcriptional activity in these cells. In addition, NT219 markedly inhibited cell viability in a dose-dependent manner. Moreover, there was a unique role for IRS2 in promoting brain metastasis of CRC, suggesting AKT and β-catenin pathways downstream of IRS2 may be involved in mediating the enhanced aggressive phenotype of IRS2-amplified CRC cells in the brain microenvironment. β-catenin signaling by Wnt has been shown to have a number of different cellular influences. Besides cellular proliferation via protein stabilization to promote cellular growth, Wnt/ β-catenin has demonstrated a role in the establishment of the blood brain barrier and impacts the tumor microenvironment, associated with the therapeutic resistance of cancer cells (Dzobo et al, 2019).
"These new mechanism of action data, together with the compelling results from our preclinical studies of NT219, further support the rationale behind combining NT219 with various targeted and immune oncology approaches, both in peripheral and nervous system tumor tissues," said Bertrand Liang, M.D., Ph.D., Chief Medical Officer of Kitov. "We are currently enrolling patients in our Phase 1/2 clinical trial of NT219 as monotherapy for the treatment of advanced solid tumors, as well as in combination with cetuximab, an epithelial growth factor receptor (EGFR) blocking monoclonal antibody, for the treatment of recurrent and/or metastatic solid tumors and head and neck cancer or colorectal adenocarcinoma. We expect top-line data from the first part of this important study in the second half of 2021."
Previously completed preclinical studies demonstrated NT219’s ability to overcome cancer drug resistance in patient-derived xenograft (PDX) models of various advanced cancer types, and to revert resistance to pembrolizumab (Keytruda). Mice treated concomitantly with a combination of pembrolizumab and NT219 demonstrated complete blockage of tumor progression. Similarly, the combination of NT219 with cetuximab sensitized resistant tumors to this therapy.