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Ref Type Abstract
Authors Yong Hu; Chen Chen; Charles Huang; Min Xu; Youqin Chen; Xiyuan Zhao; Li Zhao
Title ABM-1310, A novel BRAF Inhibitor, combined with EGFR and MEK inhibitors, inhibits colorectal tumor growth and increases overall survival in vivo
Journal Cancer Research
Vol 80
Issue 16_Supplement
Date August 15 2020
Abstract Text Colorectal cancer (CRC) is a cancer that starts in the colon or the rectum, and the current treatment mainly relies on chemotherapies. For example, ERBITUX® /cetuximab is an FDA approved targetedtherapy drug to treat CRC with wild-type KRAS, the 11% low response rate limits its clinical application. BRAF inhibitors have been widely used clinically for melanoma and lung cancer, however, they have dismally low response rate at only approximately 5% of colorectal cancer patients with BRAFv600 mutation. Here, we report that ABM-1310, a novel small molecule inhibitor of BRAF (specifically inhibit BRAFv600 mutant), has shown good potency in colon cancer xenograft models, when combined with a MEK inhibitor and EGFR antibody. In the HT-29 xenograft subcutaneous model, 10 to 25mg/kg/day oral dose of ABM-1310 combined with cetuximab (0.1mg/dose, twice a week) and 3 mg/kg/day of Binimetinib (MEK inhibitor) significantly inhibited HT-29 tumor growth with TGI of 85% to 92% after 34-days treatment. As a monotherapy or combined with cetuximab alone, ABM-1310 also brought the TGI of 74% and 82% at 25mg/kg/day, which indicates ABM-1310 played a key role in tumor growth inhibition in the combinations. Beside with Binimetinib, we also tested combination of ABM-1310 with other different MEK inhibitors in this model. ABM-1310 is highly water-soluble small molecule with high cell permeability and blood brain barrier penetration. ABM-1310 shown good efficacy in melanoma A375 (luciferase labelled cells) in the subcutaneous/intracranial/intracardiac xenograft models (brain metastasis models). In the HT-29 colon intracranial model, ABM-1310 also demonstrated significant tumor inhibition effect and increased animal overall survival. Compared with vehicle or marketed BRAF inhibitor vemurafenib, the median survival time of ABM-1310 group was >90 days vs 51 days (vemurafenib) and 38 days (vehicle), respectively. In Summary, ABM-1310, as a novel small molecule BRAF inhibitor, combined with EGFR and MEK inhibitors, has shown strong anti-tumor effect in preclinical in vivo models of colon cancer with BRAFv600 mutation, especially with brain metastasis.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
ABM-1310 ABM1310|ABM 1310 BRAF Inhibitor 21 ABM-1310 inhibits BRAF V600, including BRAF V600E, potentially leading to inhibition of tumor growth (Cancer Res (2020) 80 (16_Supplement): 4038).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colon cancer predicted - sensitive ABM-1310 + Binimetinib Preclinical - Cell line xenograft Actionable In a preclinical study, combination treatment with ABM-1310 and Mektovi (binimetinib) led to inhibition of tumor growth in a colon cancer cell line xenograft model harboring BRAF V600E (Cancer Res (2020) 80 (16_Supplement): 4038). detail...
BRAF V600E colon cancer predicted - sensitive ABM-1310 + Cetuximab Preclinical - Cell line xenograft Actionable In a preclinical study, combination treatment with ABM-1310 and Erbitux (cetuximab) led to inhibition of tumor growth in a colon cancer cell line xenograft model harboring BRAF V600E (Cancer Res (2020) 80 (16_Supplement): 4038). detail...