Reference Detail

Ref Type

Abstract

PMID

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	80	16_Supplement	August 15 2020

URL

https://aacrjournals.org/cancerres/article/80/16_Supplement/4038/643208/Abstract-4038-ABM-1310-A-novel-BRAF-Inhibitor

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
ABM-1310	ABM-1310	2	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ABM-1310		ABM1310\|ABM 1310	BRAF Inhibitor 25	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...