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Ref Type Journal Article
PMID (26240273)
Authors Nguyen M, Miyakawa S, Kato J, Mori T, Arai T, Armanini M, Gelmon K, Yerushalmi R, Leung S, Gao D, Landes G, Haak-Frendscho M, Elias K, Simmons AD
Title Preclinical Efficacy and Safety Assessment of an Antibody-Drug Conjugate Targeting the c-RET Proto-Oncogene for Breast Carcinoma.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 21
Issue 24
Date 2015 Dec 15
URL
Abstract Text The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody-drug conjugate (ADC) being developed for the treatment of breast cancer.RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single-dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys.By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose-dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy.RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078-DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552-62. ©2015 AACR.

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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
Y078-DM1 Y078-DM1 1 0
Y078-DM4 Y078-DM4 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Y078-DM1 RET Inhibitor 39 Y078-DM1 is an antibody drug conjugate composed of a RET antibody (Y078) linked to a derivative of the cytotoxic agent maytansine, which may lead to increased cytotoxicity in RET-expressing tumors (PMID: 26240273).
Y078-DM4 RET Inhibitor 39 Y078-DM4 is an antibody-drug conjugate composed of a RET antibody (Y078) linked to a derivative of the cytotoxic agent maytansine, which may lead to increased cytotoxicity in RET-expressing tumors (PMID: 26240273).
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
RET positive thyroid gland medullary carcinoma sensitive Y078-DM4 Preclinical Actionable In a preclinical study, Y078-DM4 induced cytotoxicity in a RET-expressing medullary thyroid cell line in culture (PMID: 26240273). 26240273
RET positive breast cancer sensitive Y078-DM4 Preclinical - Cell line xenograft Actionable In a preclinical study, Y078-DM4 induced cytotoxicity in RET-expressing human breast cancer cell lines in culture and inhibited tumor growth in xenograft models (PMID: 26240273). 26240273
RET over exp breast cancer sensitive Y078-DM1 Preclinical - Cell line xenograft Actionable In a preclinical study, Y078-DM1 induced cytotoxicity in a human breast cancer cell line with high levels of RET expression in culture and inhibited tumor growth in xenograft models (PMID: 26240273). 26240273