Precision Targeted Therapy with BLU-667 for RET -Driven Cancers.

Autor:	Subbiah V; Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Gainor JF; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts., Rahal R; Blueprint Medicines Corporation, Cambridge, Massachusetts., Brubaker JD; Blueprint Medicines Corporation, Cambridge, Massachusetts., Kim JL; Blueprint Medicines Corporation, Cambridge, Massachusetts., Maynard M; Blueprint Medicines Corporation, Cambridge, Massachusetts., Hu W; Blueprint Medicines Corporation, Cambridge, Massachusetts., Cao Q; Blueprint Medicines Corporation, Cambridge, Massachusetts., Sheets MP; Blueprint Medicines Corporation, Cambridge, Massachusetts., Wilson D; Blueprint Medicines Corporation, Cambridge, Massachusetts., Wilson KJ; Blueprint Medicines Corporation, Cambridge, Massachusetts., DiPietro L; Blueprint Medicines Corporation, Cambridge, Massachusetts., Fleming P; Blueprint Medicines Corporation, Cambridge, Massachusetts., Palmer M; Blueprint Medicines Corporation, Cambridge, Massachusetts., Hu MI; Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wirth L; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts., Brose MS; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania., Ou SI; Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Irvine, California., Taylor M; The Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon., Garralda E; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Miller S; Blueprint Medicines Corporation, Cambridge, Massachusetts., Wolf B; Blueprint Medicines Corporation, Cambridge, Massachusetts., Lengauer C; Blueprint Medicines Corporation, Cambridge, Massachusetts., Guzi T; Blueprint Medicines Corporation, Cambridge, Massachusetts., Evans EK; Blueprint Medicines Corporation, Cambridge, Massachusetts. eevans@blueprintmedicines.com.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2018 Jul; Vol. 8 (7), pp. 836-849. Date of Electronic Publication: 2018 Apr 15.
DOI:	10.1158/2159-8290.CD-18-0338
Abstrakt:	The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro , BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo , BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET -altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting. Significance: Patients with RET -driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET -altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836-49. ©2018 AACR. See related commentary by Iams and Lovly, p. 797 This article is highlighted in the In This Issue feature, p. 781 . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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