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Cancer Discov. 2016 Mar;6(3):286-99. doi: 10.1158/2159-8290.CD-15-1336. Epub 2015 Dec 29.

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma.

Author information

1
Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
2
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
3
Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.
4
The University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom.
5
Research Services, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
6
Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom. richard.marais@cruk.manchester.ac.uk.

Abstract

Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma.

SIGNIFICANCE:

Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments.

PMID:
26715644
DOI:
10.1158/2159-8290.CD-15-1336
[Indexed for MEDLINE]
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