Patient-derived tumor xenograft model to guide the use of BRAF inhibitors in metastatic melanoma

Melanoma Res. 2013 Oct;23(5):373-80. doi: 10.1097/CMR.0b013e328363ed92.

Abstract

Recently, the BRAF V600 inhibitor, vemurafenib, has revolutionized the therapeutic management of metastatic melanoma. However, adverse effects and the onset of resistance are frequently observed, limiting the efficacy of this treatment. Patient-derived tumor xenografts (PDTX) engrafted in immunocompromised mice have been proposed as valuable preclinical models that can predict clinical response to treatments. Here, we established a PDTX model of BRAF V600E melanoma useful for testing the efficacy of vemurafenib. First, we validated the stability of the model that was similar to the original tumor with respect to histology, immunohistochemistry, mutational status, and fluorine-18 fluorodeoxyglucose ([(18)F]FDG)-PET/computed tomography (CT). Next, the sensitivity of the xenografts to vemurafenib was determined by tumor growth inhibition and decreased in standardized uptake value on [(18)F]FDG-PET/CT. Finally, this result, using personalized PDTX, allowed successful rechallenge with vemurafenib in a patient who was administered a lower dose of vemurafenib because of the onset of adverse events. Overall, we found that PDTX provides 'real-time' results in an animal that phenocopies the biology and expected vemurafenib responses of the tumor in a patient with BRAF V600E melanoma. Thus, this 'coclinical' trial using PDTX can help guide vemurafenib treatment for metastatic melanoma.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Fluorodeoxyglucose F18
  • Humans
  • Indoles / adverse effects
  • Indoles / pharmacology*
  • Melanoma / drug therapy*
  • Melanoma / enzymology
  • Melanoma / genetics
  • Melanoma / secondary
  • Mice, SCID
  • Multimodal Imaging
  • Mutation
  • Positron-Emission Tomography
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Radiopharmaceuticals
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacology*
  • Time Factors
  • Tomography, X-Ray Computed
  • Tumor Burden / drug effects
  • Vemurafenib
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Indoles
  • Protein Kinase Inhibitors
  • Radiopharmaceuticals
  • Sulfonamides
  • Fluorodeoxyglucose F18
  • Vemurafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf