Journal article
RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors
Clinical cancer research, Vol.18(8), pp.2184-2198
04/15/2012
DOI: 10.1158/1078-0432.CCR-11-1122
PMCID: PMC3724517
PMID: 22351689
Abstract
Purpose: The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response.
Experimental Design: Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated.
Results: Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAF(V600E/K)), whereas eight of 17 (47%) tumors were BRAF wild type (BRAF(WT)). Tumor implants from 7 of 17 patients (41%) responded to RAF265 treatment with more than 50% reduction in tumor growth. Five of the 7 (71%) responders were BRAF(WT), of which 1 carried c-KITL576P and another N-RAS(Q61R) mutation, while only 2 (29%) of the responding tumors were BRAF(V600E/K). Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11.
Conclusions: Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles. Clin Cancer Res; 18(8); 2184-98. (C) 2012 AACR.
Details
- Title: Subtitle
- RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors
- Creators
- Yingjun Su - Novartis (China)Anna E. Vilgelm - Vanderbilt University Medical CenterMark C. Kelley - Vanderbilt UniversityOriana E. Hawkins - Vanderbilt University Medical CenterYan Liu - Vanderbilt University Medical CenterKelli L. Boyd - Vanderbilt UniversitySara Kantrow - Vanderbilt University Medical CenterRyan C. Splittgerber - Vanderbilt University Medical CenterSarah P. Short - Vanderbilt UniversityTammy Sobolik - Vanderbilt University Medical CenterSnjezana Zaja-Milatovic - Novartis (United States)Kimberly Brown Dahlman - Vanderbilt UniversityKatayoun I. Amiri - St Thomas' HospitalAixiang Jiang - Vanderbilt UniversityPengcheng Lu - Novartis (United States)Yu Shyr - Vanderbilt University Medical CenterDarrin D. Stuart - Vanderbilt UniversityShawn Levy - Vanderbilt UniversityJeffrey A. Sosman - Novartis (United States)Ann Richmond - St. Thomas Hospital
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.18(8), pp.2184-2198
- DOI
- 10.1158/1078-0432.CCR-11-1122
- PMID
- 22351689
- PMCID
- PMC3724517
- NLM abbreviation
- Clin Cancer Res
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 15
- Grant note
- Vanderbilt-Ingram Cancer Center K12GM068543 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) UL1TR000445 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) I01BX000196 / Veterans Affairs; US Department of Veterans Affairs TJ Martell Foundation T32HL007751 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) T32CA119925 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01FD002333 / FOOD AND DRUG ADMINISTRATION; United States Department of Health & Human Services
- Language
- English
- Date published
- 04/15/2012
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984420836302771
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