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Novel Molecular Targets for Drug Development in Non-GIST Sarcomas

Rodrigo R. Munhoz, MD; William D. Tap, MD; and Sandra P. D’Angelo, MD
Published: Saturday, Aug 22, 2015
William D. Tap, MD

William D. Tap, MD

Abstract

The characterization of molecular abnormalities implicated in the tumorigenesis of sarcomas is being increasingly applied to the classification, prognostication and, in particular situations, management of these diseases. Nevertheless, despite a growing knowledge of the genetic alterations involved, the translation of these discoveries into therapeutic success has been limited and the treatment for the majority of patients still relies on conventional cytotoxic agents. In this review, we address the emerging therapeutic strategies aimed at specific molecular targets that could potentially change this panorama.


Introduction

Sarcomas represent a diverse group of neoplasms of mesenchymal origin that correspond to approximately 1.5% of all malignancies in adults.1-4

Genetic aberrations in sarcomas occur as either simple karyotypic abnormalities, such as chromosomal translocations, amplifications, and deletions, or complex/unbalanced karyotypic changes following accumulated nonspecific gains and losses. Chromosomal translocations resulting in gene fusions and subsequent transcriptional dysregulation account for the majority of the genetic hallmarks identified in sarcomas.5,6 In addition to the formation of chimeric transcription factors involving oncogenes, translocations may result in the activation of proteins with tyrosine kinase function or autocrine growth factors. Conversely, tumors without specific cytogenetic abnormalities are characterized by genome instability, which results in multiple and alternative genomic aberrations of unclear significance and a complex karyotype.5-7

One of the major breakthroughs that emerged from a molecular-based approach is exemplified in gastrointestinal stromal tumors (GIST).8-11 Despite this initial enthusiasm, targeting molecular alterations has been less fruitful in other histologies, in which genetic alterations rarely act as driver mutations. In this review, we will focus on novel potential molecular targets in non-GIST sarcomas (Figure). PDGFR in Sarcomas Platelet-derived growth factor receptors (PDGFRs) are tyrosine-kinase receptors consisting of either α- or β-chains forming three possible receptors: PDGFR-αα, PDGFR-αβ, and PDGFR-ββ. The activation of PDGFR depends on the interaction with platelet-derived growth factor (PDGF) ligands in the extracellular domain, which include 5 different isoforms. After dimerization, each PDGFR partner phosphorylates tyrosine residues located on the cytosolic tails.12 Across different subtypes of sarcomas, signaling through PDGF/PDGFR has been shown to promote progression through cell cycle and avoidance of apoptosis, and result in pro-angiogenic effects and modulation of the tumor stroma.13-18 Activation of PDGFR results in downstream signaling through multiple pathways involving phosphatidylinositol-3-kinase (PI3K), phospholipase-C gamma (PLCγ), Rous sarcoma oncogene (SRC) kinases and rat sarcoma oncogene (RAS)/mitogen-activated protein kinase (MAPK) proteins.13 In normal cells, high expression of PDGFRβ is seen in fibroblasts, pericytes and smooth muscle, and PDGFRα in megakaryocytes, fibroblasts, myoblasts, pericytes, smooth muscle, and neurons.19

In dermatofibrosarcoma protuberans (DFSP), inhibition of PDGFβ/PDGFRβ with tyrosine kinase inhibitors20-25 resulted in significant clinical activity, leading to approval of imatinib by the US Food and Drug Administration (FDA) for the treat ment of patients with advanced/metastatic disease. The molecular hallmark of DFSP is the recurrent translocation t(17;22) (q22;q13), that results in the fusion of the collagen type I alpha 1 (COL1A1) promoter to PDGF, leading to constitutive activation of this pathway.20 In a pooled analysis including 24 patients treated with imatinib, objective response rate (ORR) was 46% and median time to tumor progression (mTTP) was 1.7 years.25


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