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Novel Molecular Targets for Drug Development in Non-GIST Sarcomas

Rodrigo R. Muhoz, MD, William D. Tap, MD, and Sandra P. D’Angelo, MD
Published Online: Feb 25,2016


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. Although the treatment for the majority of patients still relies on conventional cytotoxic agents, the elucidation of underlying genetic aberrations and mechanisms of these diseases are gradually translating into therapeutic progress. In this review, we address the emerging therapeutic strategies aimed at specific molecular targets that could potentially change the approach to patients with soft-tissue sarcomas.


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 that result from accumulated nonspecific gains and losses. Chromosomal translocations associated with 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 prompt 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. Nevertheless, the evolving molecular characterization and widespread use of next-generation sequencing techniques has unveiled a series of new potential targets through a better characterization on the molecular landscape. In this review, we will focus on novel potential molecular targets in non-GIST sarcomas, based on available clinically-relevant results.

PDGFR in Sarcomas

Platelet-derived growth factor receptors (PDGFRs) are tyrosine-kinase receptors consisting of either α- or β-chains forming 3 possible receptors: PDGFR-αα, PDGFR-αβ, and PDGFR-ββ. The activation of PDGFR occurs upon 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.14 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.13-19

In dermatofibrosarcoma protuberans (DFSP), inhibition of PDGFβ/PDGFRβ with tyrosine kinase inhibitors20-25, showed significant clinical activity, culminating with the approval of imatinib by the US Food and Drug Administration (FDA) for the treatment of patients with advanced/ metastatic disease.20-25 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

In addition, the PDGF/PDGFR pathway has been associated with the pathogenesis of different sarcomas including rhabdomyosarcoma, Kaposi’s sarcoma, synovial sarcoma, chondrosarcoma, osteosarcoma, and Ewing family sarcoma. Elevated expression of PDGFβ and co-expression of PDGFβ and PDGFRα has been correlated with high histological grades and poor prognosis in sarcomas.17,18 Postulated mechanisms include the modulation of angiogenesis, regulation of stroma-derived fibroblasts and autocrine stimulation of cellular growth.16 Overexpression of mRNA for PDGFRα and PDGF has been documented in sarcoma, highlighting the relevance of this autocrine loop.16 In addition, preclinical data suggest that blocking PDGF/PDGFR results in a potentiation of response to chemotherapy.15

Pazopanib, an oral, multi-targeted tyrosine kinase inhibitor also active against PDGFR, was shown to prolong progression-free survival (PFS) versus placebo in pretreated patients with advanced non-adipocytic soft tissue sarcomas (median PFS, 4.6 months vs 1.6 months; hazard ratio [HR], 0.31; P <.0001) in a phase III trial, and is currently approved by the FDA for clinical use.26 Similarly, regorafenib, a distinct multikinase inhibitor, resulted in improved PFS in previously treated patients with leio- myosarcoma (4.0m vs 1.9m; HR 0.49; p=0.017) and other soft-tissue sarcomas (4.6m vs 1.0m; HR 0.38; p=0.002) in a randomized, placebo controlled, phase II study. In line with these observations, two partial responses were seen in a series of 31 patients with PDGFRb-expressing solitary fibrous tumors (SFT) treated with sunitinib, also a tyrosine-kinase inhibitor. Of note, recent studies revealed a 12q13 intrachromossomal fusion in SFT, resulting in the NAB2:STAT6 fusion protein and subsequent transcriptional activation of several genes and expression of receptor tyrosine kinases.

More recently, approaches focusing on more specific inhibition of PDGFRα with olaratumab led to promising results. Olaratumab (IMC-3G3) is a recombinant IgG1-type monoclonal antibody that binds with high affinity to PDGFRα and prevents PDGF from binding to the receptor; olaratumab also blocks downstream signaling through Akt and mitogen-activated protein kinase (MAPK).16 The results of a phase 1b/2 study evaluating the efficacy of doxorubicin with or without olaratumab have been recently presented. In the randomized phase II portion of the study including 133 patients, the addition of olaratumab resulted in a dramatic gain in overall survival (OS) (median OS 25m vs 14.7m; HR 0.441; p=0.0004), despite only a marginal improvement in PFS (median PFS 6.6m vs 4.1m; HR 0.672; p=0.0615). Noteworthy, adverse events leading to treatment discontinuation were less frequent in the combination arm (13% versus 22%). A pivotal phase III trial addressing this combination in comparison to doxorubicin and placebo is currently ongoing (NCT02451943).

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Novel Molecular Targets for Drug Development in Non-GIST Sarcomas
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