Gynecologic tumors. Among the gynecologic malignancies, those that affect the ovaries, uterus, endometrium, and cervix have the highest mortality. The treatment for these neoplasms relies mostly on surgery and chemotherapy. However, these render temporary benefit and many patients still succumb to cancer relapse. Alternative therapies such as targeting growth factor receptors are being investigated. A large number of ovarian carcinomas express PDGFR? and ? (31). Similarly, PDGF-A, -C, and -D ligands are present in most ovarian tumors (24). Targeting PDGFR? using IMC-3G3 monoclonal antibody proved to enhance efficacy of chemotherapy in vitro and in vivo (25). In another study, IMC-3G3 inhibition of PDGFR? demonstrated substantial benefit in uterine cancer as well (i.e attenuated cell survival, tumor growth, and tumor angiogenesis) (26). In endometrial cancer, Western blotting analysis of 27 human cancer tissues revealed that PDGF-D expression is upregulated and associated with more aggressive features and worse prognosis.Epithelial tumors. PDGFR signaling has also been implicated in the pathogenesis of other epithelial tumors. In non-small cell lung carcinoma (NSCLC), PDGF-A/-B and PDGFR?/? expression concomitantly exacerbated patients’ prognosis (reviewed in (27)). Moreover, neutralization of PDGFR?/? with antibodies in NSCLC markedly reduced tumor size (28). However, clinical trials with imatinib, did not show improvement in progression-free survival. On the other hand, a novel triple angiokinase inhibitor targeting PDGFR? and ?, VEGFR 1-3, and FGFR 1-3 demonstrated favorable results. In two randomized clinical trials phase III (LUME-Lung 1 and LUME-Lung 2), Nintedanib, was proven effective in combination with docetaxel as a second-line option for metastatic or recurrent NSCLC of adenocarcinoma type (29).  Similarly, PDGFR? and PDGFR? expression has been documented and correlated with tumor aggressiveness and worse prognosis in breast cancer (reviewed in (30)). Likewise, studies have demonstrated that PDGF isoforms and PDGF receptors are expressed in prostate (31), hepatocellular (32-33), and colorectal (7) cancer cells, suggesting autocrine stimulatory loops. In gastric cancer, PDGF ligands and PDGFRs are expressed in stromal cells (i.e. pericytes, CAFs, lymphatic endothelial cells) but not in cancer cells nor in the vascular endothelial cells (reviewed in (6)).PDGF signaling in the tumor stroma. Apart from its autocrine functions, there has also been a keen interest in the role of PDGF signaling within the tumor microenvironment. Paracrine signaling has been implicated, wherein ligands secreted by endothelial or epithelial cells stimulate proliferation of PDGFR-expressing mesenchymal cells (6). Expression of PDGFR has been regularly demonstrated in the stromal compartment of various solid tumors including breast, colon, prostate, pancreas, ovary, skin, among others (6,7,18). Tumor-derived PDGF ligand acts on these receptors to stimulate the tumor stroma, support angiogenesis, and promote the development of cancer-associated fibroblasts.Various approaches to block PDGF/PDGFR signaling have been described. These include using anti-PDGF monoclonal antibodies, soluble extracellular parts of the PDGFR acting as ligand traps, and DNA aptamers against PDGF/PDGFR (34). These molecules afford some advantages in terms of high specificity and having minimal side effects. Recently, Olaratumab (IMC-3G3) (Lartruvo™), a recombinant human IgG monoclonal antibody that specifically binds PDGFR?, was granted approval for the treatment of advanced soft tissue sarcoma in combination with doxorubicin (20). This is the first anti-PDGF receptor antibody that was successful in translation for clinical use. It specifically blocks PDGF-AA, PDGF-BB and PDGF-CC binding and receptor activation (20). Preclinical studies confirmed encouraging results with its utility against GBM and leiomyosarcoma (3). However, clinical trials were unsuccessful in showing considerable benefit in other solid tumors such as prostate cancer, ovarian cancer, or glioma. Ongoing phase II clinical trials aim to investigate the effect of olaratumab in combination with other drugs: olaratumab + paclitaxel/carboplatin in NSCLC (NCT00918203) and nab-paclitaxel and gemcitabine +/- olaratumab in metastatic pancreatic cancer (NCT03086369).Another strategy to attenuate PDGFR signaling is to block enzymatic activity using low molecular weight compounds. Examples of such compounds are tyrosine kinase inhibitors (TKIs). TKIs compete with ATP for binding to the ATP-binding pocket in the kinases. However, these are not specific to PDGFR kinases. The most commonly used TKI in the clinics, Imatinib, targets PDGFR? and PDGFR?. At the same time, it also inhibits Abl, Kit, and Arg tyrosine kinases (34). It is typically used in non-solid tumors but was first granted FDA approval for the management of advanced GIST in 2002. It is also indicated for non-resectable DFSP. In addition, other TKIs have been developed including cediranib, nilotinib, pazopanib, sorafenib, and sunitinib. PGDF/PDGFR as prognostic biomarker. The prognostic value of PDGFR was first demonstrated in breast cancer (reviewed in (18)). Tumor tissue microarray immunohistochemistry (IHC) revealed that high stromal expression of PDGFR? correlated with poor prognostic markers such as high histopathological grade, high human epidermal growth factor receptor (HER2/neu) expression, and estrogen receptor (ER) negativity (35). Clinical data concurrently showed shorter recurrence-free survival and breast cancer-specific survival (35). In another study, global gene expression analysis divided cohorts of breast cancer patients in terms of PDGF signature scores: high versus low. Interestingly, high PDGF signature score directly correlated with large tumor size, high tumor grade, HER2/neu positivity, ER negativity, and shorter patient survival (36).  PDGFR? expression was also analyzed in normal tumor stroma of prostate cancer. IHC of tissues from more than 300 patients revealed that high stromal PDGFR? expression was associated with high Gleason score, high vessel density, large tumor size, and more advanced stage (37). Likewise, PDGFR? in the stroma of tumor and non-malignant tissue was inversely proportional to prostate cancer specific survival (37). In a recent study, high stromal expression of PDGFR? was found to be associated with prostate cancer relapse as well as biochemical failure (38). Differential expression of PDGFRs in the tumor stroma has been observed in other solid tumors including colorectal cancer, pancreatic adenocarcinoma, gastric cancer, etc (reviewed in (18)). PDGF/PDGFR as biomarker of treatment response. The PDGF/PDGFR family has also shown potential as treatment response biomarkers. For example, the irradiation of NSCLC is accompanied by upregulation of PDGFR? in the surviving cells. 


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