Platelet-Derived Growth Factor Receptor Inhibition and Chemotherapy for Castration-Resistant Prostate Cancer with Bone Metastases

Abstract

Purpose:To further assess preclinical and early clinical evidence that imatinib mesylate, a plateletderived growth factor receptor (PDGFR) inhibitor, modulates taxane activity in prostate cancer and bone metastases, a randomized study was conducted. Experimental Design: Men with progressive castration-resistant prostate cancer with bone metastases (n = 144) were planned for equal randomization to i.v. 30 mg/m 2 docetaxel on days 1, 8, 15, and 22 every 42 days with 600 mg imatinib daily or placebo, for an improvement in median progression-free survival from 4.5 to 7.5 months (two-sided a = 0.05 and b = 0.20). Secondary end points included differential toxicity and bone turnover markers, tumor phosphorylated PDGFR (p-PDGFR) expression, and modulation of p-PDGFR in peripheral blood leukocytes. Results: Accrual was halted early because of adverse gastrointestinal events. Among 116 evaluable men (57 docetaxel + imatinib; 59 docetaxel + placebo), respective median times to progression were 4.2 months (95% confidence interval, 3.1-7.5) and 4.2 months (95% confidence interval, 3.0-6.8; P = 0.58, log-rank test). Excess grade 3 toxicities (n = 23) in the docetaxel + imatinib group were principally fatigue and gastrointestinal. Tumor p-PDGFR expression was observed in 12 of 14 (86%) evaluable bone specimens. In peripheral blood leukocytes, p-PDGFR reduction was more likely in docetaxel + imatinib^treated patients compared with docetaxel + placebo (P < 0.0001), as were reductions in urine N-telopeptides (P = 0.004) but not serum bone-specific alkaline phosphatase (P = 0.099). Conclusions: These clinical and translational results question the value of PDGFR inhibition with taxane chemotherapy in prostate cancer bone metastases and are at variance with the preclinical studies. This discordance requires explanation.The metastatic phenotype of prostate cancer is highly conserved and characterized by osteoblastic bone metastases, the burden of which correlates with morbidity and mortality from the disease (1). Clarification of the molecular basis of disease progression in bone is expected to yield therapeutic strategies that may significantly transform the natural history of the disease.Several lines of evidence have implicated the platelet-derived growth factor receptor (PDGFR) in the progression of prostate cancer bone metastases. Amplification of conserved domains of tyrosine kinase receptors using degenerate primers identified PDGFR as the most commonly amplified transcript from pooled aspirate specimens from prostate cancer bone metastases (2). Immunohistochemical staining has shown high frequencies of PDGFR expression in prostate cancer bone metastases (2, 3). Our preclinical findings from an orthotopic model of prostate cancer bone metastases showed that PDGFR expression was up-regulated in PC3-MM2 cells and associated vascular endothelium within the bone microenvironment, suggestive of an organ-specific paracrine effect (4). Further, combining the PDGFR inhibitor imatinib mesylate (5) with

The α-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells

“…Recent clinical trials using imatinib mesylate (STI571, Gleevec), a small-molecule inhibitor of PDGFRseither alone (Mathew et al, 2004;Rao et al, 2005;Lin et al, 2006;Bajaj et al, 2007) or in combination with docetaxel (Mathew et al, 2007)-have been disappointing, showing significant adverse toxic effects combined with lack of efficacy in counteracting bone metastatic progression and/or improving overall survival. However, it should be considered that, although in the adult organism both PDGFRa and PDGFRb cooperate in modulating largely overlapping physiological processincluding angiogenesis, wound healing and tissue homeostasis (Heldin and Westermark, 1999;Betsholtz, 2004)-PDGFRb plays an overall predominant role (Andrae, Gallini and Betsholtz, 2008).…”

Soluble ErbB3 Levels in Bone Marrow and Plasma of Men with Prostate Cancer

“…We also obtained plasma samples from 52 men enrolled in a clinical trial of docetaxel for the treatment of bone metastases from prostate cancer (16). Those samples were obtained before and after one 6-wk period of docetaxel treatment (30 mg/m 2 on days 1, 8, 15, and 22).…”

Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

“…Examples of the latter mechanism include altered expression and/or activation of apoptotic regulators such as Clusterin (5), HSPs (6), IAPs (7), and Bcl2 (8) and components of growth factor signaling pathways, such as PI3-kinase/Akt/mTOR (9) and platelet-derived growth factor receptor (10). However, clinical trials emanating from these targets (11)(12)(13)(14)(15)(16)) have yet to make an impact in the clinical setting with the exception of cabazitaxel. Cabazitaxel is a novel tubulin-binding taxane with poor affinity for the multidrug P-glycoprotein efflux pump.…”