Accelerated disease progression in prostate cancer and bone metastases with platelet-derived growth factor receptor inhibition: Observations with tandutinib

Paul Mathew, Nizar Tannir, Shi Ming Tu, Sijin Wen, Charles C. Guo, Valerie Marcott, Benjamin Nebiyou Bekele, Lance Pagliaro

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Background: Activated platelet-derived growth factor receptor (p-PDGFR) is frequently expressed in bone metastases of castration-resistant prostate cancer (CRPC). Phase II study of tandutinib was conducted to assess the effects of a continuously administered highly potent PDGFR inhibitor in this disease state. Methods: Men with progressive CRPC, bone metastases, and prior taxane chemotherapy were treated with oral tandutinib 500 mg twice daily until disease progression under a two-stage design with the 8-week freedom-from-progression (FFP) rate as the primary endpoint. The trial was designed to have 87% power to reject a null FFP rate of 10% when the true rate was 33% (type I error rate = 0.02). Secondary endpoints included tumor expression of p-PDGFR, bone marker (urine N-telopeptide, serum bone-specific alkaline phosphatase) kinetics, in vivo monitoring of PDGFR inhibition in peripheral blood leukocytes, and correlation with survival. Results: Among 18 patients registered (aged 47-81, median 66 years), 15 were evaluable for efficacy. Five of 6 evaluable tumors were p-PDGFR positive. Mean urine N-telopeptide declined from 123.7 (baseline) to 41.0 (Cycle 2 Day 1) nmol/mmol Cr (P = 0.012). Probability of decrease in peripheral blood leukocyte p-PDGFR >0.5 versus <0.5 was associated with progression-free survival of 6 versus 8 weeks (P = 0.03, log-rank) and overall survival, 26.6 versus 42.9 weeks, respectively (P = 0.09, log-rank). Conclusions: In vivo PDGFR inhibition with tandutinib correlated with accelerated disease progression. This observation raises the hypothesis that PDGF contributes to the homeostasis of bone metastases from prostate cancer.

Original languageEnglish (US)
Pages (from-to)889-896
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume68
Issue number4
DOIs
StatePublished - Oct 2011
Externally publishedYes

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Keywords

  • Bone metastases
  • PDGF
  • Platelet-derived growth factor
  • Prostate cancer
  • Tandutinib

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

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