Androgen and c-Kit receptors in desmoplastic small round cell tumors resistant to chemotherapy: Novel targets for therapy

Robert L. Fine, Samir S. Shah, Thomas A. Moulton, Ing Ru Yu, David R. Fogelman, Michael Richardson, Howard A. Burris, Brian L. Samuels, Chatchawin Assanasen, Prakash Gorroochurn, Hanina Hibshoosh, Manuela Orjuela, James Garvin, Frederick D. Goldman, Daniel Dubovsky, David Walterhouse, Gregory Halligan

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Purpose: Desmoplastic small round cell tumor (DSRCT) is a highly fatal, mainly peritoneal cell origin cancer which predominantly affects young adult males. This predilection in young males led us to examine the role of androgen receptors (AR), testosterone, and growth factors in the biology of DSRCT. Methods: Slides were prepared from 27 multi-institutional patients all with end-stage DSRCT. Slides were stained for AR, c-Kit, various growth factors, and drug resistance-associated proteins. Immunohistochemical (IHC) expression was scored semi-quantitatively. Western blot and MTT studies were performed to validate the IHC findings of over-expression of the AR and its functional status by stimulation of growth by dihydrotestosterone, respectively. Six patients with positive AR status were treated solely with combined androgen blockade (CAB) as used for prostate cancer. Results: Twenty-two patients were male (81%) and five were female (19%) with a median age at diagnosis of 23. All patients had failed at least two prior multi-agent chemotherapy regimens and 44% had progressed after autologous stem cell transplant. DSRCT samples from 10 of 27 patients were ≥2+ IHC positive for AR (37%,P = 0.0045) and 7 of 20 patients were ≥2+ IHC positive for c-Kit (35%, P = 0.018). We found elevated IHC expression of GST-pi, MRP and thymidylate synthase in smaller subsets of patients. In vitro studies for AR by Western blot and stimulation of growth by dihydrotestosterone in MTT assays suggest that the AR in DSRCT cells is functional. Six patients with positive AR status were treated with CAB alone and three of six attained clinical benefit (1-PR, 1-MR, 1-SD) in a range of 3-4 months. The three patients who responded to CAB had normal testosterone levels before CAB, while the three who did not respond to CAB had baseline castrate levels of testosterone. Conclusions: DSRCT has significant IHC expression of AR and c-Kit in heavily pre-treated patients. The presence of significant AR expression in 37% suggests that these patients could possibly respond to CAB. The significance of c-Kit expression in 35% of DSRCT patients is unknown and warrants further investigation.

Original languageEnglish (US)
Pages (from-to)429-437
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume59
Issue number4
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Keywords

  • Androgen receptor
  • C-Kit
  • Desmoplastic small round cell tumor
  • Testosterone

ASJC Scopus subject areas

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

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