Cancer Chemotherapy and Pharmacology

, Volume 59, Issue 4, pp 429–437 | Cite as

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
Original Article

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.

Keywords

Desmoplastic small round cell tumor Androgen receptor Testosterone C-Kit 

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Robert L. Fine
    • 1
    • 11
  • Samir S. Shah
    • 1
  • Thomas A. Moulton
    • 2
  • Ing-Ru Yu
    • 3
  • David R. Fogelman
    • 1
  • Michael Richardson
    • 3
  • Howard A. Burris
    • 4
  • Brian L. Samuels
    • 5
  • Chatchawin Assanasen
    • 6
  • Prakash Gorroochurn
    • 1
  • Hanina Hibshoosh
    • 1
  • Manuela Orjuela
    • 1
  • James Garvin
    • 1
  • Frederick D. Goldman
    • 7
  • Daniel Dubovsky
    • 8
  • David Walterhouse
    • 9
  • Gregory Halligan
    • 10
  1. 1.College of Physicians and Surgeons of Columbia UniversityNew York-Presbyterian Medical Center and Morgan Stanley Children’s HospitalNew YorkUSA
  2. 2.Children’s Hospital at MontefioreBronxUSA
  3. 3.Oncotech Corporation, TustinUSA
  4. 4.Sarah Cannon Cancer CenterNashvilleUSA
  5. 5.Lutheran General HospitalPark RidgeUSA
  6. 6.Nemours Children’s ClinicPensacolaUSA
  7. 7.Children’s Hospital of IowaIowa CityUSA
  8. 8.Atlanta Cancer CareAtlantaUSA
  9. 9.Children’s Memorial HospitalChicagoUSA
  10. 10.St. Christopher’s Hospital for ChildrenPhiladelphiaUSA
  11. 11.Experimental Therapeutics Program, Division of Medical OncologyColumbia University Medical CenterNew YorkUSA

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