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

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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.

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Acknowledgments

This work is dedicated to Ari Kahane who bravely fought and died from DSRCT at age 18. This work was supported in part by the Herbert Pardes Scholar Award, Ari Kahane Memorial Fund, and a grant from Oncotech Inc. to RLF.

Authors’ disclosures of potential conflicts of interest. The following authors or their immediate family members have indicated a financial interest.

Shares Owned: Robert L. Fine, of Oncotech Inc.

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Authors and Affiliations

  1. College of Physicians and Surgeons of Columbia University, New York-Presbyterian Medical Center and Morgan Stanley Children’s Hospital, New York, NY, USA

    Robert L. Fine, Samir S. Shah, David R. Fogelman, Prakash Gorroochurn, Hanina Hibshoosh, Manuela Orjuela & James Garvin

  2. Children’s Hospital at Montefiore, Bronx, NY, USA

    Thomas A. Moulton

  3. Oncotech Corporation, , Tustin, CA, USA

    Ing-Ru Yu & Michael Richardson

  4. Sarah Cannon Cancer Center, Nashville, TN, USA

    Howard A. Burris

  5. Lutheran General Hospital, Park Ridge, IL, USA

    Brian L. Samuels

  6. Nemours Children’s Clinic, Pensacola, FL, USA

    Chatchawin Assanasen

  7. Children’s Hospital of Iowa, Iowa City, IA, USA

    Frederick D. Goldman

  8. Atlanta Cancer Care, Atlanta, GA, USA

    Daniel Dubovsky

  9. Children’s Memorial Hospital, Chicago, IL, USA

    David Walterhouse

  10. St. Christopher’s Hospital for Children, Philadelphia, PA, USA

    Gregory Halligan

  11. Experimental Therapeutics Program, Division of Medical Oncology, Columbia University Medical Center, 650 West 168th Street, Room BB 20-05, New York, NY, 10032, USA

    Robert L. Fine

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  1. Robert L. Fine
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Correspondence to Robert L. Fine.

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Fine, R.L., Shah, S.S., Moulton, T.A. et al. Androgen and c-Kit receptors in desmoplastic small round cell tumors resistant to chemotherapy: novel targets for therapy. Cancer Chemother Pharmacol 59, 429–437 (2007). https://doi.org/10.1007/s00280-006-0280-z

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  • DOI: https://doi.org/10.1007/s00280-006-0280-z

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