TY - JOUR
T1 - Androgen and c-Kit receptors in desmoplastic small round cell tumors resistant to chemotherapy
T2 - Novel targets for therapy
AU - Fine, Robert L.
AU - Shah, Samir S.
AU - Moulton, Thomas A.
AU - Yu, Ing Ru
AU - Fogelman, David R.
AU - Richardson, Michael
AU - Burris, Howard A.
AU - Samuels, Brian L.
AU - Assanasen, Chatchawin
AU - Gorroochurn, Prakash
AU - Hibshoosh, Hanina
AU - Orjuela, Manuela
AU - Garvin, James
AU - Goldman, Frederick D.
AU - Dubovsky, Daniel
AU - Walterhouse, David
AU - Halligan, Gregory
N1 - Funding Information:
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 conXicts of interest. The following authors or their immediate family members have indicated a Wnancial interest. Shares Owned: Robert L. Fine, of Oncotech Inc.
PY - 2007/3
Y1 - 2007/3
N2 - 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.
AB - 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.
KW - Androgen receptor
KW - C-Kit
KW - Desmoplastic small round cell tumor
KW - Testosterone
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U2 - 10.1007/s00280-006-0280-z
DO - 10.1007/s00280-006-0280-z
M3 - Article
C2 - 16896931
AN - SCOPUS:33846316408
SN - 0344-5704
VL - 59
SP - 429
EP - 437
JO - Cancer chemotherapy and pharmacology
JF - Cancer chemotherapy and pharmacology
IS - 4
ER -