In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1411-1411
Abstract:
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. While the establishment of standard multi-modal therapy has led to improved survival, new therapeutic approaches are desperately needed to improve outcomes in patients with metastatic and recurrent disease. Our objective was to develop a highly penetrant mouse model of RMS to study the molecular pathways of the disease and to evaluate novel anticancer agents for the treatment of RMS. The hedgehog (Hh) pathway has been demonstrated to be activated in embryonal RMS. Communication between Hh and PI3K/AKT/mTOR pathways provides a rationale for the study of mTOR inhibitors such as rapamycin in RMS therapy. We developed a novel RMS mouse model by breeding Ptch6-7 knockouts onto a tumor susceptible SKH1 genetic background. We employed these animals (n=20/group) to study the effects of mTOR inhibitor, rapamycin, on the growth and progression of RMS tumors. We found that 42% of the Ptch1+/−SKH1 mice receiving no treatment developed RMS. These tumors were confirmed to have embryonal RMS morphology. These animals spontaneously develop RMS with embryonal histology predominantly in the hind limbs. The tumors developed at approximately 20 weeks of age; thereafter they grew very prolifically. Molecular studies demonstrated high expression of both Myogenin and Myf5. The tumors also manifested Hh pathway activation. The RMS bearing animals were divided into two groups with a third group of Ptch+/+ mice acting as a wild-type control group. Group-I animals receiving no treatment served as positive controls. The increase in tumor size in these animals was compared with the tumor growth of animals treated with rapamycin. The treatment resulted in a significant decrease in the rate of tumor growth as compared to the control group (p & lt;0.05). This treatment also reduced the expression of AKT and Hh pathways, which was consistent with the tumor inhibitory response seen on a gross level. Decreases in markers of tumor invasiveness and VEGF expression were also noted. We conclude that the Ptch1+/− Skh1 mouse represents a novel murine model for aggressive embryonal RMS that recapitulates the pathobiology of human disease. Rapamycin effectively inhibits the growth of Ptch1+/− Skh1 RMS tumors providing insight into the mechanism underlying RMS tumorigenesis. mTOR inhibition with possible Hh pathway cross talk inhibition represents a promising target in the treatment of RMS in this murine model. Citation Format: Samer Zaid-Kaylani, Joseph G. Pressey, David R. Kelly, Mohammad Athar. Pathogenesis and treatment of rhabdomyosarcoma in a susceptible murine model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1411. doi:10.1158/1538-7445.AM2013-1411
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-1411
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Permalink
