In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2505-2505
Abstract:
Prostate cancer (PCa) is one of the major causes of cancer-related deaths in men. Androgen receptor (AR) and androgen sensitivity play a crucial role in the development of the disease. Thus, androgen depletion therapy has become a cornerstone of advanced PCa treatment, with or without radiotherapy. Multiple mechanisms have been proposed for the development of hormone-refractory disease, including an increase in neuroendocrine-like (NE-like) cells, which secrete survival and growth factors for surrounding tumor cells (Deeble et al., Cancer Res 2007). Neurotensin (NT) is secreted by both NE-like and cancer cells, and stimulate proliferation of PCa cells through its interaction with neurotensin receptor 1 (NTR1) (Amorino et al., Oncogene, 2007). In this report we investigate the efficacy of a NTR1 antagonist, SR48692, as a radiosensitizer in an orthotopic PC-3M xenograft model. The role of AR/sensitivity to androgen in response to SR48692 was also investigated using LNCaP and C4-2 cell lines. The latter studies were done to test the hypothesis that AR positive cells may be refractory to the raditherapy, because we had previously shown that neuropeptides from NE-like cells resulted in Src-mediated phosphorylation of AR (DaSilva et al., Cancer Res 2009). The results of the xenograft studies indicate that mice bearing PC-3M tumors and receiving the combination treatment (drug+radiation) showed a statistically significant decrease in tumor growth over radiation or SR48962 treatments alone. SR48692 was also found to radiosensitize PCa cells in vitro, independently of their androgen receptor/androgen sensitivity status. We further demonstrate that NT stimulates accumulation of AR under conditions of reduced androgen and that this activity is blocked by SR48692/radiation co-treatment. These findings suggest that in cells expressing the AR, NT reduces the efficacy of radiation by elevating AR levels and its ensuing pro-growth and -survival signals. Blocking the actions of NT by SR48692 reduces the levels of AR protein and as a result increases cellular sensitivity to radiation. However, in cells lacking the AR, another mechanism(s) of drug action must be operative. Together, our studies suggest that in AR positive or negative PCa cells, NTR1 signaling pathway(s) are novel targets for combined SR48962/radiotherapy of PCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2505. doi:10.1158/1538-7445.AM2011-2505
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-2505
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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