Methods and Compositions for the Inhibition of Stat5 in Prostate Cancer Cells
- Technology Benefits
- Efficient therapy to treat hormone resistant tumorSelective inhibition of prostate cancer cellsProvides a specific drug target against an extremely difficult-to-treat cancerExtensive cancerous cell death upon administration
- Detailed Technology Description
- The central problem in clinical management of prostate cancer is the development of hormone-refractory and metastatic disease. Androgen deprivation therapy only provides a temporary inhibition of the cancer growth before the hormone-refractory form of prostate cancer develops. Moreover, no effective pharmacologic treatments exist for elimination of residual cancer cells after prostate cancer surgery. The present invention identifies a new therapeutic target, namely, Signal Transducer and Activator of Transcription (Stat5a/b) that has potential for developing better therapeutic interventions for primary and advanced prostate cancer. It also describes various STAT5 inhibitors and an assay for diagnosing prostate cancer due to activated STAT5 in tissue samples.
- *Abstract
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Stat5 is one of the seven members of the Stat family of transcription factors in mammals and consists of two distinct, but highly homologous, gene products, the 94-kDa Stat5a and 92-kDa Stat5b. In response to Prl, Stat5a and Stat5b become activated by tyrosine phosphorylation in the C-terminal domain by Janus tyrosine kinase-2 (Jak2), which is preassociated with the cytoplasmic domain of the Prl receptor. Tyrosine phosphorylated Stat5 proteins dimerize and translocate to the nucleus, where they bind to specific response elements of target gene promoters to regulate transcription. Georgetown investigators have found that transcription factor Stat5 to be activated in a significant number of human prostate cancer specimens and that blocking Stat5 activity induces apoptosis of prostate cancer cells.;To block activated endogenous Stat5 proteins in human prostate cancer cells, Georgetown researchers generated an adenovirus for effective delivery of dominant-negative mutant of Stat5 (AdDNStat5). AdDNStat5, but not the wildtype control, induced cell death in the androgen-dependent human prostate cancer cell line, CWR22Rv and in the androgen-sensitive human prostate cancer cell line, LnCap. This result implies that apoptosis induced by blocking the activation of Stat5 is independent of responsiveness to androgens. This suggests that inhibition of Stat5 as a therapeutic approach could have a broad usefulness in the treatment of prostate cancer.
- *Publications
- Tan, S. H., Dagvadorj, A., Shen, F., Gu, L., Liao, Z., Abdulghani, J., Zhang, Y., Gelmann, E. P., Zellweger, T., Culig, Z., Visakorpi, T., Bubendorf, L., Kirken, R. A., Karras, J., and Nevalainen, M. T. Transcription factor Stat5 synergizes with androgen receptor in prostate cancer cells. Cancer Res, 68: 236-248, 2008.Li, H., Zhang, Y., Glass, A., Zellweger, T., Gehan, E., Bubendorf, L., Gelmann, E. P., and Nevalainen, M. T. Activation of signal transducer and activator of transcription-5 in prostate cancer predicts early recurrence. Clin Cancer Res, 11: 5863-5868, 2005.Li, H., Ahonen, T. J., Alanen, K., Xie, J., LeBaron, M. J., Pretlow, T. G., Ealley, E. L., Zhang, Y., Nurmi, M., Singh, B., Martikainen, P. M., and Nevalainen, M. T. Activation of signal transducer and activator of transcription 5 in human prostate cancer is associated with high histological grade. Cancer Res, 64: 4774-4782, 2004.Ahonen, T. J., Xie, J., LeBaron, M. J., Zhu, J., Nurmi, M., Alanen, K., Rui, H., and Nevalainen, M. T. Inhibition of transcription factor Stat5 induces cell death of human prostate cancer cells. J Biol Chem, 278: 27287-27292, 2003.
- *Stage of Development
- Proof of principle demonstrated in prostate tumors in vivo.
- Country/Region
- USA
