By a News Reporter-Staff News Editor at Cancer Gene Therapy Week -- Fresh data on Biotechnology are presented in a new report. According to news reporting originating from Yamaguchi, Japan, by NewsRx correspondents, research stated, "Although androgen receptor (AR) pathway inhibitors prolong survival in castrate-resistant prostate cancer (CRPC), resistance rapidly develops and is often associated with increased stress-activated molecular chaperones like clusterin (CLU) and continued AR signaling. Because adaptive pathways activated by treatment facilitate development of acquired resistance, cotargeting the stress response, activated by AR inhibition and mediated through CLU, may create conditional lethality and improve outcomes."
Our news editors obtained a quote from the research from Yamaguchi University, "Here, we report that CLU is induced by AR antagonism and silencing using MDV3100 and antisense, respectively, to become highly expressed in castrate- and MDV3100-resistant tumors and cell lines. CLU, as well as AKT and mitogen-activated protein kinase (MAPK) signalosomes, increase in response to MDV3100-induced stress. Mechanistically, this stress response is coordinated by a feed-forward loop involving p90rsk (RPS6KA)-mediated phosphoactivation of YB-1 with subsequent induction of CLU. CLU inhibition repressed MDV3100-induced activation of AKT and MAPK pathways. In addition, when combined with MDV3100, CLU knockdown accelerated AR degradation and repressed AR transcriptional activity through mechanisms involving decreased YB-1-regulated expression of the AR cochaperone, FKBP52. Cotargeting the AR (with MDV3100) and CLU (with OGX-011) synergistically enhanced apoptotic rates over that seen with MDV3100 or OGX-011 monotherapy and delayed CRPC LNCaP tumor and prostate-specific antigen (PSA) progression in vivo."
According to the news editors, the research concluded: "These data indicate that cotargeting adaptive stress pathways activated by AR pathway inhibitors, and mediated through CLU, creates conditional lethality and provides mechanistic and preclinical proof-of-principle to guide biologically rational combinatorial clinical trial design."
For more information on this research see: Cotargeting Androgen Receptor and Clusterin Delays Castrate-Resistant Prostate Cancer Progression by Inhibiting Adaptive Stress Response and AR Stability. Cancer Research, 2013;73(16):5206-5217. Cancer Research can be contacted at: Amer Assoc Cancer Research, 615 Chestnut St, 17TH Floor, Philadelphia, PA 19106-4404, USA. (American Association for Cancer Research - www.aacr.com; Cancer Research - cancerres.aacrjournals.org/)
The news editors report that additional information may be obtained by contacting H. Matsumoto, Yamaguchi University, Grad Sch Med, Dept. of Urol, Ube, Yamaguchi 755, Japan. Additional authors for this research include Y. Yamamoto, M. Shiota, H. Kuruma, E. Beraldi, H. Matsuyama, A. Zoubeidi and M. Gleave (see also technology.html">Biotechnology).
Keywords for this news article include: Asia, Biotechnology, Japan, Oncology, Yamaguchi, Prostate Cancer, Steroid Receptors, Androgen Receptors, Pre-Trial Research, Cancer Gene Therapy, Prostatic Neoplasms, DNA-Binding Proteins, Transcription Factors, Clinical Trials and Studies
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