7 research outputs found
Pilot experience of simultaneous robotic-assisted partial nephrectomy for bilateral renal tumors-single center analysis
Small Bowel Obstruction Due to an Intramesosigmoid Hernia Diagnosed by Multidetector Row Computed Tomography : A Case Report
Combination therapy with androgen receptor Nāterminal domain antagonist EPIā7170 and enzalutamide yields synergistic activity in ARāV7āpositive prostate cancer
Resistance of castrationāresistant prostate cancer (CRPC) to enzalutamide and abiraterone involves the expression of constitutively active, truncated androgen receptor (AR) splice variants (ARāVs) that lack a Cāterminal ligandābinding domain (LBD). Both fullālength AR and truncated ARāVs require a functional Nāterminal domain (NTD) for transcriptional activity thereby providing rationale for the development of ralaniten (EPIā002) as a firstāināclass antagonist of the ARāNTD. Here, we evaluated the antitumor effect of a nextāgeneration analog of ralaniten (EPIā7170) as a monotherapy or in combination with enzalutamide in prostate cancer cells that express ARāV7 that were resistant to enzalutamide. EPIā7170 had 8ā9 times improved potency compared to ralaniten. Enzalutamide increased levels of ARāV7 and expression of its target genes. Knockdown of ARāV7 restored sensitivity to enzalutamide, indicating a role for ARāV7 in the mechanism of resistance. EPIā7170 inhibited expression of genes transcriptionally regulated by fullālength AR and ARāV7. A combination of EPIā7170 and enzalutamide resulted in synergistic inhibition of proliferation of enzalutamideāresistant cells that was consistent with results from cell cycle and clonogenic assays. In addition, this drug enhanced the antitumor effect of enzalutamide in enzalutamideāresistant CRPC preclinical models. Thus, a combination therapy targeting both the NTD and LBD of AR, and thereby blocking both fullālength AR and ARāVs, has potential for the treatment of enzalutamideāresistant CRPC
Combination therapy with androgen receptor Nāterminal domain antagonist EPIā7170 and enzalutamide yields synergistic activity in ARāV7āpositive prostate cancer
Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy
Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. To address this, we used LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel. Interestingly, LNCaP95-DR cells showed cross-resistance to cabazitaxel. Furthermore, these cells had increased levels of P-glycoprotein (P-gp) and their sensitivity to both docetaxel and cabazitaxel was restored through treatment with tariquidar, a P-gp antagonist. Results generated demonstrated that P-gp mediated cross-resistance between docetaxel and cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), the knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002, an antagonist of the AR amino-terminal domain (NTD), had an inhibitory effect on the proliferation of LNCaP95-DR cells, which was similar to that achieved with the parental LNCaP95 cells. On the other hand, enzalutamide had no effect on the proliferation of either cell line. In conclusion, our results suggested that EPI-002 may be an option for the treatment of AR-V7-driven CRPC, which is resistant to taxanes
Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants
Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of Ī³H2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.Medicine, Faculty ofScience, Faculty ofNon UBCChemistry, Department ofPathology and Laboratory Medicine, Department ofReviewedFacultyOthe