Abiraterone acetate: a promising drug for the treatment of castration-resistant prostate cancer.
ABSTRACT Abiraterone acetate (CB7630), a pregnenolone analog, is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency. In clinical studies, abiraterone acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer. The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily. Side effects are minimal and mostly associated with secondary mineralocorticoid excess, owing to a compensatory increase in upstream steroids, such as deoxycorticosterone and corticosterone. These include hypertension, hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist, such as eplerenone, or low-dose corticosteroids. Currently, abiraterone acetate is being tested in a Phase III trial for men with progressive castration-resistant prostate cancer who are chemotherapy naive. A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis.
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ABSTRACT: Background:Taxanes are routinely used for the treatment of prostate cancer, however the majority of patients eventually develop resistance. We investigated the potential efficacy of EL102, a novel toluidine sulphonamide, in pre-clinical models of prostate cancer.Methods:The effect of EL102 and/or docetaxel on PC-3, DU145, 22Rv1 and CWR22 prostate cancer cells was assessed using cell viability, cell cycle analysis and PARP cleavage assays. Tubulin polymerisation and immunofluorescence assays were used to assess tubulin dynamics. CWR22 xenograft murine model was used to assess effects on tumour proliferation. Multidrug-resistant lung cancer DLKPA was used to assess EL102 in a MDR1-mediated drug resistance background.Results:EL102 has in vitro activity against prostate cancer, characterised by accumulation in G2/M, induction of apoptosis, inhibition of Hif1α, and inhibition of tubulin polymerisation and decreased microtubule stability. In vivo, a combination of EL102 and docetaxel exhibits superior tumour inhibition. The DLKP cell line and multidrug-resistant DLKPA variant (which exhibits 205 to 691-fold greater resistance to docetaxel, paclitaxel, vincristine and doxorubicin) are equally sensitive to EL102.Conclusion:EL102 shows potential as both a single agent and within combination regimens for the treatment of prostate cancer, particularly in the chemoresistance setting.British Journal of Cancer advance online publication, 19 September 2013; doi:10.1038/bjc.2013.537 www.bjcancer.com.British Journal of Cancer 09/2013; 109(8). DOI:10.1038/bjc.2013.537 · 4.82 Impact Factor
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ABSTRACT: Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.05/2013; 2013:981684. DOI:10.1155/2013/981684
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ABSTRACT: Prostate cancer (PCa) is the most common cancer in men in developed countries. Epidemiological studies have associated high blood-cholesterol levels with an increased risk of PCa, whilst cholesterol-lowering drugs (statins) reduce the risk of advanced PCa. Furthermore, normal prostate epithelial cells have an abnormally high cholesterol content, with cholesterol levels increasing further during progression to PCa. In this review, we explore why and how this occurs. Concurrent to this observation, intense efforts have been expended in cardiovascular research to better understand the regulators of cholesterol homeostasis. Here, we apply this knowledge to elucidate the molecular mechanisms driving the accumulation of cholesterol in PCa. For instance, recent evidence from our group and others show that major signalling players in prostate growth and differentiation, such as androgens and Akt, modulate the key transcriptional regulators of cholesterol homeostasis to enhance cholesterol levels. This includes modulating central carbon metabolism to sustain greater lipid synthesis. Perturbations in cholesterol homeostasis appear to be maintained even when PCa approaches the advanced, 'castration-resistant' state. Overall, this provides a link between cholesterol accumulation and PCa cell-growth. Given there is currently no cure for castration-resistant PCa, could cholesterol metabolism be a novel target for PCa therapy? Overall, this review presents a picture that cholesterol metabolism is important for PCa development: growth-promoting factors stimulate cholesterol accumulation, which in turn presents a possible target for chemotherapy. Consequently, we recommend future investigations, both to better elucidate the mechanisms driving this accumulation and applying it in novel chemotherapeutic strategies.Biochimica et Biophysica Acta 01/2013; 1835(2). DOI:10.1016/j.bbcan.2013.01.002 · 4.66 Impact Factor