Several promising targeted-therapeutics for prostate cancer (PCa), primarily affecting the androgen receptor (AR) and the PI3K/AKT/mTOR-pathway, are in various phases of development. However, despite promise, single-agent inhibitors targeting the two pathways have not shown long-term benefits, perhaps due to a complex compensatory cross talk that exists between the two pathways. Combination therapy has thus been proposed to maximize benefit. We have carried out a systematic study of two-drug combination effect of MDV3100 (AR antagonist), BKM120 (PI3K inhibitor), TKI258 (pan RTK inhibitor) and RAD001 (mTOR inhibitor) using various PCa cell lines. We observed strong synergy when AR-positive cells are treated with MDV3100 in combination with any one of the PI3K-pathway inhibitors: TKI258, BKM120, or RAD001. Growth curve based synergy determination combined with Western blot analysis suggested MDV3100+BKM120 to be the most effective in inducing cell death in such conditions. In the case of dual targeting of the PI3K-pathway BKM120+TKI258 combination displayed exquisite sensitivity in all the 5 cell lines tested irrespective of androgen sensitivity, (LNCaP, VCaP, 22Rv1, PC3 and Du145). The effect of blockade with BKM120+TKI258 in PC3 cells was similar to a combination of BKM120 with chemotherapy drug cabazitaxel.Taken together, our observation supports earlier observations that a combination of AR-inhibitor and PI3K-inhibitor is highly synergistic. Furthermore, combining BKM120 with TKI258 has better synergy than BKM120+RAD001 or RAD001+TKI258 in all the lines, irrespective of androgen sensitivity. Finally, BKM120 also displayed synergy when combined with chemotherapy drug cabazitaxel. No antagonism however was observed with any of the drug combinations.
Prostate cancer (PCa) remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT); however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC). With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC) variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258) is a pan receptor tyrosine kinase (RTK) inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR) positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development.
Clomiphene citrate (CC) is a selective estrogen receptor modulator, originally developed in 1956 and introduced into clinical medicine in 1967 for the treatment of female infertility. CC has also been explored for off-label use for male infertility and male hypogonadal symptoms. This article will review the medical literature on CC and its contribution to the treatment of male hypogonadism. A comprehensive review of the literature pertaining to CC through April 2020 was performed through PubMed. We included 52 articles that were relevant to CC. Abstracts and case reports were not included in this comprehensive review. CC as a monotherapy, as well as CC combined with vitamins and other non-Food and Drug Administration-approved substances, has been shown to have mixed results in improving male factor infertility. A variety of questionnaires have been used to describe changes in hypogonadal symptoms with CC treatment. Articles have reported conflicting outcomes regarding improved hypogonadal symptoms with CC treatment. CC is generally considered a safe drug, and the majority of CC studies do not report any significant side effects. Side effects that have been reported include headache, gynecomastia, visual disturbances, dizziness, and mood instability. CC is regarded as an effective therapy for specific patients who suffer from male factor infertility and complain of hypogonadal symptoms. More studies are needed to further validate CC's efficacy for male infertility and hypogonadism.
60 cryptorchid boys (39 unilateral and 21 bilateral) aged between 10 months and 14 years were treated by conservative methods. All boys received an initial therapy of 200 µg GnRH nasal spray (decapeptide) in each nostril three times daily for 4 weeks. Those who did not respond favorably to the GnRH treatment immediately received a follow-up therapy with 1,500 IU or boys over 7 years 2,000 IU of HCG per week for a total of 3 weeks. Immediately after completion of this therapy, the success rate was 80% (65/81 testes decended). 6 months afterwards 6 of the 48 testes suffered a relapse. Thus, 73% of the testicles were still descended 6 months after completion of therapy.
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