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Recent Advances on the Progressive Mechanism and Therapy in Castration-Resistant Prostate Cancer

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Recent Advances on the Progressive Mechanism and Therapy in Castration-Resistant Prostate Cancer Journal name: OncoTargets and Therapy Article Designation: Review Year: 2018 Volume: 11 OncoTargets and Therapy Dovepress Running head verso: Wang et al Running head recto: Novel research advancement on mechanism and therapy in CRPC open access to scientific and medical research DOI: 159777 Open Access Full Text Article REVIEW Recent advances on the progressive mechanism and therapy in castration-resistant prostate cancer Keshan Wang1 Background: Although there have been great advances in mechanisms and therapeutic methods Hailong Ruan1 of prostate cancer, the mortality rate of prostate cancer remains high. The castration-resistant Tianbo Xu1 prostate cancer (CRPC), which develops from hormone-sensitive prostate cancer, foreshadows a Lei Liu1 more dismal outcome. Concomitant with the researches in the mechanism of CRPC and therapy Di Liu1 for CRPC, more and more landmark progress has been made in recent years. Hongmei Yang2 Methods: A number of clinical and experimental studies were reviewed to indicate the novel advancement in the progressive mechanism and therapy of CRPC. Xiaoping Zhang1 Results: The androgen receptor (AR) is still a vital driver in the progression of CRPC, while other Ke Chen1 multiple mechanisms also contribute to this progression, such as tumor immunity, cancer stem 1Department of Urology, Union cells, epithelial–mesenchymal transition and DNA repair disorder. In terms of the therapeutic Hospital, Tongji Medical College, Huazhong University of Science and methods of CRPC, chemotherapy with drugs, such as docetaxel, has been the first-line therapy Technology, Wuhan 430022, China; for CRPC for many years. Besides, newer agents, which target some of the above mechanisms, For personal use only. 2 Department of Pathogenic Biology, show additional overall survival benefits for CRPC patients. These therapies include drugs School of Basic Medicine, Huazhong University of Science and Technology, targeting the androgen axis pathway (androgen synthesis, androgen receptor splice variants, Wuhan 430030, China coactivators of AR and so on), PI3K-AKT pathway, WNT pathway, DNA repair, rearrangement of ETS gene, novel chemotherapy and immunotherapy, bone metastasis therapy and so on. Understanding these novel findings on the mechanisms of CRPC and the latest potential CRPC therapies will direct us for further exploration of CRPC. Conclusion: Through comprehensive consideration, the predominant mechanism of CRPC might be the AR signal axis concomitant with tumor microenvironment, stress, immunity, tumor microenvironment and so on. For CRPC therapy, targeting the AR axis pathway and chemotherapy are the first-line treatments at present. However, with the advancements in OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 24-Dec-2018 CRPC therapy made by the researchers, other novel potential methods will occupy more and more important position in the treatment of CRPC, especially the therapies targeting the tumor microenviroment, tumor immunity and DNA repair and so on. Keywords: CRPC, androgen receptor, tumor immunity, mechanism, therapy Introduction Prostate cancer, which has the highest incidence among male malignancies in European and American countries, seriously threatens human health and affects the patients’ Correspondence: Xiaoping Zhang; life quality.1 According to the statistics, the incidence and mortality rates of prostate Ke Chen Department of Urology, Union Hospital, cancer have been increasing every year with the rapid increase in Chinese aging Tongji Medical College, Huazhong society. Specifically, the castration-resistant prostate cancer (CRPC), which develops University of Science and Technology from hormone-sensitive prostate cancer, has a much higher mortality rate compared (HUST), 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China with prostate cancer.2 Tel +86 27 8535 1625 The clinical prognosis of CRPC patients is still unsatisfactory despite the fact that Email [email protected]; [email protected] several important mechanisms and therapy advancements of CRPC have been reported. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 3167–3178 3167 Dovepress © 2018 Wang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/OTT.S159777 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Wang et al Dovepress New drugs such as docetaxel, abiraterone and enzalutamide Abiraterone acetate, one of the most common medicines for that could delay, to a certain extent, the development of CRPC, is a kind of inhibitor of CYP17 and has been proved CRPC are still the main therapy agents for CRPC in clinical to improve the prognosis of CRPC patients.5 practice.3 In recent years, numerous progressive mechanisms and therapeutic targets of CRPC have been found due to the The synthesis of intratumoral androgen efforts of the researchers. In this paper, we will review the According to previous researches, the levels of T and dihy- novel research advancements of the progressive mechanisms drotestosterone are mainly dependent on the synthesis of and therapy in CRPC. intratumoral androgen, which is based on the conversion of dehydroepiandrosterone in the prostate cancer tissues after The progressive mechanisms of androgen deprivation therapy (ADT). This kind of intratu- CRPC moral androgen synthesis mostly relies on some steroidogenic enzymes such as hydroxysteroid dehydrogenase (HSD)17β, At present, gene alteration in the androgen axis and the HSD3β and steroid-5α-reductase.6 kinase-dependent signal pathways are the most important The activities of steroidogenic enzymes are also cor- mechanisms of CRPC genesis and development. However, related with the expression of some other cytokines. accumulated evidences have indicated that tumor immunity, Transforming growth factor beta could regulate the synthesis cancer stem cells (CSCs), epithelial–mesenchymal transition of the intratumoral androgen by upregulating HSD3β and (EMT), DNA repairing disorder and other mechanisms might downregulating HSD17β; insulin-like growth factor (IGF)-β also participate in the progress of CRPC (Figure 1). could promote the synthesis of intratumoral androgen by increasing the expression of CYP17, AKR1C3 and HSD17β, De novo synthesis of androgen so as to improve the development of CRPC.7 Moreover, The levels of intratumoral androgen in some CRPC patients activin A, interleukin (IL)-6 and IGF2 could also regulate were higher than in the primary prostate cancer patients, the activities of the steroidogenic enzymes.8–10 For personal use only. although serum testosterone (T) was at the castration level Recently, it was indicated that arachidonic acid could 4 (,1.7 nmol/L) in these CRPC patients. According to the induce the synthesis of StAR, which is bound to hormone- recent research, the mechanisms of de novo synthesis of sensitive lipase and transforms the free cholesterol into androgen are discussed next. androgen in the steroid synthesis-related cells.11 Cytochrome P450 family-induced synthesis Elevation of the expression level of androgen The synthesis of T and dihydrotestosterone depends on the metabolism–related genes cytochrome P450 (CYP) family. CYP17, a member of the The upregulation of the expression level of the androgen CYP family, has been proved to play a vital role in CRPC. metabolism–related genes, such as HSD3β2, AKR1C3, OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 24-Dec-2018 $5UHODWHGSDWKZD\ 'HQRYRV\QWKHVLVRIDQGURJHQ $PSOLILFDWLRQĹ &<3IDPLO\LQGXFHGV\QWKHVLV 7UDQVFULSWLRQĹ 6\QWKHVLVRILQWUDWXPRUDODQGURJHQ <%(67$71)κ%DQGVRRQ $59V 6WHURLGJHQHWLFHQ]\PHV +6'β+6'β65'αDQGVRRQ ,QWHUDFWLRQRI$5ZLWKRWKHU '+($ '+77 PROHFXOHV &\WRNLQHV 7*)β,*)β$FWLYLQ$,/,*)DQGVRRQ ,'1X3&$0.. $QGURJHQPHWDEROLVPUHODWHGJHQHV $5PROHFXODUFKDSHURQH +63 +6'β$.5&65'α$.5&8*7% $5FRUHJXODWRU\IDFWRU 1&2$1&2$1&2$)2;$)/,, '1$UHSDLUDQGFHOO .LQDVHGHSHQGHQW (07DQGFDQFHUVWHPFHOOV F\FOH±UHODWHGPROHFXOHV &53& 3URVWDWH SDWKZD\ $5&&/&&567$7 FDQFHU 3$53V%5&$ ,QDFWLYDWLRQRI37(13,. (07 &6&V &HOOF\FOHPROHFXOHV 57.6). +VS67$77ZLVWDQGVRRQ &GNF\FOLQ$VNS Figure 1 Main progressive mechanisms of CRPC. Abbreviations: AR, androgen receptor; ARVs, AR splice variants; CRPC, castration-resistant prostate cancer; CSCs, cancer stem cells; CYP, cytochrome P450; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; EMT, epithelial–mesenchymal transition; HSP, heat shock protein; T, testosterone; HSP, heat shock protein. 3168 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Novel research advancement on mechanism and therapy in CRPC SRD5α, AKR1C2 and UGT2B15, also plays an important of the combination between AR and its ligands, while the role in the development of CRPC.12 mutation of F876L region in AR gene has been demonstrated to be correlated with enzalutamide resistance in CRPC.25 The regulatory effect of tumor microenvironment
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