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Cancer Drug Resistance 2020年第4期3卷 726-741页

作者： Maristella Bungaro Consuelo Buttigliero Marcello Tucci Medical Oncology University of TurinSan Luigi Gonzaga HospitalOrbassanoTurin 10043Italy Medical Oncology Cardinal Massaia HospitalAsti 14100Italy

In recent years,many therapeutic advances have been made in the management of castration-resistant prostate cancer,with the development and approval of many new *** androgen receptor(AR)is the main driver in prostate cancer growth and progression and the most effective therapeutic agents are still directed against this *** these,new generation hormonal agents(NHA)including enzalutamide,abiraterone acetate,apalutamide,and darolutamide have shown to improve overall survival and quality of life of prostate cancer ***,despite the demonstrated benefit,not all patients respond to treatment and almost all are destined to develop a resistant *** the resistance mechanisms are not fully understood,the most studied ones include the activation of both dependent and independent AR signalling *** findings about multiple growth-promoting and survival pathways in advanced prostate cancer suggest the presence of alternative mechanisms involved in disease progression,and an interplay between these pathways and AR *** this review we discuss the possible mechanisms of primary and acquired resistance to NHA with a focus on AR independent pathways.

关键词： castration-resistant prostate cancer androgen receptor signalling hormonal treatment enzalutamide abiraterone resistance mechanisms

Potential impact of combined inhibition of 3a-oxidoreductases and 5a-reductases on prostate cancer

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Asian Journal of Urology 2019年第1期6卷 50-56页

作者： Michael V.Fiandalo Daniel T.Gewirth James L.Mohler Department of Urology Roswell Park Comprehensive Cancer CenterBuffaloNYUSA Hauptman-Woodward Medical Research Institute BuffaloNYUSA

Prostate cancer(PCa)growth and progression rely on the interaction between the androgen receptor(AR)and the testicular ligands,testosterone and dihydrotestosterone(DHT).Almost all men with advanced PCa receive androgen deprivation therapy(ADT).ADT lowers circulating testosterone levels,which impairs AR activation and leads to PCa ***,ADT is palliative and PCa recurs as castration-recurrent/resistant PCa(CRPC).One mechanism for PCa recurrence relies on intratumoral synthesis of DHT,which can be synthesized using the frontdoor or primary or secondary backdoor *** metabolism inhibitors,such as those targeting 5a-reductase,aldo-keto-reductase family member 3(AKR1C3),or cytochrome P45017A1(CYP17A1)have either failed or produced only modest clinical *** goal of this review is to describe the therapeutic potential of combined inhibition of 5a-reductase and 3a-oxidoreductase enzymes that facilitate the terminal steps of the frontdoor and primary and secondary backdoor pathways for DHT *** of the terminal steps of the androgen metabolism pathways may be a way to overcome the shortcomings of existing androgen metabolism inhibitors and thereby delay PCa recurrence during ADT or enhance the response of CRPC to androgen axis manipulation.

关键词： Androstanediol Dihydrotestosterone Dutasteride 3a-oxidoreductases Androgen deprivation therapy abiraterone

Is there still a place for docetaxel rechallenge in prostate cancer?

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World Journal of Clinical Oncology 2015年第5期6卷 99-103页

作者： Roberto Petrioli Edoardo Francini Giandomenico Roviello Medical Oncology Unit Department of MedicineSurgery and NeurosciencesUniversity of Siena Medical Oncology Unit Policlinico Umberto Ⅰ HospitalUniversity of Rome

Three-weekly docetaxel plus prednisone is the standard first-line cytotoxic treatment for patients with metastatic castrate-resistant prostate cancer(m CRPC). Today, several new treatment options are available for patients with tumor progression after first-line docetaxel: abiraterone, enzalutamide, cabazitaxel, sipuleucel-T immunotherapy, and the radionuclide radium-223. However, despite the evolving scenario in CRPC treatment, the optimal sequencing of the innovative therapies remains unclear. The reintroduction of docetaxel at the occurrence of disease progression after a drug holiday(docetaxel rechallenge) was often proposed, and this chemotherapeutic agent showed to maintain antitumor activity in m CRPC patients. Docetaxel rechallenge may still constitute a valid treatment option mainly for patients with favorable response to first-line docetaxel, at least > 3 mo progression-free interval, age less than 75 years, good performance status, and acceptable docetaxel toxicity. The risk of cumulative toxicity must be evaluated, since sensory neuropathy, nail disorders and fatigue might occur on docetaxel rechallenge.

关键词： abiraterone acetate Docetaxel Prostate cancer Prostate-specific antigen Rechallenge

Developing New Small Molecular Drugs for Prostate Cancer Therapy

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Journal of Cancer Therapy 2013年第4期4卷 86-90页

作者： Tzu-Min Chan Horng-Jyh Harn Tzyy-Wen Chiou Shinn-Zong Lin Department of Life Science and Graduate Institute of Biotechnology National Dong Hwa University Hualien Chinese Taipei Department of Pathology China Medical University Hospital Taichung Chinese Taipei Neuropsychiatry Center China Medical University Hospital Taichung Chinese Taipei

Most of the early prostate cancer has no obvious symptoms, but its malignancy metastasis will cause largely deaths. The treatment options for patients with prostate cancer include traditional surgery, external beam therapy, hormone therapy, small molecular drug and cryosurgery. It was considered non-traditional treatments also can be used in alternative medicines for prostate cancer therapy. There are well-known molecular mechanisms and their pathogenesis, which provide potential targets for drug screening on the prostate cancer. Currently, natural plant extracts or human tissues active ingredients are widely used for the treatment of cancer. Then isolated effective substances in the extract, and further prepared large amounts of small molecule drugs by chemical synthesis. In this review, we summarized four small molecular drugs, abiraterone, docetaxel, isochaihulactone and butylidenephthalide, and their detailed anti-tumor mechanisms. These indicate that small molecular drug is a very efficient way and can be used for prostate cancer treatment.

关键词： Prostate Cancer Small Molecular Drugs abiraterone Docetaxel Isochaihulactone Butylidenephthalide

Future Directions in Metastatic Castration Resistant Prostate Cancer (mCRPC): Clinical Rationale and Use of New-Generation Hormonal Therapies

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Journal of Cancer Therapy 2013年第3期4卷 698-703页

作者： Paolo Grassi Elena Verzoni Rosanna Montone Isabella Testa Enrico Garanzini Pamela Biondani Sara Pusceddu Filippo de Braud Giuseppe Procopio Department of Medical Oncology Fondazione IRCCS Istituto Nazionale Tumori Milan Italy

Several recent studies in mCRPC have identified the mechanisms of tumoral growth after the disease becomes unresponsive to standard hormonal therapy. These studies have highlighted the importance of residual intratumoral androgens in maintaining androgen receptor (AR) transcriptional activity in mCRPC [1]. Based on this findings, it has been possible to develop drugs, blocking the key enzyme in the biosynthesis of androgens through the inhibition of cytochrome p450 17 (CYP17) such as abiraterone Acetate (AA) and drugs which directly target the AR including Enzalutamide (E) and Orteronel. Before this new knowledge, mCRPC treatment benefited from chemotherapy with taxanes. Recently a new taxane, Cabazitaxel (C), was approved in second line setting in association with prednisone. Retrospective analyses have tried to clarify the current role of chemotherapy in mCRPC patients and the right chemotherapy sequence of use of chemotherapy compared to new hormonal agents. Moreover, it would be important to address changes in the endpoints used in clinical trials, based on the stage of disease including the presence tumor-related symptoms, in order to identify the right therapeutic strategy.

关键词： Metastatic Castration Resistant Prostate Cancer abiraterone Cabazitaxel Enzalutamide