New immunotherapeutic paradigms for castration-resistant prostate cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Galluzzi L
PROVIDER: S-EPMC5178378 | biostudies-literature | 2013 Aug
REPOSITORIES: biostudies-literature
Publications
New immunotherapeutic paradigms for castration-resistant prostate cancer.
Oncoimmunology 20130807 8
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Project description:Castration-resistant prostate cancer (CRPC) is the main challenge for prostate cancer treatment. Recent studies have indicated that extending the treatments to simultaneously targeting different pathways could provide better approaches. To better understand the regulatory functions of different pathways, a system-wide study of CRPC regulation is necessary. For this purpose, we constructed a comprehensive CRPC regulatory network by integrating multiple pathways such as the MEK/ERK and the PI3K/AKT pathways. We studied the feedback loops of this network and found that AKT was involved in all detected negative feedback loops. We translated the network into a predictive Boolean model and analyzed the stable states and the control effects of genes using novel methods. We found that the stable states naturally divide into two obvious groups characterizing PC3 and DU145 cells respectively. Stable state analysis further revealed that several critical genes, such as PTEN, AKT, RAF, and CDKN2A, had distinct expression behaviors in different clusters. Our model predicted the control effects of many genes. We used several public datasets as well as FHL2 overexpression to verify our finding. The results of this study can help in identifying potential therapeutic targets, especially simultaneous targets of multiple pathways, for CRPC.
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Project description:Prostate cancer is a heterogeneous disease where the previous concept of "hormone resistance" has been changed by a new generation of hormonal therapies that have proven efficacy in the castration-resistant setting. The fact is that androgens play a crucial role in the whole clinical course of prostate cancer, even when a patient meets castration-resistance criteria. The development of abiraterone showed how important and clinically meaningful can be to achieve the lowest possible levels of testosterone, and androgen receptor overexpression, mutation, or enhanced crosstalk with other pathways, which can also be targeted with new agents tested in the last few years. New androgen biosynthesis inhibitors have been developed, such as orteronel (TAK-700), but also new antiandrogens (enzalutamide, ARN-509, ODM-201) or even agents with a dual mechanism of action (galeterone). In this review the development of new hormonal therapies following the arrival of abiraterone for the treatment of prostate cancer will be summarized.
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Project description:The treatment landscape of advanced prostate cancer continues to evolve rapidly, with newer and more active drugs being used in earlier phases of the disease based on improved overall survival. After adoption of docetaxel for metastatic castration-sensitive disease, large trials with next-generation androgen receptor-signaling inhibitors (abiraterone, enzalutamide and apalutamide) have demonstrate significant improvements in survival and important secondary endpoints. For non-metastatic castration-resistant prostate cancer, recent phase III placebo-controlled trials with enzalutamide, apalutamide and darolutamide all demonstrated benefits in improving metastasis-free survival. This review aims to summarize the clinical development of darolutamide, a novel next-generation androgen receptor antagonist, including preclinical data, clinical studies and the potential of darolutamide for the treatment of advanced prostate cancer. To date, darolutamide efficacy and tolerability has been demonstrated in the ARAMIS trial, which demonstrated an improvement in metastasis-free survival compared to placebo for non-metastatic castration-resistant prostate cancer patients with a rapid PSA doubling time. Ongoing studies will further evaluate the role of darolutamide in metastatic castration-sensitive prostate cancer in combination with docetaxel (ARASENS trial) and also in other stages of the disease.
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