Abstract
Simple SummaryProstate cancer treatment has improved over the last 20 years; despite this, approximately 33,000 men died from the disease in the United States in 2020. In view of this, new treatment options are urgently needed for advanced prostate cancer. Eradicating cancer cells by triggering apoptosis (a form of cell death) is an attractive strategy, and a novel class of drugs, called BH3 mimetics, have been designed to do this. They have been shown to work for blood cancers and may also have a role in solid cancers. Herein, we discuss cell death, focusing on the intrinsic apoptosis pathway, and consider how BH3 mimetics may be used to help treat prostate cancer.Despite major improvements in the management of advanced prostate cancer over the last 20 years, the disease remains invariably fatal, and new effective therapies are required. The development of novel hormonal agents and taxane chemotherapy has improved outcomes, although primary and acquired resistance remains problematic. Inducing cancer cell death via apoptosis has long been an attractive goal in the treatment of cancer. Apoptosis, a form of regulated cell death, is a highly controlled process, split into two main pathways (intrinsic and extrinsic), and is stimulated by a multitude of factors, including cellular and genotoxic stress. Numerous therapeutic strategies targeting the intrinsic apoptosis pathway are in clinical development, and BH3 mimetics have shown promising efficacy for hematological malignancies. Utilizing these agents for solid malignancies has proved more challenging, though efforts are ongoing. Molecular characterization and the development of predictive biomarkers is likely to be critical for patient selection, by identifying tumors with a vulnerability in the intrinsic apoptosis pathway. This review provides an up-to-date overview of cell death and apoptosis, specifically focusing on the intrinsic pathway. It summarizes the latest approaches for targeting the intrinsic apoptosis pathway with BH3 mimetics and discusses how these strategies may be leveraged to treat prostate cancer.
Highlights
Prostate cancer is the most frequently occurring cancer in men in the Western world, and was responsible for approximately 330,000 deaths in the United States in 2020 [1,2]
The majority of advanced prostate cancers respond to androgen deprivation therapy (ADT), but they inevitably progress from castration-sensitive prostate cancer (CSPC) to castration-resistant prostate cancer (CRPC), which is driven by a range of androgen receptor (AR)-dependent and independent mechanisms (e.g., AR amplification and neuroendocrine trans-differentiation, respectively) [12]
Life-prolonging treatments for advanced CRPC include taxane-based chemotherapy, novel hormonal agents, a bone specific alpha-emitting radionuclide, and an autologous cellular immunotherapy [15,16,17,18,19,20,21,22,23]. These agents were initially approved for advanced CRPC, though subsequent clinical trials have shown that docetaxel and novel hormonal agents are effective when utilized earlier in the disease course for advanced CSPC [24,25,26,27,28,29]
Summary
Prostate cancer is the most frequently occurring cancer in men in the Western world, and was responsible for approximately 330,000 deaths in the United States in 2020 [1,2]. As such, targeting the intrinsic apoptosis pathway is an attractive therapeutic strategy for advanced prostate cancer, though molecular characterization and the identification of tumors with a dependency and/or vulnerability will be critical to best utilize this approach. RIPK3 has been shown to be downregulated in prostate cancer, and its overexpression suppressed prostate cancer cell migration and invasion [66] Ferroptosis, another form of RCD, is characterized by iron-dependent lipid peroxidation, and a recent study demonstrated anti-tumor activity in prostate cancer cell line mouse xenograft models with ferroptosis inducing agents [67]
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