In addition, cross-species genome-wide regulatory network interactome analyses for human and mouse prostate cancer not only identified FOXM1 and CENPF as synergistic master regulators of prostate cancer malignancy Aytes et al. However, unlike the success of monotherapy or combination therapy in other cancer types, effective strategies have yet to emerge in the treatment of prostate cancer despite the development of checkpoint blockade immunotherapy, as discussed above Kwon et al.
Preclinical mechanistic studies have revealed novel combination strategies for the treatment of prostate cancer, leading to numerous clinical trials Table 3. First, targeting androgen signaling in combination with novel targeted therapies is being explored in androgen-responsive tumors. Further clinical trials are needed to evaluate the efficacy of these treatment regimens in human prostate cancer patients. Second, ADT, which modulates the priming of tumor-specific adaptive immune responses Mercader et al. A longitudinal study of adenocarcinoma to NEPC or small cell progression would allow us to identify key driver genes in these processes and provide novel therapeutic targets for combination therapy.
Another promising avenue for new therapeutic strategies for prostate cancer is targeting DNA damage repair pathways. Defects in the MMR pathway, which are associated with microsatellite instability and high mutational load, were shown to correlate with clinical response to the anti-PD-1 agent pembrolizumab across 12 solid cancer types, including prostate cancer, resulting in FDA approval for pembrolizumab in MMR-defective cancers Le et al.
Immunotherapy has transformed the standard of care for several malignancies, and a deeper understanding of the effects of conventional and targeted therapies on anti-tumor immunity has informed the design of combinations showing increased rates of complete and durable clinical responses Gotwals et al. In various preclinical cancer models, potent synergistic effects have been observed for agents targeting the immunosuppressive TME MDSCs, TAMs, and Tregs in combination with checkpoint inhibitors, prompting the launch of new clinical trials.
There are challenges associated with the development of effective combinations of conventional therapies, targeted therapies, and immunotherapies: Comprehensive understanding of the effects of these therapies on the patient's immune system is lacking; the efficacy, toxicity, and tolerability associated with combination therapies need to be determined through optimization of dosing regimens and sequencing, and approaches for prioritizing various combination therapies need to be developed Gotwals et al.
Given that the cancer genome and the TME coevolve during disease progression and treatment, it is important to model these interactions in refined genetic model systems as well as perform longitudinal omics analyses of patients under treatment and subsequently link all of these profiling data to clinical information to elucidate how genomic information and the TME landscape can inform and improve patient care Chin et al.
A deep understanding of prostate cancer biology and genomics, the advent of sophisticated profiling technology and artificial intelligence-based decision systems, and the capacity for multiple-armed adaptive clinical trials with longitudinal profiling all place the field in a position to save and improve the lives of many men with this disease. We thank Christopher J. Logothetis, Filippo G.
Giancotti, and Prasenjit Dey for critical reading of the manuscript and insightful comments. Spring 2 and Ronald A. Previous Section Next Section. Prostate anatomy The human and mouse prostates exhibit anatomic differences as well as cellular similarities Fig. Figure 1. Prostate neoplasia Malignant transformation of the prostate follows a multistep process, initiating as prostatic intraepithelial neoplasia PIN followed by localized prostate cancer and then advanced prostate adenocarcinoma with local invasion, culminating in metastatic prostate cancer Fig.
Figure 2. Metastatic prostate cancer Metastatic disease is the leading cause of prostate cancer-associated deaths. Model systems Many model systems have been developed to study the genetics and biology of prostate cancer. View this table: In this window In a new window. Table 1. Androgen pathway AR signaling plays a central role in the development and function of the prostate. Epigenetic deregulation Deregulation of genes controlling epigenetic processes involved in DNA modification e.
Pathologic and genomic heterogeneity Newly diagnosed prostate cancer commonly presents as multifocal disease with histopathologically distinct foci. Functional heterogeneity in prostate cancer cells Prostate cancer heterogeneity also manifests on the functional level within the cancer cell population, particularly with respect to differentiation status and lineage plasticity.
Cellular heterogeneity in the TME Significant intratumoral heterogeneity is also reflected in the diversity of cell types and the composition of the extracellular matrix comprising the TME. Figure 3. Table 2. Cancer immunotherapy Intensive effort is focused on agents that modulate the immune response through the use of antibodies, small-molecule inhibitors, engineered immune cells, vaccines, and viruses to stimulate the patient's immune system to attack and destroy cancer cells.
Cancer cell-intrinsic mechanisms conferring therapeutic resistance Various cancer cell-intrinsic mechanisms involving genetics, epigenetics, and metabolomics can dictate therapeutic responses and shape the composition of the TME. Cell-intrinsic mechanisms of immunoresistance Several cell-intrinsic mechanisms of immunoresistance have been identified in preclinical models and patients receiving immunotherapy, although most of these observations were in cancer types other than prostate cancer Pitt et al. TME-driven mechanisms of resistance to conventional and novel cancer therapies Stroma—epithelium interactions play critical roles in the development of the prostate gland Cunha et al.
TME-mediated chemoresistance With respect to chemoresistance mechanisms, WNT16B expression is induced in the TME after cytotoxic chemotherapy, which in turn activates WNT signaling in prostate cancer cells in a paracrine manner, promoting chemoresistance and tumor progression Sun et al. Table 3. Selective clinical trials in prostate cancer. Prognostic determination in newly diagnosed prostate cancer An enduring unmet need is the accurate management of newly diagnosed prostate cancer.
Science-driven therapeutic development The rapid development in computational approaches has identified and will continue to identify novel driver genes in prostate cancer.
Previous Section. Conditional loss of Nkx3. Mol Cell Biol 22 : — En route to metastasis: circulating tumor cell clusters and epithelial-to-mesenchymal transition. Trends Cancer 1 : 44 — Google Scholar. Epigenetics in prostate cancer. Prostate Cancer : Medline Google Scholar. Alix-Panabieres C , Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer 14 : — CrossRef Medline Google Scholar.
Circulating tumor cells and circulating tumor DNA. Annu Rev Med 63 : — Allis CD , Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet 17 : — B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature : — Genes Dev 27 : — Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts.
Proc Natl Acad Sci : — Mol Cell 59 : — Mortality results from a randomized prostate-cancer screening trial. N Engl J Med : — Treatment outcomes and tumor loss of heterozygosity in germline DNA repair-deficient prostate cancer. Eur Urol 72 : 34 — AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. Clinical significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol 35 : — Examining the utility of patient-derived xenograft mouse models.
Nat Rev Cancer 15 : — Fc-Optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors.
Immunity 46 : — CrossRef Google Scholar. The long tail of oncogenic drivers in prostate cancer. Nat Genet 50 : — Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell : — Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. BET bromodomain inhibitors enhance efficacy and disrupt resistance to AR antagonists in the treatment of prostate cancer. Mol Cancer Res 14 : — Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer.
Nat Commun 8 : Histone modifications and cancer. Cold Spring Harb Perspect Biol 8 : a Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 4 : Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer. Clin Cancer Res 9 : — Cancer Cell 25 : — Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer.
Clin Cancer Res 21 : — Punctuated evolution of prostate cancer genomes. Nat Genet 44 : — The emergence of precision urologic oncology: a collaborative review on biomarker-driven therapeutics. Eur Urol 71 : — The reactive stroma microenvironment and prostate cancer progression.
Endocr Relat Cancer 19 : R — R Definition of molecular determinants of prostate cancer cell bone extravasation. Cancer Res 73 : — Tumour heterogeneity in the clinic. Enzalutamide in metastatic prostate cancer before chemotherapy. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol 35 : 40 — Beltran H , Demichelis F. Prostate cancer: intrapatient heterogeneity in prostate cancer.
Nat Rev Urol 12 : — Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov 1 : — A phase 2 study of the aurora kinase A inhibitor alisertib for patients with neuroendocrine prostate cancer NEPC. Ann Oncol 27 : LBA Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.
Prostate cancer - Wikipedia
Nat Med 22 : — Benafif S , Eeles R. Genetic predisposition to prostate cancer. Br Med Bull : 75 — A review of prostate cancer genome wide association studies GWAS.
Cancer Epidemiol Biomarkers Prev 27 : — Patient-derived xenografts undergo mouse-specific tumor evolution. Nat Genet 49 : — Expression signature of the mouse prostate.