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Radiation therapy (RT) remains an integral component of modern oncology care, with most cancer patients receiving radiation as a part of their treatment plan. The main goal of ionizing RT is to control the local tumor burden by inducing DNA damage and apoptosis within the tumor cells. The advancement in RT, including intensity-modulated RT (IMRT), stereotactic body RT (SBRT), image-guided RT, and proton therapy, have increased the efficacy of RT, equipping clinicians with techniques to ensure precise and safe administration of radiation doses to tumor cells. In this review, we present the technological advancement in various types of RT methods and highlight their clinical utility and associated limitations. This review provides insights into how RT modulates innate immune signaling and the key players involved in modulating innate immune responses, which have not been well documented earlier. Apoptosis of cancer cells following RT triggers immune systems that contribute to the eradication of tumors through innate and adoptive immunity. The innate immune system consists of various cell types, including macrophages, dendritic cells, and natural killer cells, which serve as key mediators of innate immunity in response to RT. This review will concentrate on the significance of the innate myeloid and lymphoid lineages in anti-tumorigenic processes triggered by RT. Furthermore, we will explore essential strategies to enhance RT efficacy. This review can serve as a platform for researchers to comprehend the clinical application and limitations of various RT methods and provides insights into how RT modulates innate immune signaling.

Improved clinical predictors for disease progression are needed for localised prostate cancer, since only a subset of patients develop recurrent or refractory disease after first-line treatment. Therefore, we undertook an unbiased analysis to identify RNA biomarkers associated with metastatic progression after prostatectomy. Prostate cancer samples from patients treated with radical prostatectomy at three academic institutions were analysed for gene expression by a high-density Affymetrix GeneChip platform, encompassing more than 1 million genomic loci. In a discovery cohort, all protein-coding genes and known long non-coding RNAs were ranked by fold change in expression between tumours that subsequently metastasised versus those that did not. The top ranked gene was then validated for its prognostic value for metastatic progression in three additional independent cohorts. 95% of the gene expression assays were done in a Clinical Laboratory Improvements Amendments certified laboratory facility. All genes were assessed for their ability to predict metastatic progression by receiver-operating-curve area-under-the-curve analyses. Multivariate analyses were done for the primary endpoint of metastatic progression, with variables including Gleason score, preoperative prostate-specific antigen concentration, seminal vesicle invasion, surgical margin status, extracapsular extension, lymph node invasion, and expression of the highest ranked gene. 1008 patients were included in the study: 545 in the discovery cohort and 463 in the validation cohorts. The long non-coding RNA SChLAP1 was identified as the highest-ranked overexpressed gene in cancers with metastatic progression. Validation in three independent cohorts confirmed the prognostic value of SChLAP1 for metastatic progression. On multivariate modelling, SChLAP1 expression (high vs low) independently predicted metastasis within 10 years (odds ratio [OR] 2·45, 95% CI 1·70–3·53; p<0·0001). The only other variable that independently predicted metastasis within 10 years was Gleason score (8–10 vs 5–7; OR 2·14, 95% CI 1·77–2·58; p<0·0001). We identified and validated high SChLAP1 expression as significantly prognostic for metastatic disease progression of prostate cancer. Our findings suggest that further development of SChLAP1 as a potential biomarker, for treatment intensification in aggressive prostate cancer, warrants future study. Prostate Cancer Foundation, National Institutes of Health, Department of Defense, Early Detection Research Network, Doris Duke Charitable Foundation, and Howard Hughes Medical Institute.

Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet. Prostate cancer progression may be enhanced by a high-fat diet. Here the authors show that a diet high in saturated fats enhance the MYC-driven transcriptional program, a feature that independently predicts prostate cancer progression and death.

Postoperative radiotherapy has an important role in the treatment of prostate cancer, but personalised patient selection could improve outcomes and spare unnecessary toxicity. We aimed to develop and validate a gene expression signature to predict which patients would benefit most from postoperative radiotherapy. Patients were eligible for this matched, retrospective study if they were included in one of five published US studies (cohort, case-cohort, and case-control studies) of patients with prostate adenocarcinoma who had radical prostatectomy (with or without postoperative radiotherapy) and had gene expression analysis of the tumour, with long-term follow-up and complete clinicopathological data. Additional treatment after surgery was at the treating physician’s discretion. In each cohort, patients who had postoperative radiotherapy were matched with patients who had not had radiotherapy using Gleason score, prostate-specific antigen concentration, surgical margin status, extracapsular extension, seminal vesicle invasion, lymph node invasion, and androgen deprivation therapy. We constructed a matched training cohort using patients from one study in which we developed a 24-gene Post-Operative Radiation Therapy Outcomes Score (PORTOS). We generated a pooled matched validation cohort using patients from the remaining four studies. The primary endpoint was the development of distant metastasis. In the training cohort (n=196), among patients with a high PORTOS (n=39), those who had radiotherapy had a lower incidence of distant metastasis than did patients who did not have radiotherapy, with a 10-year metastasis rate of 5% (95% CI 0–14) in patients who had radiotherapy (n=20) and 63% (34–80) in patients who did not have radiotherapy (n=19; hazard ratio [HR] 0·12 [95% CI 0·03–0·41], p<0·0001), whereas among patients with a low PORTOS (n=157), those who had postoperative radiotherapy (n=78) had a greater incidence of distant metastasis at 10 years than did their untreated counterparts (n=79; 57% [44–67] vs 31% [20–41]; HR 2·5 [1·6–4·1], p<0·0001), with a significant treatment interaction (pinteraction<0·0001). The finding that PORTOS could predict outcome due to radiotherapy treatment was confirmed in the validation cohort (n=330), which showed that patients who had radiotherapy had a lower incidence of distant metastasis compared with those who did not have radiotherapy, but only in the high PORTOS group (high PORTOS [n=82]: 4% [95% CI 0–10] in the radiotherapy group [n=57] vs 35% [95% CI 7–54] in the no radiotherapy group [n=25] had metastasis at 10 years; HR 0·15 [95% CI 0·04–0·60], p=0·0020; low PORTOS [n=248]: 32% [95% CI 19–43] in the radiotherapy group [n=108] vs 32% [95% CI 22–40] in the no radiotherapy group [n=140]; HR 0·92 [95% CI 0·56–1·51], p=0·76), with a significant interaction (pinteraction=0·016). The conventional prognostic tools Decipher, CAPRA-S, and microarray version of the cell cycle progression signature did not predict response to radiotherapy (pinteraction>0·05 for all). Patients with a high PORTOS who had postoperative radiotherapy were less likely to have metastasis at 10 years than those who did not have radiotherapy, suggesting that treatment with postoperative radiotherapy should be considered in this subgroup. PORTOS should be investigated further in additional independent cohorts. None.

Prostate cancer (PCa) is the second-leading cause of cancer-related deaths in men. PCa cells require androgen receptor (AR) signaling for their growth and survival. Androgen deprivation therapy (ADT) is the preferred treatment for patients with locally advanced and metastatic PCa disease. Despite their initial response to androgen blockade, most patients eventually will develop metastatic castration-resistant prostate cancer (mCRPC). Bone metastases are common in men with mCRPC, occurring in 30% of patients within 2 years of castration resistance and in >90% of patients over the course of the disease. Patients with mCRPC-induced bone metastasis develop lesions throughout their skeleton; the 5-year survival rate for these patients is 47%. Bone-metastasis-induced early changes in the bone that proceed the osteoblastic response in the bone matrix are monitored and detected via modern magnetic resonance and PET/CT imaging technologies. Various treatment options, such as targeting osteolytic metastasis with bisphosphonates, prednisone, dexamethasone, denosumab, immunotherapy, external beam radiation therapy, radiopharmaceuticals, surgery, and pain medications are employed to treat prostate-cancer-induced bone metastasis and manage bone health. However, these diagnostics and treatment options are not very accurate nor efficient enough to treat bone metastases and manage bone health. In this review, we present the pathogenesis of PCa-induced bone metastasis, its deleterious impacts on vital organs, the impact of metastatic PCa on bone health, treatment interventions for bone metastasis and management of bone- and skeletal-related events, and possible current and future therapeutic options for bone management in the continuum of prostate cancer disease.

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P < 0.001) and ETS (P = 0.02) expression, decreased SPINK1 expression (P < 0.001), and basal-like (P < 0.001) molecular subtypes. After adjusting for confounders, the AAM group was associated with higher expression of CRYBB2, GSTM3, and inflammation genes (IL33, IFNG, CCL4, CD3, ICOSLG), and lower expression of mismatch repair genes (MSH2, MSH6) (p < 0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. EAM group was associated with higher levels of fatty acid metabolism, DNA repair, and WNT/beta-catenin signaling. Based on cell lines data, AAM were predicted to have higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM.Walter Rayford, Alp Tuna Beksac et al. investigated gene expression alterations in African-American and European-American men who underwent radical prostatectomy for prostate cancer. The observed differences include higher expression of inflammation genes and lower expression of mismatch repair genes in African-American men.

Heat shock protein 90 (HSP90) is a molecular chaperone protein essential for cellular survival. Functionally, HSPs promote proper protein folding, prevent misfolding, and restore three-dimensional protein structure which is critical following toxic cellular stresses. Recently, targeting HSP90 pharmacologically has gained traction in cancer therapy. Oncogenic cells depend on their ability to withstand endogenous (anoxia, nutrient deprivation, pH changes, and deranged signaling pathways) and exogenous (chemotherapy and radiation therapy) stressors for survival. Pharmacological inhibition of HSP90 destabilizes proteins and leads to degradation through the proteasome. This article will review the utility of HSP90 inhibition, as well as the current adoption in clinical trials and practice.

Currently there is controversy surrounding the optimal way to treat patients with prostate cancer in the post-prostatectomy setting. Adjuvant therapies carry possible benefits of improved curative results, but there is uncertainty in which patients should receive adjuvant therapy. There are concerns about giving toxicity to a whole population for the benefit of only a subset. We hypothesized that making post-prostatectomy treatment decisions using genomics-based risk prediction estimates would improve cancer and quality of life outcomes. We developed a state-transition model to simulate outcomes over a 10 year horizon for a cohort of post-prostatectomy patients. Outcomes included cancer progression rates at 5 and 10 years, overall survival, and quality-adjusted survival with reductions for treatment, side effects, and cancer stage. We compared outcomes using population-level versus individual-level risk of cancer progression, and for genomics-based care versus usual care treatment recommendations. Cancer progression outcomes, expected life-years (LYs), and expected quality-adjusted life-years (QALYs) were significantly different when individual genomics-based cancer progression risk estimates were used in place of population-level risk estimates. Use of the genomic classifier to guide treatment decisions provided small, but statistically significant, improvements in model outcomes. We observed an additional 0.03 LYs and 0.07 QALYs, a 12% relative increase in the 5-year recurrence-free survival probability, and a 4% relative reduction in the 5-year probability of metastatic disease or death. The use of genomics-based risk prediction to guide treatment decisions may improve outcomes for prostate cancer patients. This study offers a framework for individualized decision analysis, and can be extended to incorporate a wide range of personal attributes to enable delivery of patient-centered tools for informed decision-making.

In this Review, the authors discuss the novel, technologically advanced radiotherapy modalities for the primary treatment of men with prostate cancer. Advancements in image-guided and intensity-modulated techniques are discussed, focusing on how these modalities contributed to the development of high-dose-rate brachytherapy, stereotactic body radiotherapy and particle beam therapy. Conventional treatment options for clinically localized, low-risk prostate cancer include radical prostatectomy, external-beam radiotherapy (EBRT) and low-dose-rate brachytherapy. Advances in image-guided radiotherapy (IGRT) since the 1980s, the development of intensity-modulated radiotherapy (IMRT) during the 1990s and evidence from radiobiological models—which support the use of high doses per fraction—have developed alongside novel advanced radiotherapy modalities that include high-dose-rate brachytherapy (HDR-BT), stereotactic body radiotherapy (SBRT) and proton beam therapy. The relationship between the outcomes of and toxicities experienced by patients with prostate cancer treated with HDR-BT, SBRT and particle-beam therapy should provide urologists and oncologists an understanding of the continually evolving technology in prostate radiotherapy. On the basis of published evidence, conventionally fractionated EBRT with IMRT is considered the standard of care over conventional 3D conformal radiotherapy, whereas HDR-BT boost is an acceptable treatment option for selected patients with intermediate-risk and high-risk prostate cancer. SBRT and proton therapy should not be used for patients (regardless of disease risk group) outside the setting of a clinical trial. Finally, comparative effectiveness research should be conducted to provide a framework for evaluating advanced radiotherapy technologies by comparing the benefits and harms of available therapeutic options to optimize the risk:benefit ratio and improve cost effectiveness. Key Points Image-guided radiotherapy and intensity-modulated radiotherapy have been important in the development of novel radiotherapy modalities Similarly, radiobiological models, which support high dose per fraction delivery, have been critical for the introduction and evolution of high-dose-rate brachytherapy (HDR-BT), stereotactic body radiotherapy (SBRT) and proton beam therapy HDR-BT boost is a relatively well-established advanced radiotherapy modality that is suitable for certain patients with intermediate-risk and high-risk prostate cancer Patients of all risk groups can be offered SBRT and proton beam therapy, but only in the setting of a clinical trial because, to date, high-level evidence of efficacy and safety are lacking Comparative effectiveness research will provide a framework for evaluating advanced radiotherapy technologies by comparing the benefits and harms of the available options to optimize the risk:benefit ratio and improve cost effectiveness

Recent evidence indicates an important role for the retinoblastoma (RB) tumor suppressor in the development of castration resistance in prostate cancer. In this Review, the authors describe the current state of knowledge regarding the implications of RB loss for disease progression, and consider the potential opportunities for developing RB as a metric with which to predict therapeutic response. It is generally held that the retinoblastoma (RB) tumor suppressor functions in multiple tissues to protect against tumor development. However, preclinical studies and analysis of tumor samples of early disease did not support an important role of RB loss in the origin of prostate cancer. By contrast, recent observations in the clinical setting and subsequent modeling of RB function indicate that the tumor suppressor has specialized roles in controlling androgen receptor expression in prostate cancer, and primarily functions to prevent progression to the castration-resistant stage of disease. Furthermore, preclinical models have now shown that loss of RB expression or functional activity decreases the effectiveness of hormone therapy, yet seems to increase sensitivity to a subset of chemotherapeutic agents. Here, the current state of knowledge regarding the implications of RB loss for prostate cancer progression will be reviewed, and potential opportunities for developing RB as a metric to predict therapeutic response will be considered. Key Points The retinoblastoma (RB) tumor suppressor is frequently lost or functionally inactivated in castration-resistant prostate cancer RB protects against progression to castration resistance in part through modulation of androgen receptor expression and activity Xenograft models of human prostate cancer suggest that RB downregulation contributes to the emergence of the castration-resistant phenotype Although RB-deficient tumors may respond poorly to hormone therapy, evidence in multiple cancer types suggest that tumors low in RB exhibit a heightened initial response to chemotherapy Tumor cells deficient in RB function show tissue-specific and context-specific loss of DNA damage checkpoints RB status is a candidate for development as a pharmacodynamic marker of transition to castration resistance and as a predictive marker of response to therapy that might guide therapeutic decisions