Repurposing FDA approved drugs as radiosensitizers for treating hypoxic prostate cancer

Abstract Background The presence of hypoxia is a poor prognostic factor in prostate cancer and the hypoxic tumor microenvironment promotes radioresistance. There is potential for drug radiotherapy combinations to improve the therapeutic ratio. We aimed to investigate whether hypoxia-associated genes could be used to identify FDA approved drugs for repurposing for the treatment of hypoxic prostate cancer. Methods Hypoxia associated genes were identified and used in the connectivity mapping software QUADrATIC to identify FDA approved drugs as candidates for repurposing. Drugs identified were tested in vitro in prostate cancer cell lines (DU145, PC3, LNCAP). Cytotoxicity was investigated using the sulforhodamine B assay and radiosensitization using a clonogenic assay in normoxia and hypoxia. Results Menadione and gemcitabine had similar cytotoxicity in normoxia and hypoxia in all three cell lines. In DU145 cells, the radiation sensitizer enhancement ratio (SER) of menadione was 1.02 in normoxia and 1.15 in hypoxia. The SER of gemcitabine was 1.27 in normoxia and 1.09 in hypoxia. No radiosensitization was seen in PC3 cells. Conclusion Connectivity mapping can identify FDA approved drugs for potential repurposing that are linked to a radiobiologically relevant phenotype. Gemcitabine and menadione could be further investigated as potential radiosensitizers in prostate cancer

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer.

BACKGROUND: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer. METHOD: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). RESULTS: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P \u3c .05), with borderline significances achieved in the other two (P \u3c .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours. CONCLUSION: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients

An International Expert Delphi Consensus to Develop Dedicated Geriatric Radiation Oncology Curriculum Learning Outcomes

Purpose: The management of older adults with cancer is rapidly becoming a significant challenge in radiation oncology (RO) practice. The education of future radiation oncologists in geriatric oncology is fundamental to ensuring that older adults receive high-quality care. Currently RO trainees receive little training and education in geriatric oncology. The objective of this study was to define core geriatric RO curriculum learning outcomes relevant to RO trainees worldwide. Methods and Materials: A 2-stage modified Delphi consensus was conducted. Stage 1 involved the formation of an expert reference panel (ERP) of multiprofessional experts in geriatric oncology and/or RO and the compilation of a potential geriatric RO learning outcomes set. Stage 2 involved 3 iterative rounds: round 1 and round 2 (both online surveys), and an intervening ERP round. These aimed at identifying and refining ideal geriatric RO learning outcomes. Invited participants for round 1 and 2 included oncology health care professionals with expertise across RO, geriatric oncology, and/or education and consumers. Predefined Delphi consensus definitions were applied to the results of rounds 1 and 2. Results: An ERP of 11 experts in geriatric oncology and/or RO was formed. Seventy potential knowledge- and skill-based learning outcomes were identified. In round 1, 103 of 179 invited eligible Delphi participants completed the survey (58% response rate). The ERP round was conducted, resulting in the exclusion of 28 learning outcomes. In round 2, 54 of 103 completed the survey (52% response rate). This identified a final total of 33 geriatric RO learning outcomes. Conclusions: The geriatric RO learning outcomes described in this study form an international consensus that can inform RO training bodies worldwide. This represents the first fundamental step in developing a global educational framework aimed at improving RO trainee knowledge and skills in geriatric oncology.</p