Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

“Purpose: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation. Experimental Design: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry and positron emission tomography (PET)-imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 localized prostate cancer patients treated with curative-intent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan-Meier method. Results: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately prior to irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (p=0.0106). Conclusion: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio.”

Unstable Chromosomes Linked to Less Favorable Response to Radiation Therapy and Surgery in Prostate Cancer Patients

“Detailed evaluation of a prostate cancer tumor biopsy may predict treatment outcomes for image-guided radiation therapy (IGRT) or surgery for prostate cancer, according to research presented today at the American Society for Radiation Oncology’s (ASTRO’s) 55th Annual Meeting. The study results indicate that patients who have abnormal levels of breaks at common fragile sites (CFSs), sites within the chromosomes that are sensitive to DNA damage, are more likely to have their cancer to return—treatment failure. These CFSs break abnormalities are usually associated with instability of the cell’s DNA, a phenomenon that is particularly associated with cancer.”

TMPRSS2-ERG Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair

“BACKGROUND: Pre-clinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers (PCa), may be a surrogate for DNA repair status and therefore a biomarker for DNA damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). METHODS: Pre-treatment biopsies from two cohorts of intermediate-risk PCa patients (T1/T2, GS < 8, PSA < 20ng/mL) (> 7 years follow-up) were analyzed: (1) 126 patients with DNA samples assayed by array Comparative Genomic Hybridization for TMPRSS2-ERG fusion (CGH-cohort); and (2), 118 patients whose biopsies were scored within a tissue microarray (TMA) immunostained for ERG overexpression (surrogate for TMPRSS2-ERG fusion) (IHC-cohort). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir + 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using Cox proportional hazards models. RESULTS: TMPRSS2-ERG fusion by aCGH was identified in 27 patients (21%) in the CGH-cohort and ERG overexpression was found in 59 patients (50%) in the IHC-cohort. In both cohorts TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analyses. CONCLUSIONS: In two similarly-treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these PCa have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.”