Preclinical data highlight AZD1390 as a potentially powerful new therapy to enhance brain tumor patient responses to radiotherapy.

Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited central nervous system (CNS) bioavailability; thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested for efficacy and impact on tumor and healthy brain. Both AZ31 and AZ32 blocked the DNA damage response and radiosensitized GBM cells AZ32, with enhanced blood-brain barrier (BBB) penetration, was highly efficient as radiosensitizer in syngeneic and human, orthotopic mouse glioma model compared with AZ31. Furthermore, human glioma cell lines expressing mutant p53 or having checkpoint-defective mutations were particularly sensitive to ATMi radiosensitization. The mechanism for this p53 effect involves a propensity to undergo mitotic catastrophe relative to cells with wild-type p53., apoptosis was >6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low-dose radiation. AZ32 is the first ATMi with oral bioavailability shown to radiosensitize glioma and improve survival in orthotopic mouse models. These findings support the development of a clinical-grade, BBB-penetrating ATMi for the treatment of GBM. Importantly, because many GBMs have defective p53 signaling, the use of an ATMi concurrent with standard radiotherapy is expected to be cancer-specific, increase the therapeutic ratio, and maintain full therapeutic effect at lower radiation doses. .

BACKGROUND: Success rates with salvage radiotherapy (SRT) in men who have a postprostatectomy biochemical relapse are suboptimal. One treatment‐intensification strategy includes elective irradiation of the pelvic lymph nodes with whole pelvis radiotherapy (WPRT). METHODS: An inter‐institutional retrospective cohort study compared outcomes for patients who received SRT at 2 separate academic institutions with disparate treatment paradigms: almost exclusively favoring WPRT (n = 112) versus limiting treatment to the prostate bed (PBRT) (n = 135). Patients were excluded if they had lymph node involvement or if they received androgen‐deprivation therapy. The Cox proportional hazards model was used to adjust for potential confounders. RESULTS: In total, 247 patients were analyzed with a median follow‐up of 4 years. The pre‐SRT prostate‐specific antigen (PSA) level (adjusted hazard ratio [HR], 1.58; P < .0001) and a Gleason score of 8 to 10 (adjusted HR, 3.21; P < .0001) were identified as independent predictors of increased risk of biochemical PSA progression after SRT. However, WPRT was not independently associated with biochemical progression‐free survival in the multivariate model (adjusted HR, 0.79; P = .20). Neither low‐risk patients nor high‐risk patients (defined a priori by a preoperative PSA level ≥20 ng/mL, a pathologic Gleason score between 8 and 10, or pathologic T3 tumor classification) benefited from WPRT. Overall survival was similar between treatment groups. When restricting the analysis to patients with pre‐SRT PSA levels ≥0.4 ng/mL (n = 139), WPRT was independently associated with a 53% reduction in the risk of biochemical progression (adjusted HR, 0.47; P = .031). CONCLUSIONS: WPRT did not improve outcomes among the entire group but was independently associated with improved biochemical control among patients with pre‐SRT PSA levels ≥0.4 ng/mL. Cancer 2013. © 2012 American Cancer Society.

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Disparate treatment paradigms exist for SRT that may impact patient outcomes. Variability includes patient selection, treatment design, and recommendations for ADT. Many reference formulas to predict the benefit of pelvic lymph node irradiation that are not yet validated in the postprostatectomy setting. These data make it clear that well-designed, prospective clinical trials are needed to better evaluate the role of larger treatment fields, dose escalation, and ADT for the thousands of patients who are treated with postprostatectomy SRT each year.