Faculty Bibliography

BACKGROUND:To determine if proton radiotherapy (PT), compared to intensity modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma. METHODS:Eligible patients were randomized unblinded to PT vs. IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes. RESULTS:A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45 to 1.75; P=0.74). PT was associated with a lower rate of fatigue (24% vs. 58%, P=0.05), but otherwise there were no significant differences in patient-reported outcomes at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44 to 1.23; P=0.24) or OS (HR, 0.86; 95% CI, 0.49 to 1.50; P=0.60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P=0.02). CONCLUSIONS:In this signal seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for glioblastoma and cognitive preservation in patients with lower grade gliomas with a longer survival time.

Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.

PROBLEM/OBJECTIVE:Physician-scientists are individuals trained in both clinical practice and scientific research. Often, the goal of physician-scientist training is to address pressing questions in biomedical research. The established pathways to formally train such individuals are, mainly, MD-PhD programs and physician-scientist track residencies. Although graduates of these pathways are well equipped to be physician-scientists, numerous factors, including funding and length of training, discourage application to such programs and impede success rates. APPROACH/METHODS:To address some of the pressing challenges in training and retaining burgeoning physician-scientists, New York University Grossman School of Medicine formed the Accelerated MD-PhD-Residency Pathway in 2016. This pathway builds on the previously established accelerated three-year MD pathway to residency at the same institution. The Accelerated MD-PhD-Residency Pathway conditionally accepts MD-PhD trainees to a residency position at the same institution through the National Resident Matching Program. OUTCOMES/RESULTS:Since its inception, 2 students have joined the Accelerated MD-PhD-Residency Pathway, which provides protected research time in their chosen residency. The pathway reduces the time to earn an MD and PhD by one year and reduces the MD training phase to three years, reducing the cost and lowering socioeconomic barriers. Remaining at the same institution for residency allows for the growth of strong research collaborations and mentoring opportunities, which foster success. NEXT STEPS/UNASSIGNED:The authors and institutional leaders plan to increase the number of trainees that are accepted into the Accelerated MD-PhD-Residency Pathway and track the success of these students through residency and into practice to determine if the pathway is meeting its goal of increasing the number of practicing physician-scientists. The authors hope this model can serve as an example to leaders at other institutions who may wish to adopt this pathway for the training of their MD-PhD students.

BACKGROUND:We investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM). METHODS:Patients enrolled in a randomized phase II trial received PT (n=28) or XRT (n=56), concomitantly with temozolomide. ALC was measured before, weekly during, and within 1 month after radiotherapy. Whole-brain mean dose (WBMD) and brain dose-volume indices were extracted from planned dose distributions. Univariate and multivariate logistic regression analyses were used to identify independent predictive variables. The resulting model was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS:Rates of G3+L were lower in men (7/47 [15%] vs. women (19/37 [51%], P<0.001)), and for PT (4/28 [14%] vs. XRT (22/56 [39%], P=0.024)). G3+L was significantly associated with baseline ALC, WBMD, and brain volumes receiving 5‒40 Gy(RBE) or higher (i.e., V5 through V40). Stepwise multivariate logistic regression analysis identified being female (odds ratio [OR] 6.2, 05% confidence interval [CI] 1.95‒22.4, P=0.003), baseline ALC (OR 0.18, 95% CI 0.05‒0.51, P=0.003) and whole brain V20 (OR 1.07, 95% CI 1.03‒1.13, P=0.002) as the strongest predictors. ROC analysis yielded an area under the curve of 0.86 (95% CI 0.79-0.94) for the final G3+L prediction model. CONCLUSIONS:Sex, baseline ALC, and whole brain V20 were the strongest predictors of G3+L for patients with GBM treated with radiation and temozolomide. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.