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.

Ionizing radiation causes DNA damage and is a mainstay for cancer treatment, but understanding of its genomic impact is limited. We analyzed mutational spectra following radiotherapy in 190 paired primary and recurrent gliomas from the Glioma Longitudinal Analysis Consortium and 3,693 post-treatment metastatic tumors from the Hartwig Medical Foundation. We identified radiotherapy-associated significant increases in the burden of small deletions (5-15 bp) and large deletions (20+ bp to chromosome-arm length). Small deletions were characterized by a larger span size, lacking breakpoint microhomology and were genomically more dispersed when compared to pre-existing deletions and deletions in non-irradiated tumors. Mutational signature analysis implicated classical non-homologous end-joining-mediated DNA damage repair and APOBEC mutagenesis following radiotherapy. A high radiation-associated deletion burden was associated with worse clinical outcomes, suggesting that effective repair of radiation-induced DNA damage is detrimental to patient survival. These results may be leveraged to predict sensitivity to radiation therapy in recurrent cancer.

PURPOSE/OBJECTIVES/OBJECTIVE:To report our dosimetric analysis of the hippocampi (HC) and the incidence of perihippocampal tumor location in patients with≥25 brain metastases who received stereotactic radiosurgery (SRS) in single or multiple sessions. Materials/Methods Analysis of our prospective registry identified 89 patients treated with SRS for ≥ 25 brain metastases. HC avoidance regions (HA-region) were created on treatment planning MRIs by 5mm expansion of HC. Doses from each session were summed to calculate HC dose. The distribution of metastases relative to the HA-region and the HC was analyzed. RESULTS:Median number of tumors irradiated per patient was 33 (range 25-116) in a median of 3 (range1-12) sessions. Median bilateral HC Dmin (D100), D40, D50, Dmax, and Dmean (Gy) was 1.88, 3.94, 3.62, 16.6, and 3.97 for all patients, and 1.43, 2.99, 2.88, 5.64, and 3.07 for patients with tumors outside the HA-region. Multivariate linear regression showed that the median HC D40, D50, and Dmin were significantly correlated with the tumor number and tumor volume (p <0.001). Of the total3059 treated tumors,83 (2.7%) were located in the HA-region in 57% evaluable patients; 38 tumors (1.2%) abutted or involved the HC itself. CONCLUSIONS:Hippocampal dose, is higher in patients with tumors in the HA-region; however, even for patients with a high burden of intracranial disease and tumors located in the HA-regions, SRS affords hippocampal sparing. This is particularly relevant in light of our finding of eventual perihippocampal metastases in more than half of our patients.

Glioblastoma (GBM) is highly resistant to chemo- and immune-based therapies and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells (GSCs) using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes medium-chain fatty acids (MCFAs), due to its consistently high score and high expression among models and upregulation in GBM compared to normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism could exploit a key metabolic feature of GBM.

BACKGROUND:Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O 6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly ADP-ribose polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide. METHODS:VERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the 6-month progression-free survival (PFS-6m) in the experimental arm. RESULTS:A total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36-57%) in the experimental arm and 31% (95% CI: 18-46%) in the standard arm. Median OS was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals. CONCLUSION/CONCLUSIONS:The veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.

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.

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.

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.

Background/UNASSIGNED:It remains unknown how the COVID-19 pandemic has changed neuro-oncology clinical practice, training, and research efforts. Methods/UNASSIGNED:We performed an international survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents, April 24-May 17, 2020. We assessed clinical practice and research environments, institutional preparedness and support, and perceived impact on patients. Results/UNASSIGNED:Of 582 respondents, 258 (45%) were US-based and 314 (55%) international. Ninety-four percent of participants reported changes in their clinical practice. Ninety-five percent of respondents converted at least some practice to telemedicine. Ten percent of practitioners felt the need to see patients in person, specifically because of billing concerns and pressure from their institutions. Sixty-seven percent of practitioners suspended enrollment for at least one clinical trial, including 62% suspending phase III trial enrollments. More than 50% believed neuro-oncology patients were at increased risk for COVID-19. Seventy-one percent of clinicians feared for their own personal safety or that of their families, specifically because of their clinical duties; 20% had inadequate personal protective equipment. While 69% reported increased stress, 44% received no psychosocial support from their institutions. Thirty-seven percent had salary reductions and 63% of researchers temporarily closed their laboratories. However, the pandemic created positive changes in perceived patient satisfaction, communication quality, and technology use to deliver care and mediate interactions with other practitioners. Conclusions/UNASSIGNED:The pandemic has changed treatment schedules and limited investigational treatment options. Institutional lack of support created clinician and researcher anxiety. Communication with patients was satisfactory. We make recommendations to guide clinical and scientific infrastructure moving forward and address the personal challenges of providers and researchers.