Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 for oncogenic activation in GBM, yet targeting EGFRvIII has yielded limited clinical success to date. In this study, we employed patient-derived xenograft (PDX) models expressing EGFRvIII to determine the key points of therapeutic vulnerability within the EGFRvIII-STAT5 signaling axis in GBM. Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). STAT5 phosphorylation is independent of JAK1 and JAK2 signaling, instead requiring Src family kinase (SFK) activity. Saracatinib, an SFK inhibitor, attenuates phosphorylation of STAT5 and preferentially sensitizes EGFRvIII+ GBM cells to undergo apoptotic cell death relative to wild-type EGFR. Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival.

Background: Radiation necrosis (RN) is a clinically relevant complication of stereotactic radiosurgery (SRS) for intracranial metastasis (ICM) treatments. Radiation necrosis development is variable following SRS. It remains unclear if risk factors for and clinical outcomes following RN may be different for melanoma patients. We reviewed patients with ICM from metastatic melanoma to understand the potential impact of RN in this patient population. Methods: Patients who received SRS for ICM from melanoma at Mayo Clinic Arizona between 2013 and 2018 were retrospectively reviewed. Data collected included demographics, tumor characteristics, radiation parameters, prior surgical and systemic treatments, and patient outcomes. Radiation necrosis was diagnosed by clinical evaluation including brain magnetic resonance imaging (MRI) and, in some cases, tissue evaluation. Results: Radiation necrosis was diagnosed in 7 (27%) of 26 patients at 1.6 to 38 months following initial SRS. Almost 92% of all patients received systemic therapy and 35% had surgical resection prior to SRS. Patients with RN trended toward having larger ICM and a prior history of surgical resection, although statistical significance was not reached. Among patients with resection, those who developed RN had a longer period between surgery and SRS start (mean 44 vs 33 days). Clinical improvement following treatment for RN was noted in 2 (29%) patients. Conclusions: Radiation necrosis is relatively common following SRS for treatment of ICM from metastatic melanoma and clinical outcomes are poor. Further studies aimed at mitigating RN development and identifying novel approaches for treatment are warranted.

Background: Molecular testing (MT) is utilized in neuro-oncology with increasing frequency. The aim of this study was to determine clinical practice patterns to acquire this information, interpret and utilize MT for patient care, and identify unmet needs in the practical clinical application of MT.Methods: We conducted a voluntary online survey of providers within the Society for Neuro-Oncology (SNO) membership database between March and April 2019.Results: We received 152 responses out of 2022 SNO members (7.5% of membership). 88.8% of respondents routinely order MT for newly diagnosed gliomas. Of those who do not, testing is preferentially performed in younger patients or those with midline tumors. 82.8% use MT in recurrent gliomas. Other common indications included: metastatic tumors, meningioma, and medulloblastoma. Many providers utilize more than one resource (36.0%), most frequently using in-house (41.8%) over commercially available panels. 78.1% used the results for clinical decision-making, with BRAF, EGFR, ALK, and H3K27 mutations most commonly directing treatment decisions. Approximately, half (48.5%) of respondents have molecular tumor boards at their institutions. Respondents would like to see SNO-endorsed guidelines on MT, organized lists of targeted agents available for specific mutations, a database of targetable mutations and clinical trials, and more educational programs on MT.Conclusion: This survey was marked by several limitations including response rate and interpretation of MT. Among respondents, there is routine use of MT in Neuro-Oncology, however, there remains a need for increased guidance for providers to effectively incorporate the expanding genomic data resulting from MT into daily Neuro-Oncology practice.