Frederick F. Lang - US grants

SUMMARY: ADMINISTRATIVE CORE (CORE A) The Administrative Core, led by Dr. Frederick Lang (Director) and Dr. Juan Fueyo (Co-Director), provides critical centralized administrative support to ensure the success of the entire SPORE. The specific objectives of the Administrative Core are to: ? Oversee and administer all SPORE activities. ? Oversee all SPORE Projects and Core activities. ? Oversee the Developmental Research and Career Enhancement Programs. ? Promote integration and communication between the SPORE, the Brain Cancer Program, and the Cancer Center Support Grant. ? Ensure compliance with institutional, governmental, and NCI regulations. ? Communicate and consult with the NCI program officer and other staff to ensure timely preparation and submission of reports, publications, and important events that affect management of the SPORE. ? Oversee and administer all fiscal and budgetary activities of the SPORE. ? Manage and provide quality assurance, including data quality control, in cooperation with the Biostatistics and Bioinformatics Core. ? Coordinate meetings of the Executive Committee, Internal and External Advisory Boards, monthly investigator meetings, lectures, and symposia. ? Ensure compliance with and improvement of policies for recruitment of women and minorities. ? Coordinate with other Brain Cancer SPORE programs and investigators, as well as other organ site SPORE programs, to promote research communication in meetings, distribution of materials, electronic communications, and evaluation of progress reports.

SUMMARY: PROJECT 1 To improve the notoriously poor outcome of patients with malignant gliomas, we developed a novel oncolytic adenovirus, Delta-24-RGD, that selectively replicates in and destroys glioma cells. This virus was tested in a first-in-human Phase I clinical trial in patients with recurrent malignant gliomas (NCT00805376), in which dramatic complete (>95% tumor reduction) and durable (>3 years) responses were observed in 12% of patients. Data from this trial contributed to the groundbreaking paradigm shift demonstrating that the Delta-24-RGD oncolytic virus is a form of immunotherapy. Specifically, analyses of clinical responses and post treatment surgical specimens demonstrated that the oncolytic effect of Delta-24-RGD is followed by an anti-tumor cytotoxic T cell immune response that is capable of resulting in complete tumor regression in a small but significant percentage of patients. These clinical data emphasize the urgent need to amplify the anti-tumor immune response as a means of enhancing the efficacy of Delta-24-RGD. To this end, in this proposal we pursue two convergent approaches whose foundations rest on the concept that immune responses to tumors are mediated by 1) immune checkpoints molecules that attenuate immune responses and against which FDA-approved inhibitors are available, and 2) immune costimulatory molecules which activate immune responses and are ideal to ?arm? Delta-24-RGD. In our first approach, we combine Delta-24-RGD with the immune checkpoint inhibitor Pembrolizumab (MERCK), that is directed against the cell surface checkpoint receptor PD-1. We take advantage of the pretreatment biopsy specimens obtained from an ongoing Phase I/II clinical trial of this combination in patients with recurrent gliomas (the CAPTIVE trial, NCT02798406), to not only assess the safety and efficacy of this combination, but also to assess biomarkers for response (Aim 1). In our second approach, we develop and test next-generation Delta-24-RGD viruses that are armed with the cDNA of the ligands of immune co-stimulatory receptors (OX40L, GITRL, 4-1BB). We have already constructed and fully characterized the anti-glioma effects of Delta-24-RGDOX, which carries OX40L, and our data show that Delta-24-RGDOX more efficiently eradicates gliomas compared with Delta-24-RGD in immunocompetent animal models. Therefore, in Aim 2 of this proposal we assess the safety and biological effects of Delta-24-RGDOX on patient tumors in a unique treat-resect-treat clinical trial. Lastly, in Aim 3 we characterize the anti-glioma effects of additional next generation viruses Delta- 24-GREAT (which contains GITRL) and Delta-24-ACT (which contains 4-1BBL) alone and in combination with Delta-24-RGD, to define potential synergy of these viruses. If successful, Project 1 will usher in a new age of oncolytic viral therapies for the treatment of malignant gliomas, for which there is currently no effective treatment.

SUMMARY: OVERALL The overarching goal of this Brain Cancer SPORE renewal application is to improve the notoriously poor outcome of patients with glioblastoma (GBM). This goal will be achieved through the development of a multidisciplinary and highly translational research program that seeks to discover and rapidly translate novel and mechanistically diverse treatment strategies, including biological, immunological and targeted strategies, and by developing prognostic and predictive biomarkers that inform individualized approaches to GBM treatment, while also exploring pathogenesis and risk through genetic-based epidemiological studies in minority populations. By pursuing the strategies of this research program, all projects in the current funding period (2013-18) have successfully transitioned from the bench to clinical trials, including testing of a novel oncolytic virus, Delta-24- RGD, in multiple clinical trials; completing a biological-endpoint Phase II clinical trial of a PI3K-targeted agent, BKM-120; meeting IND requirements for a first-in-human trial of a new immune-modulatory p-STAT-3 inhibitor, WP1066; and validating prognostic biomarkers in clinical trial datasets, while also testing a molecular predictor of radiation sensitivity. In this renewal application we propose three translational research projects that organically evolved from the successes of our current SPORE, and which are supported by four mission-critical Cores (Administrative, Pathology/Biorepository, Biostatistics/ Bioinformatics, Animal). Our Developmental Research Program (DRP) and Career Enhancement Program (CEP) continue as incubators of new projects and portals for new investigators. The aims of our projects are: Project 1: Exploit the capacity of Delta-24-RGD to activate anti-glioma immunity by completing a clinical trial combining Delta-24-RGD with Pembrolizumab, and by testing next-generation Delta-24-RGD viruses that are armed with immune stimulatory molecules: OX40L, GITRL, and 4-1BBL, while analyzing anti-Ad5 antibodies as a biomarker in response to therapy. Project 2: Attack metabolic vulnerabilities of GBMs through the development and clinical testing of a novel inhibitor of oxidative phosphorylation (OxPhos), IACS-010759, that efficiently kills GBMs harboring genetic or epigenetic mutations that impair glycolysis (e.g. ENO1 deletions), and by evaluating a new hypoxia-responsive PET probe, 18F-FAZA, as a readout of OxPhos inhibition and target engagement of IACS-010759. Project 3: Decipher germline and somatic genomic landscape of gliomas in Black and Hispanic minority populations, whose prognosis and survival differ than GBM patients of White European descent. Germline SNP data will be combined with extensive molecular profiling in case-matched tumors. A detailed analysis will be performed to determine ancestry composition and how it influences risk for gliomas and clinical outcome in minorities.