The candidate is an academic neurosurgeon at Massachusetts General Hospital with training in the management of cranial and spinal oncologic diseases. He has an established track record in contributing to the genomics of central nervous system tumors. Through carefully selected mentors and collaborators, coursework, and meetings, the candidate seeks to develop an independent research effort at the completion of this career development award. His primary mentor is Dr. Bob Carter, who has significant expertise in the characterization of circulating exosomes from patients with glioma. The proposal is to further develop the candidate's research effort on perioperative genotyping of tumors of both solid and liquid biopsies. Gliomas are a group of intrinsic primary central nervous system tumors, with widely-ranging natural history and different treatment. Recent studies have identified recurrent mutations in IDH, TERT promoter, H3F3A, and BRAF that resolve the expected survival and response to therapies. The candidate has previously developed a rapid and sensitive genotyping assay that can detect these mutations within 30 minutes to secure an intraoperative molecular diagnosis of a glioma specimen.
The first aim will be to establish the genotyping assay as a clinical test for as an adjunct for intraoperative diagnosis and perioperative monitoring. First, under mentorship from Dr. Iafrate and Dr. Lennerz, pathologists who specialize in molecular diagnostics, the candidate will learn the process of CLIA-certification in order to establish the described genotyping assay as a clinical test. This test will then be used to analyze stereotactic brain biopsies together with Dr. Stemmer-Rachamimov, a neuropathologist, to determine if augmenting frozen section analysis with molecular information results in achieving a pathologic diagnosis from an earlier core biopsy. In the second aim, the candidate will work with Dr. Cahill, a neurosurgeon, to obtain marginal biopsies from glioma resection to quantify tumor mutation allele fraction using the qPCR-based approach. This cohort will then be followed prospectively to correlate the spatiotemporal risk profile of tumor progression with the calculated allele fraction; the results of which could have implications on adjuvant radiation therapy field planning. In the third aim, blood samples will be prospectively collected from patients with glioma at specified time points with support from Dr. Batchelor, a neuro-oncologist. The cell free tumor DNA fraction from these specimens will be analyzed for the recurrent hotspot mutations covered in this assay. The detection of low abundance alleles in liquid biopsies is challenging and Dr. Carter's research expertise will guide the candidate's technical approach. Incidentally, BRAF and TERT promoter mutations are highly prevalent in malignant melanoma. Therefore, in collaboration with Dr. Sullivan, a melanoma oncologist, the candidate will apply this approach to the longitudinal analysis of blood samples obtained from patients with metastatic melanoma to assess treatment response. Collectively, the hypothesis to be tested is that if perioperative targeted mutational analysis of solid tumor specimens and liquid biopsies further establishes pathologic diagnosis and assessment of treatment response, respectively, then a clinical assay that provides this information can guide surgical and adjuvant therapy decisions. We propose that a similar approach can be similarly extended to other solid tumors characterized by well-defined mutations.
Recent large-scale genomic characterization studies of glioma have identified recurrent hotspot mutations that segregate the natural history and response to surgical and adjuvant treatment of these primary central nervous system tumors. We have developed an assay to detect the presence of these mutations in solid tumor specimens and liquid biopsies, even in those with low abundance of these alleles. In this project we propose the establishment of this assay as a clinical test for the analysis of biopsies and blood specimens acquired from patients with glioma as a method to augment intraoperative diagnosis and perioperative monitoring of treatment response. !
