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Read the Brastianos Lab 2017-2018 Annual Report
Priscilla K. Brastianos, MDAssistant Professor of MedicineHarvard Medical SchoolMass General Cancer Center
The Brastianos laboratory studies genomic drivers of human brain tumors. A lack of understanding of the molecular drivers of many brain tumors has hampered the development of novel therapies for many brain cancers. Our overarching objective is to characterize molecular drivers of both primary brain tumors and brain metastases, and accelerate the development of novel therapeutic approaches for these diseases.
We recently discovered clinically significant genetic drivers in meningiomas, craniopharyngiomas, hemangioblastomas, glioneuronal tumors and brain metastases. We are currently investigating the role of these genomic drivers as potential therapeutic targets. Additionally, we are expanding our investigations to further elucidate the molecular evolution of the metastatic process to the central nervous system.
Priscilla K. Brastianos, MDPrincipal Investigator
Characterizing Genomic Drivers of Craniopharyngiomas
Craniopharyngiomas are epithelial tumors that arise in the pituitary stalk along the path of the craniopharyngeal duct. There are two main subtypes of craniopharyngiomas, the adamantinomatous form that is more common in children and the papillary form that predominantly occurs in adults. Craniopharyngiomas can cause profound clinical sequelae both through mass effect at presentation and through morbidity of treatment. Attempted surgical resection is usually the initial treatment of craniopharyngioma, but because these tumors adhere to critical brain and vascular structures, incomplete resection is common. Incompletely excised tumors have a propensity to recur, frequently with cysts, with firm adhesions between the recurrent tumor and the surrounding structures such that curative surgery is exceedingly difficult. As a result, most patients suffer lifelong sequelae. Radiation therapy, often used as an adjunct after surgery, can contribute to these complications. No effective treatment besides surgery and radiation is known for craniopharyngiomas, and incomplete knowledge of the molecular mechanisms that drive craniopharyngiomas has limited the development of targeted therapies for this tumor. We recently comprehensively characterized the molecular drivers of craniopharyngiomas. We identified activating mutations in CTNNB1 in nearly all adamantinomatous craniopharyngiomas and recurrent mutations in BRAF (resulting in p.Val600Glu) in nearly all papillary craniopharyngiomas. The CTNNB1 and BRAF mutations were clonal in each tumor subtype, and we detected no other recurrent mutations or genomic aberrations in either subtype. These findings have important implications for the diagnosis and treatment of these neoplasms. We recently treated a patient with multiple recurrent papillary craniopharyngioma with a BRAF and MEK inhibitor and achieved an exceptional therapeutic response. We will be conducting a multicenter trial in papillary craniopharyngiomas to further investigate the role of targeted therapies in these tumors. Circulating biomarkers and genomic analysis of craniopharyngiomas will be employed to investigate mechanisms of resistance.
Identifying Molecular Drivers of Meningiomas
Meningiomas are the most common primary nervous system tumor, with no known effective systemic therapy. The tumor suppressor NF2 was reported to be disrupted in approximately half of meningiomas but the complete spectrum of genetic changes remained undefined. Recently, we have comprehensively characterized meningiomas. Through whole-genome, whole-exome and targeted sequencing, we demonstrated that most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. We confirmed NF2 inactivation in 43% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L). These are known drivers in other cancer types. We also demonstrated that these tumors exhibited evidence of activation of their pathways. Notably, these mutations were present in therapeutically challenging tumors of the skull base. Because therapeutic targets for SMO and AKT1 mutations are currently in clinical use in other cancers, we are now conducting a prospective national multicenter Phase 2 study of an AKT1, SMO, or FAK inhibitor in patients with recurrent or progressive meningiomas harboring AKT1, SMO, or NF2 mutations, respectively. The trial is activated at more than 300 sites throughout the US. We will be genomically characterizing prospectively collected samples to identify biomarkers of response and mechanisms of resistance.
Central Nervous System Metastasis Program
Brain metastases are a common complication of cancer, with a dismal prognosis. There is a limited understanding of the oncogenic alterations harbored by brain metastases and whether these are shared with their primary tumors or other metastatic sites. The metastases to understand the molecular pathways that drive these tumors. In our initial analysis of 101 matched brain metastases and primary tumors, we elucidated the evolutionary patterns that drive metastasis. In all cancer samples, we observed branched objectives of the Central Nervous System Metastasis Program are to (1) identify novel therapeutic targets through comprehensive genomic, transcriptomic and epigenomic characterization, (2) functionally characterize candidate drivers through in vitro and in vivo models of metastasis, and (3) accelerate the application of our scientific findings to the clinical setting. In collaboration with the Broad Institute, and with many national and international institutions, currently we are comprehensively characterizing the genomics of brain evolution, in that all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 56% of cases, we found clinically actionable alterations in the brain metastases that are not detectable in the matched primary tumor. In contrast, spatially and temporally separated brain metastasis sites were more genetically homogenous. Extracranial metastases and regional lymph nodes were highly divergent from brain metastases. We are evaluating the biological significance of our findings in in vitro and in vivo assays of metastasis. Our hope is that the findings from our genomic studies, and functional studies in animal models will provide us with an understanding of the molecular pathways that drive brain metastases, which will allow us to develop more rational therapeutic approaches for this disease.
Alvarez-Breckenridge, C., Miller, J., Nayyar, N., Gill, G., Kaneb, A., D’Andrea, M., Farago, F., Le, L., Lee, J., Cheng, J., Zheng, Z., Butler, W., Multani, P., Chow Maneval, E., Paek, S., Toyota, B., Dias-Santagata, D., Santagata, S., Romero, J., Shaw, A., Yip, S., Cahill, D., Batchelor, T., Iafrate, Brastianos, P.K. (2017) Clinical and radiographic response following targeting of novel BCAN-NTRK1 fusion in glioneuronal tumors. Nature Precision Oncology. In Press
Shankar, G.M., Abedalthagafi, M., Vaubel, R., Merrill, P.H., Nayyar, N., Gill, C.G., Brewster, R. Bi, W., Agarwalla, P.K., Thorner, A.R., Reardon, D.A., Al-Mefty, O., Wen, P.Y., Alexander, B.M., van Hummelen, P., Batchelor, T.T., Ligon, K.L., Ligon, A.H., Meyerson, M., Dunn, I.F., Beroukhim, R., Louis, D.N., Perry, A., Carter, S.L., Giannini, C., Curry, W.T., Cahill, D.P.,* Barker, F.G.,* Brastianos, P.K.,* Santagata, S.* (2017). Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro-Oncology. 19(4):535-545.
Brastianos PK, Shankar GM, Gill CM, Taylor-Weiner A, Nayyar N, Panka DJ, Sullivan RJ, Frederick DT, Abedalthagafi M, Jones PS, Dunn IF, Nahed BV, Romero JM, Louis DN, etz G, Cahill DP, Santagata S, Curry WT Jr, Barker FG 2nd. Dramatic Response of BRAF V600E Mutant Papillary Craniopharyngioma to Targeted Therapy. J Natl Cancer Inst. 2015 Oct 23;108(2).
Brastianos PK, Carter SL, Santagata S, etal. Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov. 2015 Nov;5(11):1164-77.
Brastianos PK, Taylor-Weiner A, Manley PE, Jones RT, Dias-Santagata D, Thorner AR, Lawrence MS, Rodriguez FJ, Bernardo LA, Schubert L, Sunkavalli A, Shillingford N, Calicchio ML, Lidov HG, Taha H, Martinez-Lage M, Santi M, Storm PB, Lee JY, Palmer JN, Adappa ND, Scott RM, Dunn IF, Laws ER Jr, Stewart C, Ligon KL, Hoang MP, Van Hummelen P, Hahn WC, Louis DN, Resnick AC, Kieran MW, Getz G, Santagata S. Exome sequencing identifies BRAF mutations in Papillary craniopharyngiomas. Nat Genet. 2014 Feb;46(2):161-5.
Brastianos PK, Horowitz PM, Santagata S, Jones RT, McKenna A, Getz G, Ligon KL, Palescandolo E, Van Hummelen P, Ducar MD, Raza A, Sunkavalli A, Macconaill LE, Stemmer-Rachamimov AO, Louis DN, Hahn WC, Dunn IF, Beroukhim R. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet. 2013 Mar;45(3):285-9.
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