Gliomas are the most common solid tumors of childhood, with pediatric gliomas among the most recalcitrant. Activation of both mitogen protein kinase (MAPK) and phosphatidylinositol-3' kinase (PI3K) signaling in pediatric low-grade gliomas (PLGG) indicates possible efficacy for agents that target these cascades. This proposal assesses molecular underpinnings of response to promising targeted agents for clinical treatment of PLGGs, and incorporates preclinical testing of novel and translatable combination therapies to (1) define the best therapy for each molecular aberration identified in PLGGs, including BRAF alterations and recently described non-BRAF fusion genes, (2) overcome innate, intrinsic resistance to MAPK/ERK and PI3K/mTOR inhibitors and (3) address acquired resistance in the PLGG setting. We will capitalize on a rapidly accruing multi-institutional phase 2 clinical trial of everolimus for recurrent PLGGs in which acquisition of tissue from all children will allow us to test the hypothesis that PI3K/mTOR activation will predict response to mTOR inhibition. We will further capitalize on our recent success in cloning all PLGG BRAF-fusions characterized to date as well as recently described non-BRAF fusion genes. We hypothesize that each molecular subtype of PLGG will require a distinct and separate targeted approach to maximize efficacy and overcome resistance. Our overall goal is to set the stage for a personalized combinatorial approach for the treatment of PLGGs by generating pre-clinical and clinical data that will determine the best combination of agents for each molecular subtype and enable the next generation of clinical trials in which rational drug combinations are administered to appropriate patients in hypothesis-driven studies.

Public Health Relevance

Although the molecular underpinnings of PLGGs represent an ideal platform for personalized approaches and targeted therapeutics are available, studies defining the appropriate agents for each PLGG alteration are lacking. We address this impediment first by harnessing molecular data of a clinical trial to define molecular features of those children most likely to respond; and second by performing pre-clinical studies incorporating rational combinations that maximize efficacy and overcome resistance for each given molecular profile.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS091620-01
Application #
8865159
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fountain, Jane W
Project Start
2015-09-30
Project End
2020-07-31
Budget Start
2015-09-30
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$549,581
Indirect Cost
$91,921
Name
Dana-Farber Cancer Institute
Department
Type
Organized Research Units
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Fan, Qi Wen; Nicolaides, Theodore P; Weiss, William A (2018) Inhibiting 4EBP1 in Glioblastoma. Clin Cancer Res 24:14-21
Haas-Kogan, Daphne; Indelicato, Daniel; Paganetti, Harald et al. (2018) National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury. Int J Radiat Oncol Biol Phys 101:152-168
Ilkhanizadeh, Shirin; Sabelström, Hanna; Miroshnikova, Yekaterina A et al. (2018) Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma. Mol Cancer Res 16:777-790
An, Zhenyi; Aksoy, Ozlem; Zheng, Tina et al. (2018) Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. Oncogene 37:1561-1575
An, Zhenyi; Knobbe-Thomsen, Christiane B; Wan, Xiaohua et al. (2018) EGFR Cooperates with EGFRvIII to Recruit Macrophages in Glioblastoma. Cancer Res 78:6785-6794
Griveau, Amelie; Seano, Giorgio; Shelton, Samuel J et al. (2018) A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment. Cancer Cell 33:874-889.e7
Zheng, Tina; Ménard, Marie; Weiss, William A (2017) Neuroblastoma Metastases: Leveraging the Avian Neural Crest. Cancer Cell 32:395-397
Raleigh, David R; Solomon, David A; Lloyd, Shane A et al. (2017) Histopathologic review of pineal parenchymal tumors identifies novel morphologic subtypes and prognostic factors for outcome. Neuro Oncol 19:78-88
Fan, QiWen; Aksoy, Ozlem; Wong, Robyn A et al. (2017) A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma. Cancer Cell 31:424-435
Wahl, Michael; Chang, Susan M; Phillips, Joanna J et al. (2017) Probing the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in gliomas: A phase 2 study of everolimus for recurrent adult low-grade gliomas. Cancer 123:4631-4639

Showing the most recent 10 out of 17 publications