Neuro-Oncology Research: Sandeep Mittal, MD, FRCSC, FACS
Basic and Translational Research Program Overview
Dr. Mittal is Director of the Translational Neuro-Oncology Research Laboratory located at the Hudson-Webber Cancer Research Center, Karmanos Cancer Institute
The lab has several ongoing research projects focusing on brain tumor neurobiology for primary tumors meningiomas and glioblastomas and metastatic brain tumors derived from primary breast or lung cancer. Current lab members include research lab manager Sharon K. Michelhaugh, PhD, Cancer Biology graduate student Anthony R. Guastella, BS, and research assistant Sam Kiousis, MS.
In the Translational Neuro-Oncology Research Laboratory, we take advantage of our unique capability to utilize freshly-resected patient brain tumor specimens. In addition to traditional tissue studies, we also generate in vivo models of human brain tumors in collaboration with Lisa A. Polin, PhD and the Animal Model and Therapeutics Evaluation Core (Karmanos Cancer Institute/Wayne State University).
A complete list of Dr. Mittal’s publications can be found here
As part of our NIH-funded collaboration with Csaba Juhász, M.D. Ph.D, (Depts. of Pediatrics and Neurology), we have expanded our studies of tryptophan metabolism in brain tumors to include meningiomas (http://www.ncbi.nlm.nih.gov/pubmed/26092774). These tumors, arising from the arachnoid cap cells, are the most common primary brain tumor, and we have found that the kynurenine pathway of tryptophan metabolism is prominent and that molecular imaging with our radiotracer 11C-alpha-methyl-tryptophan (AMT) correlates with levels of tryptophan metabolizing enzymes. Furthermore, we have generated patient-derived xenograft models of human meningioma in immunocompromised mice (http://www.ncbi.nlm.nih.gov/pubmed/26174772) from our cell line KCI-MENG1, generated from a WHO Grade I meningioma tumor specimen. We are also developing a model from a WHO Grade III meningioma tumor specimen, KCI-MENG3.
Patient survival after glioblastoma diagnosis is dismal despite aggressive treatment strategies including surgery, radiotherapy, and chemotherapy. We have therefore developed patient-derived xenograft models that closely mimic the human disease. Our pre-clinical models share the same imaging characteristics with the 11C-alpha-methyl-tryptophan (AMT) radiotracer and will be invaluable for our translational studies of tryptophan metabolism. Anthony’s award winning poster from the 2015 International Society for Tryptophan Research meeting highlights our pre-clinical glioblastoma models.
These pre-clinical models of human glioblastoma will also be used for immunotherapy studies using bispecific antibody-armed T cells in collaboration with Larry Lum, M.D., DSc and Archana Thakur, Ph.D. In glioblastoma, EGFR amplification is found in ~50% of tumors. Our preliminary studies have used EGFR-targeted armed T cells co-injected with U87 glioblastoma cells. The T cells prevented the development of intracranial tumors and led to healthy survival in mice.
BREAST CANCER BRAIN METASTASES
Our recent study of breast cancer brain metastases in collaboration with Aliccia Bollig-Fischer, Ph.D., identified copy number variations of potential oncogenic drivers that were specific to the metastatic brain lesions, and were not the predominant drivers of the primary breast cancers. At the time of publication, this was the largest data set specifically assaying copy number variation in metastatic brain tumors derived from breast cancer (http://www.ncbi.nlm.nih.gov/pubmed/25970776). We are also developing patient-derived xenograft models of metastatic brain tumors from the different molecular subtypes of primary breast cancer. Hormone-negative, HER2+ and triple negative breast cancer have higher incidence rates of metastatic brain lesions than hormone-positive breast cancers. We currently have two mouse xenograft models of breast cancer brain metastases that are profiles, with several others in development. Studies are planned in collaboration with Nerissa Viola-Villegas, PhD, using the Her2+ model.
LUNG CANCER BRAIN METASTASES
Metastatic brain tumors derived from primary lung cancer are the most common brain tumor type. We have therefore developed a series of patient-derived xenograft models from patient specimens of lung cancer brain metastases. Pilot studies using the radiotracer 11C-alpha-methyl-tryptophan (AMT) in mice bearing these xenografts are underway.
In addition to the subcutaneous tumors shown above, we have also developed one of these tumor models into an orthotopic model by stereotactic injection of tumor cells into the mouse brain. Studies are planned in collaboration with Larry H. Matherly, Ph.D., to use this mouse model in pre-clinical studies of agents that target the proton-coupled folate transporter.