National Cancer Institute awards $1.52 million to Drs. Sandeep Mittal, Csaba Juhasz
Monday, April 07, 2014
The National Institutes of Health has renewed a $1.5 million R01 grant to improve treatment and clinical outcome of brain tumors by exploiting mechanisms related to abnormalities of tumoral tryptophan metabolism.
Dr. Sandeep Mittal
Sandeep Mittal, M.D., F.R.C.S.C., F.A.C.S., co-leader of the Neuro-Oncology Multidisciplinary Team at Karmanos Cancer Center and Csaba Juhász, M.D., Ph.D., professor of Pediatrics and of Neurology at Wayne State University School of Medicine (WSU SOM) are co-principal investigators on the study “Tryptophan Metabolism in Human Brain Tumors.” They will use the renewable five-year, $1,522,683 grant (CA123451-06A1) from the National Cancer Institute now through Jan. 31, 2019.
“Tryptophan is an essential amino acid, and studies in the last decade demonstrated that abnormal breakdown of tryptophan may play a major role in the ability of cancers to evade the immune system and resist current therapies,” Dr. Mittal said, who is also an associate professor of Neurosurgery and Oncology at WSU SOM. “Our current ability to improve survival of patients with brain tumors is hindered by several factors, including inaccurate delineation of tumor-infiltrated brain tissue for initial treatment, delayed recognition of tumor recurrence and the inability of our immune system to overcome tumoral immunosuppressive mechanisms. Our goal is to utilize advanced imaging techniques incorporating tryptophan imaging to address these issues and improve the diagnosis, treatment and prognosis of patients with various brain tumors.”
In this new phase of clinical studies, the duo will combine neuroimaging techniques such as magnetic resonance imaging and positron emission tomography with tumor tissue assays to exploit processes related to abnormal tumoral tryptophan metabolism to achieve three goals:
- Improve pre-treatment tumor delineation and differentiation using tryptophan PET in newly-diagnosed primary and metastatic brain tumors;
- Improve post-treatment detection of glioma (brain or spine tumors) recurrence by quantitative assessment of PET images combined with clinical MRI;
- Understand histopathologic, molecular and imaging correlates of the tryptophan-metabolizing kynurenine pathway in primary gliomas and metastatic brain tumors, and to understand mechanisms that lead to tumoral immune suppression in these tumors.
Dr. Csaba Juhasz
Dr. Juhasz works at the PET Center and Translational Imaging Laboratory at Children’s Hospital of Michigan, where he and a team of investigators, including Drs. Diane and Harry Chugani, Otto Muzik and Tom Mangner, pioneered the use of tryptophan PET imaging in studying human tumors.
“Alpha-methyl-L-tryptophan, the radiotracer used in our PET studies, is unique for Wayne State University and currently not available in other centers in the United States,” Dr. Juhasz said. “Using a quantitative approach of PET image analysis, we found several useful clinical applications, such as estimating brain tumor proliferative activity, differentiating various tumor types and detecting recurrent gliomas accurately.”
In tumor tissue studies guided by Dr. Mittal at the Translational Neuro-Oncology Research Laboratory, which he directs at the Barbara Ann Karmanos Cancer Institute, they discovered that gliomas, meningiomas – a tumor that arises from the membranes surrounding the brain and spinal cord – and metastatic brain tumors commonly overexpress two key enzymes of tryptophan metabolism via the kynurenine pathway.
“The tumors use this mechanism to suppress the host immune cells and evade the immune system. Blocking these enzymes – and/or other synergistic enzymes and molecules – could be a powerful new approach to reverse this effect and assist the immune system to fight these tumors more effectively,” Dr. Juhász added.
Study results will improve the clinical outcome of patients with brain tumors and also can be readily applied to other forms of cancer, such as breast, lung and prostate.
“Right now there are a handful of new drugs being tested in pre-clinical and early clinical trials for their ability to break tumoral immune resistance by targeting the indoleamine-2,3-dioxygenase enzyme. Our molecular imaging approach will be instrumental to identify tumors that would be most likely to respond to these new treatments, and also for monitoring drug effects by imaging, without invasive surgical procedures,” Dr. Mittal said. The combined PET/MRI approach could also lead to more accurate pre- and post-treatment detection and more effective treatment of brain tumors and extracranial cancers.
“We hope that this unique imaging approach will be adopted and used by other cancer centers in the country,” Dr. Juhász said.