Imaging a Hallmark of Cancer: Noninvasive Metabolic Imaging of Tert Expression in Brain Tumors
Abstract
Objective and Rationale: Telomeres are caps on chromosomes that protect our DNA. They shorten with every cell division and must be replaced for cell proliferation to continue. Therefore, in order to proliferate in an uncontrolled manner, all cancer cells must find a mechanism to synthesize telomeres. Telomerase reverse transcriptase (TERT) is the key protein for telomere synthesis. It is absent in normal cells and is exclusively reactivated in cancer cells, including brain tumor cells. Inhibitors of TERT expression specifically kill tumor cells and are currently under development. TERT is, therefore, both a tumor biomarker and a therapeutic target. In spite of its critical role, non-invasive methods of detecting TERT are lacking. Currently the standard method for detecting TERT requires analysis of DNA from tumor tissue, which is unsuitable for two reasons: (1) this procedure is invasive, and (2) the anatomical location of brain tumors can make it difficult to obtain tumor tissue. Therefore, the objective of this grant application is to identify non-invasive imaging biomarkers of TERT expression in brain tumors. Previous studies and our preliminary data show that brain tumor cells that express TERT also show multiple metabolic changes that can be detected using a non-invasive, clinically applicable imaging method known as magnetic resonance spectroscopy (MRS). Therefore, the rationale of this grant is that MRS can be used to non-invasively detect brain tumors and measure their response to therapy via detection of an underlying molecular hallmark of cancer (i.e., TERT). Applicability: There is a critical need to non-invasively image TERT for several reasons. First, when brain tumor patients present with a lesion in the brain, it can be difficult to judge whether the lesion is a result of tumor recurrence or the result of brain reaction to injury (“gliosis”), or edema, or the result of treatment with radiation or chemotherapy (“pseudoprogression or radiation necrosis”). For this reason, non-invasive imaging tools that can confidently diagnose glioma recurrence are needed, because this will minimize unnecessary surgery while also helping to identify those patients for whom surgical intervention is urgently needed. Since TERT expression is inherently linked to tumor proliferation, imaging TERT will allow visualization of the presence of “true” tumor and differentiate from gliosis/edema/treatment-related effects. Second, since inhibitors of TERT expression are under development, imaging TERT will enable measurement of tumor response to these emerging therapies. They can also be used to track, repeatedly over time, the development of resistance to treatment. This will aid drug discovery and will provide companion imaging biomarkers for future clinical trials with these inhibitors. Third, since TERT is essential for tumor proliferation, imaging TERT can allow clinicians to monitor response to standard therapies such as radiation and chemoradiotherapy. Fourth, since TERT is also a hallmark of other cancers such as liver cancer and melanoma, the insights and biomarkers from our work can potentially be applied to these other tumor types as well. This proposal, therefore, directly addresses the Fiscal Year 2019 Peer Reviewed Cancer Research Program Military Health Focus Area of “gaps in early detection, diagnosis and treatment planning” for brain tumor patients. Advancing the Field: Once our MRS imaging biomarkers have been validated in preclinical models, it will take 2-4 years to translate the technology to the clinic. In the clinic, imaging TERT will endow the community with a much-needed means of conveniently and clearly characterizing a patient’s lesion as a “true” tumor in a manner that allows for early detection of recurrence and response to standard therapies. Furthermore, prior experience with drug development programs suggests that companion imaging biomarkers like the ones proposed in this grant accelerate the clin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010553
Entities
People
- Pavithra Viswanath
Organizations
- United States Army
- University of California, San Francisco