Despite improved diagnosis and therapeutic options, prognosis of patients with brain tumors remains poor. The overall goal of our research, as outlined in this renewal grant application, is to improve diagnosis and treatment of human brain tumors by exploiting mechanisms related to tumoral abnormalities of tryptophan metabolism. In the first grant period, we used molecular imaging with the PET radiotracer ?[11C]-methyl-L-tryptophan (AMT) to detect and differentiate newly diagnosed and recurrent gliomas. AMT is different from several other amino acid PET tracers in that rather than being incorporated into proteins it is metabolized via the immunosuppressive kynurenine pathway, which is upregulated in various cancers. Using AMT tracer kinetic analysis we were able to estimate tumor proliferative activity, differentiate low-grade glioma types, and distinguish recurrent gliomas fro radiation injury. On co-registered, fused PET/MRI images, we have also observed AMT accumulation beyond the MRI-detected tumor mass, in tumor-infiltrated brain tissue. This is in keeping with the notion that glioma cells infiltrate variably beyond the solid tumor mass into the surrounding brain parenchyma. Building upon our preliminary data, in Aim 1 of the proposed studies we will use the degree of AMT accumulation, measured non-invasively on PET, as a surrogate marker of tumor cell density in tumor-infiltrated brain parenchyma. We will validate this by detailed histopathologic comparisons and then determine whether the extent of PET-defined tumor removal is a predictor of post-surgical tumor recurrence;we will also differentiate primary gliomas from common brain metastases by AMT uptake characteristics.
In Aim 2, we will assess the accuracy of quantitative AMT PET and perfusion MRI in patients treated for malignant astrocytic gliomas by post-surgery chemoradiation for differentiating early tumor progression (d6 months after initial treatment) from pseudo-progression, a recently emerged clinical dilemma. We will also test the value of these neuroimaging techniques in predicting the time and location of late (>6 months) tumor recurrence as well as survival before signs of progression on conventional MRI.
In Aim 3 we will study mechanisms of tryptophan metabolism in tumor samples obtained from gliomas and common metastatic brain tumors. We will focus on histopathologic and imaging correlates of tumoral kynurenine, the central metabolite of the kynurenine pathway. Kynurenine can be produced by two key enzymes (indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase) and is a recently recognized endogenous ligand for the aryl hyrocarbon receptor (AHR), an important cell-cycle regulator whose activation plays a role in both tumor progression and immune suppression. The expected results will lead to novel treatment approaches targeting tumoral tryptophan-to-kynurenine metabolism (that could be blocked by specific enzyme inhibitors) and/or modulating AHR-mediated transcription. We will also assess AMT metabolic rates, estimated by PET, as an imaging marker of tumoral immune suppression. This will be useful to monitor treatment response in clinical trials of emerging inhibitors.
Our ability to improve survival of patients with newly diagnosed and recurrent brain tumors is hindered by several factors, including inaccurate delineation of tumor-infiltrated brain tissue for initial treatment, delayed recognition of tumor recurrence or progression, and also our inability to overcome tumoral immunosuppressive mechanisms. In this project, we combine multi-modal imaging (PET and MRI) with tumor tissue assays to exploit processes related to abnormal tumoral tryptophan metabolism in order to address the above issues in primary brain tumors and brain metastases. The results are expected to lead to a more accurate tumor targeting at initial treatment, earlier detection of post treatment tumor recurrence, and development of novel therapeutic strategies to overcome tumoral immune suppression thus improving outcome after treatment. ! ! !!
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