Research Project 2 (RP2) is based on preliminary data and studies performed during ICMIC 2. The goal of this project is to develop non-invasive methods to distinguish indolent from aggressive cancers and to monitor evolution of a tumor to a more malignant state. These very pragmatic issues of cancer care are relevant to many patients and are of high potential impact. The central theme of this project is the integration of non-invasive imaging in the development of new paradigms to advance cancer care.
In Aim 1 we propose to determine whether elevated lactate is a general characteristic of tumors with genetic mutations activating the PTEN/PI3K/AKT, Our goal is broader and is to determine whether this is a general characteristic of a more aggressive/metastatic tumor phenotype. Since PTEN/PI3K/AKT mutations and deletions are commonly present in aggressive/metastatic tumors and a poor prognostic factor across multiple tumor types, we focus on this signaling pathway. A series of isogenic tumors across a broad range of cancers (breast, prostate, colon, glioma) will be studied. We will determine if lactate levels, LDHA expression, glucose and glutamine metabolism, and gene array profiles are concordant. We will determine if the MRS-determined metabolic changes/differences are concordant with measures of ^^FDG uptake, gene array profile analyses (in collaboration with RP4), and phenotypic behavior (growth, metastases) in prostate and other tumor models.
In Aim 2 we will determine if LDH-A is potentially an important target for developing new anti-neoplastic drugs and whether MRS measurements can be used as a non-invasive measure of target inhibition.
In Aim 3 we will collaborate with RP 3 and 4 to determine if changes in metabolism can be used as an early marker of response to novel specific targeted therapies. We will perform MRS and PET (RP4) studies on novel therapies that are, or will shortly be in clinical evaluation. We hypothesize that successful therapy will induce a lower glycolytic (and glutaminolytic) state and will be reflected in tumor metabolism (lactate levels, glycolytic and glutaminolytic rates and ^^FDG uptake). Our long term goal is to translate the preclinical MR imaging results obtained in.this project to comparable clinical imaging studies.
RP2 is a preclinical study, but is designed to be readily translated to the clinic. We address a critical question of determining which patients need to be treated and when do they need treatment. These preclinical studies will demonstrate that non-invasive metabolic measurements can: 1) predict aggressive tumor behavior, 2) can be used as a marker for developing and optimizing new drugs, and/or 3) predict treatment response.
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