Friday, May 10, 2024
5/10/2024
Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver malignancy in the United States and worldwide. iCCA has a dismal prognosis, with just a 20% 5-year survival rate, and the incidence of this condition has been increasing over the last few decades. Many factors contribute to the poor prognosis of iCCA, including issues with current diagnostic capabilities and limited treatment options. There has been significant progress in the last decade in understanding the molecular mechanisms underlying iCCA, including identifying isocitrate dehydrogenase (IDH) gain of function as one of the most common mutations specific to iCCA, with R132 being the most common. This mutation results in alpha-ketoglutarate (a-KG) being metabolized to 2-Hydroxyglutarate (2HG), an oncometabolite and a surrogate marker of the mutation. This mutation provides the potential for the development of precision medicine strategies for IDH mutant iCCA. Many new therapeutics for IDH mutant iCCA using small molecule inhibitors of mutant IDH have been developed, with the ClarIDHy trial showing promising phase III results. However, despite these advances, accurate diagnosis of iCCA, particularly diagnosing subtypes, remains challenging, slowing the implementation of appropriate treatment strategies. Current noninvasive diagnostic approaches for iCCA, such as Contrast-Enhanced Ultrasound (CEUS), Magnetic Resonance Imaging (CE-MRI), and Computed Tomography (CT), have varied reports of sensitivity18–20. Importantly, these techniques lack high specificity in the 30% of patients who present with cirrhosis, risking a misdiagnosis of hepatocellular carcinoma (HCC). Furthermore, these imaging techniques cannot determine the specific subtype of iCCA without invasive procedures. Biopsies, the gold standard for confirming iCCA diagnosis, have a long turnaround time and may be unsuitable for molecular analysis in up to 20% of cases. Due to these limitations, there is a clinical need for minimally invasive and fast imaging tools capable of detecting iCCA with IDH mutation and differentiating iCCA from HCC. To address this need, we propose the use of hyperpolarized MRI as a novel diagnostic approach for identifying mIDH-producing iCCA. By leveraging the enhanced sensitivity and spectral characteristics of hyperpolarized carbon-13 (13C) labeled a-KG and its metabolites, we aim to study the dynamics of mIDH's enzymatic behavior in vitro and in vivo. We will optimize the imaging parameters for this technique and build towards accurate noninvasive identification of IDH-mutant iCCA. Aim 1: Optimize an existing pulse sequence to maximize sensitivity to 2HG through spectral editing. Aim 2: Characterize the dynamics and sensitivity of hyperpolarized 1-13C diethyl Alpha-ketoglutarate metabolism in mIDH intrahepatic Cholangiocarcinoma (iCCA) cells. Aim 3: Noninvasively identify IDH-mutated Cholangiocarcinoma using Hyperpolarized diethyl 1-13C Alpha-ketoglutarate in patient-derived-xenograft mouse models.
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