Wednesday, April 2, 2025
4/2/2025
Molecular Imaging and Metabolotheranostics of PDAC-Induced Cachexia - Cachexia induced by pancreatic ductal adenocarcinoma (PDAC) results in significant morbidity, mortality, and poor response to treatment including immune therapy. We intend to apply our molecular and functional imaging capabilities, and our experience in developing theranostic nanoparticles (NPs) that deliver small interfering RNA (siRNA), to focus on reversing PDAC-induced cachexia. We found that a cachexia inducing PDAC xenograft induced profound changes in brain, plasma and tumor interstitial fluid glutamine levels that led us to focus on the glutamine/glutamate axis and disruption of glutamine metabolism in Aims 1 and 2 of this application. Our preliminary data with human plasma and human PDAC tissue further support targeting the glutamine/glutamate axis. Of all the visceral organs, the spleen showed the highest number of metabolic changes and the largest weight loss with cachexia. Downregulating the glutamine transporter, SLC1A5, significantly reduced body weight loss compared to empty vector or wild type tumors of similar volumes, and normalized spleen weights to those of normal non-tumor bearing mice or mice with non-cachexia inducing tumors. Since the spleen is a major reservoir of immune cells, the splenic weight loss and metabolic alterations have prompted us to focus on the spleen and tumor immune environments with cachexia, and following disruption of glutamine metabolism, in Aim 3. In Aim 1 we will focus on the glutamine/glutamate axis, studying preclinical PDAC models in immune suppressed as well as immune competent mice with SLC1A5 and glutaminase 1 and 2 (GLS1/2) downregulated. These studies will expand our understanding of the effects of downregulating these target genes on cachexia, and on tumor and organ metabolism using 1H magnetic resonance spectroscopy (MRS), transcriptomics, and molecular characterization. In Aim 2, we will downregulate these target genes in established wild type tumors using biocompatible dextran siRNA NPs that can be imaged to detect tumor delivery and biodistribution. We will also evaluate a pharmacological inhibitor of SLC1A5, V-9302, and of GLS, CB-839, and determine the effects of treatment with siRNA NPs and of pharmacological inhibitors on cachexia and on tumor and organ metabolism using 1H MRS. CB-839 is already in clinical trials for solid cancers, presenting a more immediate strategy for reversing or reducing cachexia. In Aim 3 we will investigate changes in T-cell exhaustion and myeloid derived suppressor cells combined with metabolic changes in the spleen and tumor with or without glutamine disrupted. Mass spectrometry imaging will be used to relate spatial metabolic information to immunostaining. Studies in Aim 3 will include investigating paired spleen and tumor tissue from PDAC patients with or without weight loss and loss of muscle mass as identified in CT scans. The three aims are designed to advance understanding of the consequences of cachexia on organ metabolism and the immune microenvironments in the spleen and tumor, and the role of glutamine metabolism disruption on reversing or reducing these consequences.
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