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Principal Investigator: M. CELESTE SIMON
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $921,582
Funding agency: National Cancer Institute
Project Summary
Renal cell carcinoma is among the ten most prevalent malignances in the United States, exhibiting an
increased incidence in both men and women since 2001. The most common kidney cancer subtype is “clear
cell” renal cell carcinoma (ccRCC), which accounts for ~75% of all cases. For early-stage disease, surgical
resection of ccRCCs can be curative, although survival drops significantly for advanced, metastatic cancers.
Multiple therapies are now available to ccRCC patients, including anti-angiogenic VEGF/receptor tyrosine
kinase inhibitors, immune checkpoint blockade, mTORC1-based drugs, and a novel HIF-2a inhibitor.
However, not all patients respond to these treatments and five-year relapse rates now approach 40%, and the
majority of these cases develop metastases. Importantly, ccRCCs lack common oncogenic mutations
observed in other human cancers, including PI3K, PTEN, TP53, and KRAS, which hinders successful
treatment using corresponding targeted therapies. Instead, we have generated copy number variation,
transcriptomic, and metabolomic data to identify multiple metabolic pathways that are universally altered in
ccRCC tumors. These include loss of the gluconeogenic enzyme fructose-1,6-bisphosphate 1 (FBP1) and
urea cycle enzymes, including argininosuccinate synthetase 1 (ASS1), argininosuccinate lyase (ASL), and
arginase 2 (ARG2). Finally, ccRCCs exhibit unusually high numbers of lipid droplets, organelles which store
triglycerides and cholesterol esters and a hallmark of this disease. By delineating the molecular consequences
of these universal metabolic changes, we have developed new therapeutic strategies to target most patients
diagnosed with this kidney cancer subtype. Moreover, our findings have been extended to other cancers such
as hepatocellular carcinoma (HCC) and soft tissue sarcoma (STS) which appear to engage in highly similar
metabolic reprogramming. Our data demonstrate that “senolytics” like ABT-263 could be deployed for the
treatment of HCC, whereas ITX-5061, an inhibitor of the HDL cholesterol transporter SCARB1, may be
effective for treating ccRCC. The results are paradigm-shifting in that understandable skepticism remains
regarding the utility of “drugging” cancer metabolism, considering the metabolic heterogeneity, plasticity, and
redundancy observed in various cancers. However, our results using autochthonous in vivo tumor models
provide a rationale for deeper exploration. Ongoing and future work will investigate how consistent metabolic
adaptations within the tumor parenchyma impact stromal components, such as fibroblasts and immune cells,
based on an arsenal of complementary in vitro and in vivo models, that include novel autochthonous HCC and
STS mouse models and ccRCC and HCC patient derived xenografts and organoids. A principal conceptual
innovation of our recent work is the demonstration that multiple metabolic networks are consistently altered
(~100%) in genetically diverse cancers like ccRCC, HCC, and STS, and the identification of novel, highly
feasible therapeutic strategies.
Terms: <1-Phosphatidylinositol 3-Kinase><ARG2><ARG2 gene><Abscission><Angiogenesis Antagonists><Angiogenesis Blockers><Angiogenesis Inhibitors><Angiogenetic Antagonists><Angiogenetic Inhibitors><Angiogenic Antagonists><Angiogenic Inhibitors><Angiostatic Agents><Anti-Angiogenetic Agents><Anti-Angiogenic Agents><Anti-Angiogenic Drugs><Anti-Cancer Agents><Antiangiogenesis Agents><Antiangiogenic Agents><Antiangiogenic Drugs><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Antioncogene Protein p53><Argininosuccinase><Argininosuccinate Synthetase><Biochemical Pathway><Body Tissues><C-K-RAS><Cancer Drug><Cancers><Cell Body><Cells><Cellular Tumor Antigen P53><Cholesterol Esters><Cholesteryl Esters><Clear cell renal cell carcinoma><Complex><Copy Number Polymorphism><Data><Diagnosis><Disease><Disorder><Disseminated Malignant Neoplasm><Drops><Drugs><Enzyme Gene><Enzymes><Excision><Exhibits><Extirpation><Fibroblasts><Fructose><Future><Genetic Alteration><Genetic Change><Genetic defect><Grawitz Tumor><HDL Cholesterol><HDL Cholesterol Lipoproteins><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatoma><Heterogeneity><High Density Lipoprotein Cholesterol><Human><Hypernephroid Carcinoma><Hypernephroma><Immune><Immunes><In Vitro><Incidence><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Kidney Cancer><Kidney Carcinoma><Levulose><Lipids><Liver Cells Carcinoma><MMAC1><MMAC1 protein><Malignant Neoplasms><Malignant Tumor><Medication><Metabolic><Metabolic Networks><Metabolic Pathway><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Modeling><Modern Man><Molecular><Mutated in Multiple Advanced Cancers 1><Mutation><Neighborhoods><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Neovascularization Inhibitors><Nephroid Carcinoma><Oncogene K-Ras><Oncogenic><Oncoprotein p53><Operative Procedures><Operative Surgical Procedures><Organelles><Organoids><Output><P53><PDX model><PHTS gene><PHTS protein><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PTEN><PTEN gene><PTEN protein><PTEN1><PTK Inhibitors><PTK Receptors><Patient derived xenograft><Patients><Pharmaceutical Preparations><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Phosphoprotein P53><Phosphoprotein pp53><Primary carcinoma of the liver cells><Protein TP53><Protein Tyrosine Kinase Inhibitors><PtdIns 3-Kinase><RASK2><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Relapse><Removal><Renal Adenocarcinoma><Renal Cancer><Renal Carcinoma><Renal Cell Adenocarcinoma><Renal Cell Cancer><Renal Cell Carcinoma><Research><Secondary Neoplasm><Secondary Tumor><Soft tissue sarcoma><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><TK Inhibitors><TP53><TP53 gene><TRP53><Therapeutic><Tissues><Transmembrane Receptor Protein Tyrosine Kinase><Triacylglycerol><Triglycerides><Tumor Protein p53><Tumor Protein p53 Gene><Tumor-Specific Treatment Agents><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Tyrosine Kinase Inhibitor><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><United States><VEGF><VEGFs><Vascular Endothelial Growth Factors><Woman><Work><alpha-Lipoprotein Cholesterol><anti-cancer drug><antiangiogenic><arginase 2><arginase II><argininosuccinate lyase><argininosuccinate synthase><arginosuccinate lyase><arginosuccinate synthase><cancer cell metabolism><cancer metabolism><cancer metastasis><cancer sub-types><cancer subtypes><ccRCC><check point blockade><checkpoint blockade><cholesterol transporters><copy number variant><copy number variation><drug/agent><genome mutation><immune check point blockade><immune checkpoint blockade><in vivo><in vivo Model><inhibitor><innovate><innovation><innovative><kidney adenocarcinoma><liver carcinoma><malignancy><men><metabolism measurement><metabolomics><metabonomics><mouse model><murine model><mutated in multiple advanced cancers 1 protein><neoplasm/cancer><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><p53 Antigen><p53 Genes><p53 Tumor Suppressor><patient derived xenograft model><phosphatase and tensin homologue on chromosome ten><protein p53><resection><senolytics><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptomics><tumor><tumor cell metabolism><tumor cell metastasis><tumor metabolism><urea cycle><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog>