{"doi":"10.13023/etd.2021.370","title":"DELINEATING THE ROLE OF FATTY ACID METABOLISM TO IMPROVE THERAPEUTIC STRATEGIES FOR COLORECTAL CANCER","abstract":"Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the world, comprising over 1 million new cases each year and over 500,000 deaths. CRC, when detected at an early stage of disease development, can be effectively treated, with a 5-year survival rate of over 90%. Such standard treatments include surgical resection of the primary tumor in combination with adjuvant chemotherapy. However, even with advancements in surgical procedures and chemotherapeutic targets, when CRC progresses to a more advance stage, the 5-year survival rate decreases significantly to just under 14%. This stark decrease in patient survival rate can be directly contributed to the lack of effective chemotherapeutics as well as relapse, which occurs in 30-50% of patients treated for CRC and results in a far more aggressive disease. With such a large rate of CRC relapse and drastically low survival rates, the need for new therapeutic targets for the disease are particularly needed. Dysregulation of fatty acid (FA) metabolism has been identified as a hallmark of cancer and a key proponent to CRC development and progression. FAs are used for a multitude of purposes within the cell, such as signaling molecules, components of membrane synthesis, and most importantly, as a direct energy source. Two different pathways contribute to FA utilization in cancer cells. First, FAs can be synthesized de novo. FA Synthase (FASN), a key enzyme of de novo FA synthesis, catalyzes the synthesis of palmitate from acetyl-CoA and malonyl-CoA. Another prominent pathway utilized by cells to obtain FAs is exogenous FA uptake via transmembrane FA transporters including FA Translocase (CD36). CD36 is a multifunctional glycoprotein, is primarily involved in the binding and transportation of low-density lipoproteins and long-chain/ultra-long-chain FAs. My research assessed the role of CD36 in CRC growth and metastasis as well as the relationship between CD36 and FASN, particularly, the aspect of this relationship when de novo lipid synthesis is inhibited using novel FASN inhibitors. FASN upregulation has been previously shown to contribute to primary CRC growth and progression to metastasis. Chemical inhibition of FASN via a novel FASN inhibitor TVB-3664, has shown significant promise in the treatment of CRC in vitro by reducing CRC proliferation via a decrease is cellular respiration. Interestingly, pre-clinical evaluation of this inhibitor in patient derived xenografts (PDXs) in vivo suggests that high expression of FASN does not determine a positive response to FASN-targeted therapy and only approximately 30% of PDXs exhibit significant tumor reduction. These results suggest that there may be alternative pathways which may contribute to FASN inhibition resistance. CD36 has been studied in various diseases, including glioblastoma, breast, ovarian, and oral carcinomas, where it has been found to significantly contribute to disease progression and metastasis. However, CD36 has not yet been thoroughly investigated in CRC, and has not been studied in relation to de novo lipid synthesis. My studies show that CD36 is upregulated in CRC primary and metastatic tumors and an increased expression level of CD36 is associated with an increase in FA uptake. Furthermore, CD36 inhibition significantly decreases proliferation of CRC established and primary cell lines in vitro, and knockdown of CD36 reduces subcutaneous xenograft tumor growth in vivo. Most excitingly, inhibition of FASN significantly and specifically upregulates CD36 expression, but not other FA transporters, in human tissues, established and primary cell lines, and genetically modified mice with heterozygous and homozygous deletion of FASN. This upregulation of CD36 in the presence of FASN inhibition resulted in a CD36 specific increase in the uptake of exogenous FA analogues, further supporting the role of CD36 as a potential compensatory mechanism to FASN-targeting therapy. Additionally, inhibition of FASN and","journal":"UKnowledge (University of Kentucky)","year":2021,"id":226280,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9584,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":279696,"name":"James Drury","orcid":null,"position":0,"is_corresponding":true}],"reference_count":292,"raw_metadata":null,"created_at":"2026-07-18T23:54:34.185847Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}