Friday, April 26, 2024
4/26/2024
Project Summary Liver cancer remains one of the most lethal cancers worldwide, second only to pancreatic ductal adenocarcinoma (PDAC), with hepatocellular carcinoma (HCC) making up at least 85% of liver cancer cases. The most effective treatment options for HCC are for early- to intermediate-stage HCC. Unfortunately, due to the absence of signs and symptoms in the early stages, most HCC patients are not diagnosed until advanced-stage of disease, and therefore can only be treated with systemic therapies. First-line therapy for advanced HCC was recently updated to a combination treatment of atezolizumab plus bevacizumab, and while this update is encouraging, progression-free survival currently remains around 7 months. Thus, more effective strategies to treat advanced HCC are still desperately needed. Our lab recently identified an antisense oligonucleotide (ASO) that targets glucose metabolism through alternative splicing of pyruvate kinase (PKM) pre-mRNA, which could be used as a therapy to treat HCC. PKM pre-mRNA undergoes mutually exclusive alternative splicing that results in expression of either the PKM1 or PKM2 isoform. PKM2 is well known to be preferentially upregulated in HCC. Its low enzymatic activity can create a bottleneck at the end of glycolysis that potentially promotes tumor growth by shunting upstream glycolytic intermediates into various biosynthesis pathways. Given that PKM1 has higher enzymatic activity, our ASO-based PKM splice-switching (APSS) therapy is designed to redirect alternative splicing from PKM2 to PKM1, thereby relieving the PKM2-induced bottleneck, and reducing the accumulation of glycolytic intermediates. Currently, our therapy has achieved reduced tumor growth in two pre-clinical models of HCC. Despite these promising results, we have yet to establish a precise metabolic explanation by which APSS therapy results in reduced HCC growth, as well as to evaluate its efficacy in combination with current HCC therapies. My hypothesis is that our APSS therapy reduces serine synthesis in HCC and promotes dependence on extracellular serine to sustain production of purine nucleotides. Additionally, I hypothesize that combination treatment of APSS therapy with sorafenib will re-sensitize sorafenib-resistant HCC tumors. I plan to utilize in vivo stable isotope tracing with LC-MS in HCC xenografts in order to obtain a comprehensive profile of HCC metabolism in response to APSS therapy. Additionally, I will establish sorafenib-resistant HCC xenografts in order to identify potential synergy between our APSS therapy and sorafenib. The significance of the proposed research is that it will: (i) improve our understanding of PKM alternative splicing in tumorigenesis; (ii) help to identify synergistic therapies that reinforce the effects of our APSS therapy; and (iii) provide further justification for the eventual testing of our APSS therapy in clinical trials for advanced HCC.
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