Abstract 285: Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma
Authors: zhang xinyi , Lee Won D. , Leitner Brooks P. , Zhu Wanling , Li Zongyu , Gaspar Rafael C. , Halberstam Alexandra A. , Robles Briana , Rabinowitz Joshua D. , Perry Rachel J. 
Published: April 2023

Abstract
In this study, we identified a potential practice-changing approach, dichloroacetate (DCA), to harness metabolic adjuvant therapy to treat cancer-related fatigue (CRF). CRF is one of the most common complications in patients with multiple cancer types. Although CRF severely affects patients’ quality of life and adherence to potentially curative treatment, there have only been single symptom-relieving adjuvant therapies but no effective pharmaceutical treatment for CRF. In this study, we used YUMMER1.7 murine melanoma as the model to study CRF. Mice with late-stage YUMMER1.7 melanoma (3 weeks after tumor xenograft) have significant decreases in muscle performance, including decrease forelimb grip strength, maximum running speed, maximum oxygen consumption and motivation for movement. Dichloroacetate (DCA) has been considered as a potential therapy to slow tumor growth, based largely on its effects in vitro to halt cell division. We found that although DCA did not affect tumor growth, DCA unexpectedly preserved muscle performance in mice with late-stage compared with early-stage tumors. DCA-treated mice had significantly preserved grip strength (9.5% decrease in DCA-treated late-stage mice vs. 29% in non-treated mice), maximum running speed (13% decrease in DCA-treated mice vs. 31% in non-treated mice) and VO2 peak (no significant reduction in DCA-treated mice whereas non-treated mice decreased by 26%). The daily running distance was also significantly higher in DCA-treated mice compared with non-treated mice during the third week after tumor xenograft. Meanwhile, motivation for movement was fully reserved. Moreover, we found that DCA could relieve treatment-worsened CRF in murine YUMMER1.7 melanoma (treated with anti-PD1 immunotherapy) and MC38 colon cancer (treated with 5-fluorouracil chemotherapy) without affecting the efficacy of these treatments. An in vivo liquid chromatography-mass spectrometry/mass spectrometry-based isotope tracer study suggests that DCA treatment may postpone proteolysis in muscle of tumor-bearing mice. Concentrations of 6 free amino acids (arginine, asparagine, leucine, lysine, methionine and threonine) were increased in muscle from late-stage non-treated mice, consistent with increased proteolysis and/or less amino acid utilization in muscle tissue during advanced-stage tumor progression. Such elevation was reversed by DCA treatment. We also discovered lower concentration of serine and glycine in DCA-treated muscle tissue, which provide precursors for antioxidants to adapt to oxidative stress. The abnormal increase of muscle mitochondrial membrane potential, which may enhance reactive oxygen species production, was also reversed in DCA-treaded mice. In all, this study provides evidence for DCA as the first potential adjuvant pharmaceutical treatment to maintain physical function and motivation in cancer patients experiencing CRF.
Citation Format: xinyi zhang, Won D. Lee, Brooks P. Leitner, Wanling Zhu, Zongyu Li, Rafael C. Gaspar, Alexandra A. Halberstam, Briana Robles, Joshua D. Rabinowitz, Rachel J. Perry. Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 285.