Abstract 6608: Therapeutic enzyme depletion of L-serine for the treatment of serine auxotrophic tumors

Abstract The non-essential amino acid L-serine (serine) plays an important role in cancer cell growth due to its diverse biosynthetic functions. In many cancer cells, serine can be taken up from the circulation or can be synthesized through the serine synthesis pathway (SSP). We have recently discovered that luminal breast tumors are auxotrophic for serine due to lineage-specific silencing of the SSP gene PSAT1, rendering luminal breast cancer cells sensitive to serine deprivation both in vitro and in vivo. At present the only way to reduce serine availability for tumors in vivo is through dietary serine starvation, which in mice reduces circulating serine levels by ~50% and has been shown to inhibit the growth of numerous mouse models of cancer. Importantly, dietary serine is achieved in mice using a synthetic protein-free diet that may be difficult for humans to sustain. Nevertheless, dietary serine starvation is currently being explored in a clinical trial for pancreatic cancer. To circumvent some of the challenges associated with dietary serine starvation, we have developed a therapeutic serine degrading enzyme that we are exploring as a potential treatment for serine auxotrophic tumors. Our enzyme, eSDH, is based on the human serine dehydratase enzyme that facilitates the pyridoxal phosphate-dependent irreversible deamination of serine to pyruvate and ammonia. Relative to wild-type serine dehydratase, eSDH has significantly improved stability in serum as well increased activity towards serine. Injection of eSDH into mice is well-tolerated and leads to long-term, near-complete (>95%) reduction in circulating serine levels without the need for dietary changes. Importantly, eSDH treatment inhibits the growth of serine auxotrophic cancer cells in vitro and in vivo. We are currently assessing the efficacy of eSDH treatment in advanced models of luminal/ER+ breast cancer and when utilized in combination with endocrine therapy and other standard-of-care treatments for luminal/ER+ cancer patients. In addition to the degradation of serine, eSDH also depletes circulating L-threonine (threonine), which could contribute to the in vivo activity of eSDH. However, we have recently developed new eSDH variants that are highly selective for serine over threonine and show enhanced specificity for serine auxotrophic cancer cells. In conclusion, we have developed a prototypical therapeutic serine degrading enzyme that may provide an opportunity to clinically achieve more complete serine starvation in patients without the need for restrictive dietary changes. Citation Format: Vipin Rawat, Huiping Zhao, Ladan Mashouri, Prarthana Prasanth, Kelly Conger, Sarita Bhetawal, Alessandra Araujo, Everett Stone, Jonathan Coloff. Therapeutic enzyme depletion of L-serine for the treatment of serine auxotrophic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6608.