Abstract PS4-04-24: Pharmacological Repurposing of Natural Products for Triple-Negative Breast Cancer

Abstract Breast cancer affects approximately 1 in 8 women in the United States, with triple-negativebreast cancer (TNBC), representing 10–15% of all cases. TNBC is characterized by lowexpression of estrogen, progesterone, and HER2 receptors, which limits the efficacy ofapproved therapeutics targeted against these receptors. The molecular subtyping of TNBCshas been valuable in the search for new genetic and pharmacological vulnerabilities against thisheterogeneous disease and includes basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M),and luminal androgen receptor (LAR) subtypes. We previously screened natural productextracts for selective cytotoxic efficacy among TNBC cell lines representing each of thesesubtypes, which led to the identification of the diterpenoid yuanhuacine as highly selectiveagainst the BL2 subtype, both in vitro and in vivo antitumor studies. This is notable as BL2tumors represent 13% of TNBCs and have the lowest pathological complete response rate toneoadjuvant chemotherapy among these molecular subtypes at 0%. Further studies havedemonstrated that structurally and functionally related ingenane diterpenoids in clinicaldevelopment for the topical treatment of skin malignancies, including tigilanol tiglate andingenol-3-angelate, retain BL2 subtype-selective activity with over one-thousand-fold selectivity,providing a unique opportunity for drug repurposing.To support these efforts, we have taken a multipronged approach to identify the mechanism ofselectivity of these compounds against BL2 TNBC cells, perform structure-activity relationship(SAR) and pharmacokinetic studies to inform on repurposing this drug class for systemicadministration, and determine their efficacy in combination with standard of care chemotherapy.We have demonstrated that the selective activity of yuanhuacine and ingenane diterpenoids isdue to activation of PKCβ, which is elevated in cell lines representing the BL2 TNBC subtype.The evaluation of sixteen structurally related compounds with potency in BL2 cell lines rangingfrom 0.07 – 50,000 nM with 3 – 300,00-fold selectivity for this subtype has informed on the SARfor BL2-specific cytotoxicity. In vitro pharmacokinetic studies have further demonstratedpotential liabilities of this drug class that need to be taken into account with systemicadministration that will be used in combination with SAR studies to inform on medicinalchemistry efforts to prioritize compounds for antitumor efficacy studies in BL2 tumor models anddevelop compounds with a greater therapeutic index than yuanhuacine. We have also identifiedoptimal combinations of these highly BL2-selective compounds with standard of carechemotherapeutics to identify drug pairings that would have optimal efficacy in heterogenousBL2-enriched TNBC tumors. Finally, we have identified additional tumor types that expressPKCβ, including pediatric cancers, and determined the potential for ingenane diterpenoids forrepurposing in a broader group of cancers through molecular profiling. Together, these studiesinform on the potential to repurpose a class of natural products developed for skin cancer for thetreatment of a molecularly defined subtype of TNBC to improve targeted treatment options forthese patients. Citation Format: M. A. Perez, C. S. Fermaintt, A. Risinger. Pharmacological Repurposing of Natural Products for Triple-Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-04-24.