Abstract 2095: Peptide-based pivoting of p53 to target metastatic breast cancer

Abstract The inability to target distant metastases limits the treatment of late-stage cancers. At least in part, this is due to the lack of optimal targeted therapies and treatment resistance to the remaining standard of care consisting of chemo-/radio- therapy. Here, we show that cancer cells that are irreparably damaged can withstand cell death through a process we define as “scarring”. In scarred cells, p53 is phosphorylated at Ser46 and Ser392 and localizes into progressive multifocal leukemia (PML) nuclear bodies. We have identified scarring in over a quarter of metastatic breast, colon, stomach and ovarian cancer. Thus, pivoting scarred p53 towards cell death in scarred cancer could establish a novel broad-range therapeutic opportunity against metastatic cancer. Targeting p53 with small molecules has proven challenging. We developed cell-penetrating peptides that selectively bind scarred p53. One of our lead compounds, CL04177 dissociates p53 from its PML scaffold leading to its a nuclear exclusion and initiation of the transcription-independent mitochondrial apoptosis. To examine the role of scarring as a therapeutic target, we focused on triple-negative breast cancer (TNBC). TNBC cells are marked by the expression of p53 and PML compared to other breast cancer subtypes. In cytotoxicity experiments, CL04177 specifically targeted TNBC over other breast cancer subtypes. Further investigation into how this compound can target metastatic cells revealed that scarred features are upregulated in metastasis-initiating cells of organoids when induced to invade in contact with collagen and that CL04177 can induce apoptosis specifically in these invading strands. In vivo, CL04177 showed favorable pharmacokinetics and -dynamics and a clear safety profile. Importantly, when dosed at 10-fold below its Maximally Tolerated Dose, CL04177 strongly reduced primary tumor mass and metastatic dissemination to the liver of TNBC cell line-derived orthotopic xenografts. This data indicates a new concept of scarred p53 in cancer progression and metastasis. Moreover, peptides that release scarring markers from nuclear structures can eliminate aggressive cancers in vitro and, most importantly, in vivo, e.g., in p53-mutated, metastatic TNBC. This ability introduces a conceptually new therapeutic option, especially for types of cancer for which there is a high unmet medical need. Citation Format: Diana Putavet, Marjolein P. Baar, Johannes H. Lehmann, Antoine Khalil, Tao Shi, Thijs Koorman, Tobias B. Dansen, Patrick WB Derksen, Michael Teifel, Tobias Madl, Nicholas Sarlis. Peptide-based pivoting of p53 to target metastatic breast cancer [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 2095.