Abstract 6174: ATX-101, a peptide drug targeting PCNA, enhances the effect of gemcitabine in liposarcoma and leiomyosarcoma

Abstract Soft tissue sarcomas are heterogeneous mesenchymal neoplasms and account for 1% of all cancers in adults. Over 50 sarcomas subtypes have been classified and many have very limited treatment options which include surgery, chemotherapy and radiation. Two of the most common sarcomas are liposarcoma and leiomyosarcoma which are often treated with chemotherapies such as doxorubicin, dacarbazine and gemcitabine with low response rates. There is now more than ever an urgent need for new therapies for sarcoma. PCNA (Proliferating Cell Nuclear Antigen) is considered to be a key regulator of DNA and cell cycle control. In addition, it has been implicated to have roles in metabolism, cellular signaling and some immunological functions. PCNA forms complexes with proteins bearing a novel PCNA-interacting Peptide Motif called APIM (AlkB homolog 2 PCNA Interacting Motif). This binding usually occurs during stress responses such as those achieved during cancer therapy or cancer development. By preventing stress proteins from repairing or defending themselves, cancer therapies can be made more effective. We examined the in vitro effects of ATX-101, a PCNA-APIM protein interaction blocking peptide, on liposarcoma cell lines LS141, DDLS, SW872, 93T449 and 94T778 and leiomyosarcoma cell lines SK-LMS, SK-UT1 and SK-UT-1B. Cell survival, as measured by cell proliferation assays, indicated IC50s of 7.5-15µM with ATX-101. Enhanced combination effects with ATX-101 and chemotherapies such as doxorubicin, irinotecan and gemcitabine were also observed by proliferation assay. Synergism, with ATX-101 and gemcitabine, was indicated with SynergyFinder analysis. Cell cycle changes exhibited increases of S and G2 phases when treated with ATX-101 and gemcitabine. This correlated with increase of cell cycle proteins, cyclin B1 and cyclin A2. Western blot observations included increase of apoptotic marker, cleaved caspase 3, and DNA damage marker, pH2A.X. In addition, immunofluorescence assay showed increasing pH2A.X with ATX-101 and gemcitabine. In vivo studies revealed ATX-101 enhanced gemcitabine decrease of tumor volume in leiomyosarcoma cell line xenograft, SK-UT1. Tumor target inhibition by western blot showed increased pH2A.X and cleaved PARP along with decreased RAD51 API protein with combination treatment. Taken these observations and results, there is strong evidence of combining gemcitabine with ATX-101 in liposarcoma and leiomyosarcoma. Citation Format: Elgilda Musi, Tahir Sheikh, Matthew Ingham, Sminu Bose, Gary K. Schwartz. ATX-101, a peptide drug targeting PCNA, enhances the effect of gemcitabine in liposarcoma and leiomyosarcoma [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 6174.