ATX-101, a Peptide Targeting PCNA, Has Antitumor Efficacy Alone or in Combination with Radiotherapy in Murine Models of Human Glioblastoma

Giovanni Luca Gravina; Alessandro Colapietro; Andrea Mancini; Alessandra Rossetti; Stefano Martellucci; Luca Ventura; Martina Di Franco; Francesco Marampon; Vincenzo Mattei; Leda Assunta Biordi; Marit Otterlei; Claudio Festuccia

doi:10.3390/cancers14020289

ATX-101, a Peptide Targeting PCNA, Has Antitumor Efficacy Alone or in Combination with Radiotherapy in Murine Models of Human Glioblastoma

Cancers (Basel). 2022 Jan 7;14(2):289. doi: 10.3390/cancers14020289.

Authors

Affiliations

¹ Department of Biotechnological and Applied Clinical Sciences, Division of Radiation Oncology, University of L'Aquila, 67100 L'Aquila, Italy.
² Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, 67100 L'Aquila, Italy.
³ Department of Biotechnological and Applied Clinical Sciences, Laboratory of Cellular Pathology, University of L'Aquila, 67100 L'Aquila, Italy.
⁴ Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas, 02100 Rieti, Italy.
⁵ Division of Pathology, San Salvatore Hospital, 67100 L'Aquila, Italy.
⁶ Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00100 Rome, Italy.
⁷ Department of Biotechnological and Applied Clinical Sciences, Laboratory of Medical Oncology, University of L'Aquila, 67100 L'Aquila, Italy.
⁸ APIM Therapeutics A/S, N-7100 Rissa, Norway.
⁹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), N-7006 Trondheim, Norway.

Abstract

Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes PCNA an attractive target in anticancer therapies. Here, we show that a cell-penetrating peptide containing the AlkB homolog 2 PCNA-interacting motif (APIM), ATX-101, has antitumor activity in a panel of human glioblastoma multiforme (GBM) cell lines and patient-derived glioma-initiating cells (GICs). Their sensitivity to ATX-101 was not related to cellular levels of PCNA, or p53, PTEN, or MGMT status. However, ATX-101 reduced Akt/mTOR and DNA-PKcs signaling, and a correlation between high Akt activation and sensitivity for ATX-101 was found. ATX-101 increased the levels of γH2AX, DNA fragmentation, and apoptosis when combined with radiotherapy (RT). In line with the in vitro results, ATX-101 strongly reduced tumor growth in two subcutaneous xenografts and two orthotopic GBM models, both as a single agent and in combination with RT. The ability of ATX-101 to sensitize cells to RT is promising for further development of this compound for use in GBM.

Keywords: APIM-peptide; DNA damage signaling; GBM.