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Metastatic castration resistant prostate cancer (mCRPC) relapses due to acquired resistance to docetaxel-based chemotherapy and remains a major threat to patient survival. In this report, we tested the effectiveness of a dual CXCR4/E-selectin antagonist, GM-I1359, in vitro and in vivo, as a single agent or in combination with docetaxel (DTX). This agent was compared to the single CXCR4 antagonist, CTCE-9908, and E-selectin antagonist, GMI-1271. Here we demonstrate that CXCR4 antagonism reduced growth and enhanced DTX treatment in PCa cell lines as well as restored DTX effectiveness in DTX-resistant cell models. The efficacy of dual antagonist was higher respect to those observed for single CXCR4 antagonism. GM1359 impacted bone marrow colonization and growth in intraventricular and intratibial cell injection models. The anti-proliferative effects of GMI-1359 and DTX correlated with decreased size, osteolysis and serum levels of both mTRAP and type I collagen fragment (CTX) in intra-osseous tumours suggesting that the dual CXCR4/E-selectin antagonist was a docetaxel-sensitizing agent for bone metastatic growth. Single agent CXCR4 (CTCE-9908) and E-selectin (GMI-1271) antagonists resulted in lower sensitizing effects compared to GMI-1359. These data provide a biologic rationale for the use of a dual E-selectin/CXCR4 inhibitor as an adjuvant to taxane-based chemotherapy in men with mCRPC to prevent and reduce bone metastases. [ABSTRACT FROM AUTHOR]

Simple Summary: PCNA is an interesting target for cancertreatment due to its essential activities in DNA replication and repair and its recently discovered regulatory roles in cellular signaling. Here, we demonstrate that ATX-101, a peptide targeting PCNA, has antitumor effects as a single agent and radiosensitizing properties in glioblastoma multiforme models. 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. [ABSTRACT FROM AUTHOR]

Metastatic castration resistant prostate cancer (mCRPC) relapses due to acquired resistance to docetaxel-based chemotherapy and remains a major threat to patient survival. In this report, we tested the effectiveness of a dual CXCR4/E-selectin antagonist, GM-I1359, in vitro and in vivo, as a single agent or in combination with docetaxel (DTX). This agent was compared to the single CXCR4 antagonist, CTCE-9908, and E-selectin antagonist, GMI-1271. Here we demonstrate that CXCR4 antagonism reduced growth and enhanced DTX treatment in PCa cell lines as well as restored DTX effectiveness in DTX-resistant cell models. The efficacy of dual antagonist was higher respect to those observed for single CXCR4 antagonism. GM1359 impacted bone marrow colonization and growth in intraventricular and intratibial cell injection models. The anti-proliferative effects of GMI-1359 and DTX correlated with decreased size, osteolysis and serum levels of both mTRAP and type I collagen fragment (CTX) in intra-osseous tumours suggesting that the dual CXCR4/E-selectin antagonist was a docetaxel-sensitizing agent for bone metastatic growth. Single agent CXCR4 (CTCE-9908) and E-selectin (GMI-1271) antagonists resulted in lower sensitizing effects compared to GMI-1359. These data provide a biologic rationale for the use of a dual E-selectin/CXCR4 inhibitor as an adjuvant to taxane-based chemotherapy in men with mCRPC to prevent and reduce bone metastases.