Dataset Information

Dual CXCR4 and E-Selectin Inhibitor, GMI-1359, Shows Anti-Bone Metastatic Effects and Synergizes with Docetaxel in Prostate Cancer Cell Intraosseous Growth.

ABSTRACT: 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.

SUBMITTER: Festuccia C

PROVIDER: S-EPMC7017374 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Dual CXCR4 and E-Selectin Inhibitor, GMI-1359, Shows Anti-Bone Metastatic Effects and Synergizes with Docetaxel in Prostate Cancer Cell Intraosseous Growth.

Festuccia Claudio C Mancini Andrea A Gravina Giovanni Luca GL Colapietro Alessandro A Vetuschi Antonella A Pompili Simona S Ventura Luca L Delle Monache Simona S Iorio Roberto R Del Fattore Andrea A Fogler William W Magnani John J

Cells 20191220 1

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 g ...[more]

PMID: 31877673

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Project description:Diffusion of new cancer treatments can be both inefficient and incomplete. The uptake of new treatments over time (diffusion) has not been well studied. We analyzed the diffusion of docetaxel in metastatic prostate cancer. We identified metastatic prostate cancer patients diagnosed from 1995 to 2007 using the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare database. Medicare claims through 2008 were analyzed. We assessed cumulative incidence of docetaxel by socioeconomic, demographic, and comorbidity variables, and compared diffusion patterns to landmark events including release of phase III results and FDA approval dates. We compared docetaxel diffusion patterns in prostate cancer to those in metastatic breast, lung, ovarian, and gastric cancers. To model docetaxel use over time, we used the classic "mixed influence" deterministic diffusion model. All statistical tests were two-sided. We identified 6561 metastatic prostate cancer patients; 1350 subsequently received chemotherapy. Among patients who received chemotherapy, docetaxel use was 95% by 2008. Docetaxel uptake was statistically significantly slower (P < .01) for patients older than 65 years, blacks, patients in lower income areas, and those who experienced poverty. Eighty percent of docetaxel diffusion occurred prior to the May, 2004 release of phase III results showing superiority of docetaxel over standard-of-care. The maximum increase in the rate of use of docetaxel occurred nearly simultaneously for prostate cancer as for all other cancers combined (in 2000). Efforts to increase the diffusion of treatments with proven survival benefits among disadvantaged populations could lead to cancer population survival gains. Docetaxel diffusion mostly preceded phase III evidence for its efficacy in castration-resistant prostate cancer, and appeared to be a cancer-wide-rather than a disease-specific-phenomenon. Diffusion prior to definitive evidence indicates the prevalence of off-label chemotherapy use.

Project description:Prostate cancer (PC) is one of the leading causes of death in males. Available treatments often lead to the appearance of chemoresistant foci and metastases, with mechanisms still partially unknown. Within tumour mass, autophagy may promote cell survival by enhancing cancer cells tolerability to different cell stresses, like hypoxia, starvation or those triggered by chemotherapic agents. Because of its connection with the apoptotic pathways, autophagy has been differentially implicated, either as prodeath or prosurvival factor, in the appearance of more aggressive tumours. Here, in three PC cells (LNCaP, PC3, and DU145), we tested how different autophagy inducers modulate docetaxel-induced apoptosis. We selected the mTOR-independent disaccharide trehalose and the mTOR-dependent macrolide lactone rapamycin autophagy inducers. In castration-resistant PC (CRPC) PC3 cells, trehalose specifically prevented intrinsic apoptosis in docetaxel-treated cells. Trehalose reduced the release of cytochrome c triggered by docetaxel and the formation of aberrant mitochondria, possibly by enhancing the turnover of damaged mitochondria via autophagy (mitophagy). In fact, trehalose increased LC3 and p62 expression, LC3-II and p62 (p62 bodies) accumulation and the induction of LC3 puncta. In docetaxel-treated cells, trehalose, but not rapamycin, determined a perinuclear mitochondrial aggregation (mito-aggresomes), and mitochondria specifically colocalized with LC3 and p62-positive autophagosomes. In PC3 cells, rapamycin retained its ability to activate autophagy without evidences of mitophagy even in presence of docetaxel. Interestingly, these results were replicated in LNCaP cells, whereas trehalose and rapamycin did not modify the response to docetaxel in the ATG5-deficient (autophagy resistant) DU145 cells. Therefore, autophagy is involved to alter the response to chemotherapy in combination therapies and the response may be influenced by the different autophagic pathways utilized and by the type of cancer cells.

Project description:ObjectivesTo assess cabazitaxel versus docetaxel re-challenge for the treatment of metastatic castrate refractory prostate cancer (CRPC) patients previously treated with docetaxel at inception of primary hormone therapy.Patients and methodsThe CANTATA trial was a prospective, two-arm, open-label, phase II study conducted in eight UK centres. Patients over the age of 18, with histologically proven, metastatic prostate cancer who had been previously treated with up to 6 cycles of docetaxel as part of the STAMPEDE trial (or treated with the same drug outside of the trial at primary diagnosis) and had a performance status (PS) of 0-2, were eligible. Patients who progressed during primary treatment with docetaxel or had received prior systemic chemotherapy were excluded. Cabazitaxel (25 mg/m2) or docetaxel (75 mg/m2) was administered via intravenous infusion every 3 weeks with oral prednisolone (10 mg) for up to 10 cycles, until disease progression, death or unacceptable toxicity. The primary outcome was clinical progression-free survival (PFS) as defined by either date of pain progression, date of a cancer-related skeletal-related event, or date of death from any cause. Analyses were by intention to treat. EudraCT number: 2012-003835-40.ResultsBetween 7 March 2013 and 4 January 2016, 15 patients with a median age of 70 years (range 54-76) were recruited; seven received cabazitaxel, eight docetaxel. The study was halted due to slow accrual. The median clinical PFS time in the cabazitaxel group was 6.2 months compared with 8.4 for the docetaxel group (95% confidence intervals were not reached due to the small number of patients). A total of 13 serious adverse events were reported.ConclusionDue to the low number of patients recruited, meaningful comparisons could not be made. However, toxicity was in line with known outcomes for these agents, demonstrating it is feasible and safe to deliver chemotherapy to men relapsing with CRPC after upfront chemotherapy.

Dataset Information

Dual CXCR4 and E-Selectin Inhibitor, GMI-1359, Shows Anti-Bone Metastatic Effects and Synergizes with Docetaxel in Prostate Cancer Cell Intraosseous Growth.

Publications

Dual CXCR4 and E-Selectin Inhibitor, GMI-1359, Shows Anti-Bone Metastatic Effects and Synergizes with Docetaxel in Prostate Cancer Cell Intraosseous Growth.

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