Abstract
Abstract The interaction between the chemokine receptor CXCR4 and its ligand, CXCL12, has been shown in pre-clinical models to facilitate tumour metastasis and to be involved in tissue repair and in recruitment of hematopoietic precursors. AMD3100, a potent CXCR4 antagonist, has been approved by FDA for stem cell mobilization in patients with multiple myeloma and non-Hodgkin lymphoma. Several other CXCR4 inhibitors are in clinical development (BTK140, CTCE-9908, MDX-1338 and POL6326), with the aim of inhibiting the development and progression of metastasis. In the rational design of CXCR4 inhibitors, a new class of cyclic peptide CXCL12-based CXCR4 inhibitors was discovered (IT Patent M12010A 000096; PCT WO2011/092575 A1) and validated for efficacy in in vitro and in vivo models. Among the tested peptides RFF-1 showed potent and specific inhibitory effects on CXCR4-mediated functions in multiple in vitro assays (P-ERK induction, migration and calcium mobilization CXCL12-induced and binding to CXCR4). C57/BL mice were injected with B16 melanoma cells transfected with human CXCR4. A 4,5 fold reduction in lung metastases was observed after 10 days treatment with 2 mg/kg intraperitoneally (i.p.) RFF-1 compared to the CXCR4 inhibitor AMD3100 (1.25mg/kg i.p), the powerful CXCR4 inhibitor not suitable for prolonged administration, that reduced lung metastases of about 4 fold. In another model of mouse osteosarcoma, K7M2 murine cells, were injected in Balb/C mice. A 3 fold reduction in lung metastases was observed after 15 days treatment with 10 mg/kg i.p. RFF-1 whereas AMD3100 treatment (2.5mg/kg i.p.) lead to 1.8 fold increase in lung metastases. Additionally, a 30% reduction in primary cell growth was achieved in a subcutaneous model of human renal cancer SN12C cells when i.p. treated with 2 mg/kg RFF-1. With the aim to evaluate RFF-1 efficacy in hematopoietic stem cell (HSC) mobilization DBA/2 healthy mice were injected with a single s.c. RFF-1 dose and peripheral blood HSC mobilization was evaluated by colony forming unit assay. Treatment with 30 mg/kg RFF-1 results in rapid, potent and durable mobilization of HSC reaching faster the peak compared to 20 mg/kg AMD3100. These results have prompted us to pursue the clinical development of peptide RFF-1. A first in human Phase I trial is planned to determine the maximal tolerated dose and recommended Phase 2 dose, toxicity profile, pharmacokinetics and antitumor activity of RFF-1 in patients with refractory solid tumors. The Phase I-II study of a novel CXCR4 antagonist provides the opportunity to develop settings in diseases where there is increasing evidence of a role for CXCR4 in the development and progression of metastases such as relapsed glioblastoma, neoadjuvant colorectal and breast cancer, and advanced prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4645. doi:1538-7445.AM2012-4645
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.