ly2510924 and Neoplasm-Metastasis

The chemokine (C-X-C Motif) receptor 4 (CXCR4) and its ligand, stromal-cell derived factor-1 (SDF-1), are frequently overexpressed in a variety of solid tumors, and are believed to play important roles in the regulation of organ-specific metastasis, tumor growth, invasion, and survival. In this randomized Phase 2 trial, we evaluated the safety and efficacy of LY2510924 (LY), a peptide antagonist of CXCR4, combined with sunitinib (SUN) in the first-line treatment of advanced renal cell carcinoma (RCC).. Eligible patients were randomized (2:1) to receive LY (20 mg SC daily) + SUN (50 mg PO daily for 4 weeks followed by 2 weeks off) or SUN alone. Response was assessed after two cycles; patients continued treatment until tumor progression or intolerable toxicity. The study was powered to detect a 47 % increase in median progression-free survival (PFS).. One hundred eight patients were randomized and treated (LY + SUN, 72; SUN, 36); median duration of treatment of five cycles. Observed median PFS was 8.1 months with LY + SUN and 12.3 months with SUN; Bayesian time-to-event HR 1.23; 95 % credible interval: 0.74, 1.96. LY was well tolerated; the toxicity profile was typical of SUN. No efficacy differences were seen between treatments groups when subsets with high versus low levels of CXCR4 tumor expression were compared.. The addition of LY to SUN in the first-line treatment of metastatic RCC was well tolerated, but did not improve the PFS or overall survival (OS) vs. SUN alone. CXCR4 remains an unproven therapeutic target for the treatment of RCC.. NCT01391130.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indoles; Male; Neoplasm Metastasis; Peptides, Cyclic; Pyrroles; Receptors, CXCR4; Sunitinib

Emerging evidence demonstrates that stromal cell-derived factor 1 (SDF-1) and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC50 value of 0.079 nmol/L, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nmol/L. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC50 value of 0.26 nmol/L and inhibited SDF-1/CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho-Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small-molecular inhibitor in preclinical species. LY2510924 showed dose-dependent inhibition of tumor growth in human xenograft models developed with non-Hodgkin lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinical studies for cancer.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chemokine CXCL12; Disease Models, Animal; Dogs; Drug Stability; Female; Humans; Macaca fascicularis; Male; Mammary Neoplasms, Experimental; Mice, Inbred C57BL; Neoplasm Metastasis; Peptides, Cyclic; Rats, Sprague-Dawley; Receptors, CXCR4; Signal Transduction; Xenograft Model Antitumor Assays