burixafor (GPC-100)

P2, N=40, Recruiting, GPCR Therapeutics, Inc. | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

Key secondary objectives include: assessment of safety and tolerability of GPC-100 and propranolol with and without G-CSF, evaluation of the pharmacodynamics by determining levels of circulating CD34 + cell counts and levels of the chemokine CXCL12 in peripheral blood, and assessment of mean time to ANC and platelet count recovery after ASCT. Exploratory objectives are also included to discover key biomarkers for patient selection, to evaluate cancer/stem/immune cell profiles, and to evaluate treatment impact on patient quality of life.

Co-treatment with CXCL12 and the β2AR agonist epinephrine synergistically increases β-arrestin recruitment to CXCR4 and calcium flux. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

At maximal levels, the CD34 cell counts increased 3- to 14-fold from baseline levels. These results provide support for continued clinical development of burixafor.

Previous studies indicate that stress hormones like epinephrine and norepinephrine exert stimulatory effects on cancer progression by modulating tumorigenesis, proliferation, and metastasis via B2AR signaling...Propranolol improved mobilization induced by a single administration of both GPC-100 and AMD3100...Additionally, combination treatment with G-CSF, GPC-100 and Pro may prove to be best-in-class mobilization therapy for ASCT in MM patients, especially those that fail to mobilize with standard of care. As a result, we will initiate a 2 arm, Phase 2 clinical trial evaluating both GPC-100 + Pro, and the triple combination of G-CSF + GPC-100 + Pro in Q4 of 2022.

siRNA knockdown against Pyk2 or FAK in three primary glioblastoma cell lines, developed from the investigated specimens, in combination with the cytokine receptor inhibitors gefitinib (1 μM), DMPQ (200 nM), and burixafor (1 μM) identified EGF, PDGFβ, and SDF-1α as key extracellular factors in the Pyk2- and FAK-dependent activation of invadopodia formation and the migration of glioma cells. EGF and IL-6 were identified as regulators of the Pyk2- and FAK-dependent activation of cell viability and mitosis.