Pretreatment hepatocyte growth factor and thrombospondin-1 levels predict response to high-dose chemotherapy for multiple myeloma

Abstract

Our aim was to establish whether the pretreatment levels of angiogenesis activators and inhibitors can be used to predict clinical responses to treatment that included high-dose chemotherapy with peripheral stem cell support.We analyzed samples and treatment outcomes of 96 patients with MM enrolled in the CMG 2002 randomized clinical trial and treated with induction chemotherapy and high-dose chemotherapy with stem cell support. Concentrations of vascular endothelial growth factor (VEGF), hepatocytar growth factor (HGF), basic fibroblastic growth factor (bFGF), thrombospondin-1 (TSP-1), endostatin, and angiostatin were measured in the peripheral blood plasma and in the bone marrow plasma at diagnosis.Pretreatment HGF concentrations in the peripheral blood plasma as well as in the bone marrow plasma of patients who achieved complete or very good partial response were significantly lower than those in patients who had partial or worse response. Patients with complete or very good partial response had higher TSP-1 levels in the bone marrow plasma than the partial or insufficient response subgroups. There were no correlations between the pretreatment levels of VEGF, bFGF, endostatin, or angiostatin and the treatment response.Pretreatment concentrations of HGF and TSP-1 were predictive factors for treatment response. Patients with low angiogenesis rate as determined by the relative HGF and TSP-1 concentrations were more likely to achieve complete or very good partial response after high-dose chemotherapy.

Levels of angiogenic factors in patients with multiple myeloma correlate with treatment response

“…On the other hand, Cibeira and collaborators have not confirmed any correlation between response rate and VEGF level [22]. We are the first to report that the angiogenesis inhibitor TSP-1 increases in patients who achieve CR or VGPR after first-line treatment for MM [23].…”

“…We have also found that pretreatment concentrations of HGF and TSP-1 are predictive factors for treatment response. Patients with low angiogenesis rate as determined by HGF and TSP-1 concentrations were more likely to achieve complete or very good partial response after high-dose chemotherapy and probably had better prognosis than others [23].…”

Phase IB study of cabozantinib in patients with relapsed and/or refractory multiple myeloma

“…Ibrutinib is the first in a class of US Food and Drug Administration (FDA)-approved Bruton tyrosine kinase inhibitor that acts by blocking B-cell antigen receptor signaling and changing the tumor microenvironment, 6 thereby reducing malignant proliferation of B cells and inducing apoptosis. [6][7][8] It is indicated in relapsed/refractory and in treatment-naïve 17p-deleted CLL.…”

“…1 HGF and HGF receptor protein (MET) have been implicated in myeloma pathogenesis based on the observation that elevated HGF levels are associated with worse prognosis [2][3][4] and lack of response to chemotherapy. 5,6 In addition, MM cells express HGF, creating a putative autocrine HGF/MET loop. [7][8][9] In vitro models demonstrated myeloma cell growth inhibition through MET or HGF inhibition.…”

A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases

“…Dysregulation of the HGF/c-Met signaling axis can lead to aberrant cell proliferation and drug resistance and promote cell migration, invasive growth, and angiogenesis (3)(4)(5)(6)(7)(8)(9), and is observed in many malignancies, including those of the pancreas, lung, stomach, breast, and kidney (3,5,(10)(11)(12)(13)(14)(15)(16).…”