Targeting Bone Marrow to Potentiate the Anti-Tumor Effect of Tyrosine Kinase Inhibitor in Preclinical Rat Model of Human Glioblastoma

Abstract

Antiangiogenic agents caused paradoxical increase in pro-growth and pro-angiogenic factors and caused tumor growth in glioblastoma (GBM). It is hypothesized that paradoxical increase in pro-angiogenic factors would mobilize Bone Marrow Derived Cells (BMDCs) to the treated tumor and cause refractory tumor growth. The purposes of the studies were to determine whether whole body irradiation (WBIR) or a CXCR4 antagonist (AMD3100) will potentiate the effect of vatalanib (a VEGFR2 tyrosine kinase inhibitor) and prevent the refractory growth of GBM. Human GBM were grown orthotopically in three groups of rats (control, pretreated with WBIR and AMD3100) and randomly selected for vehicle or vatalanib treatments for 2 weeks. Then all animals underwent Magnetic Resonance Imaging (MRI) followed by euthanasia and histochemical analysis. Tumor volume and different vascular parameters (plasma volume (vp), forward transfer constant (Ktrans), back flow constant (kep), extravascular extracellular space volume (ve) were determined from MRI. In control group, vatalanib treatment increased the tumor growth significantly compared to that of vehicle treatment but by preventing the mobilization of BMDCs and interaction of CXCR4-SDF-1 using WBIR and ADM3100, respectively, paradoxical growth of tumor was controlled. Pretreatment with WBIR or AMD3100 also decreased tumor cell migration, despite the fact that ADM3100 increased the accumulation of M1 and M2 macrophages in the tumors. Vatalanib also increased Ktrans and ve in control animals but both of the vascular parameters were decreased when the animals were pretreated with WBIR and AMD3100. In conclusion, depleting bone marrow cells or CXCR4 interaction can potentiate the effect of vatalanib.

Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma

“…The effect of AMD3100 in comparison to VEGF pathway inhibitors has been extensively researched in preclinical in vivo models [94,149,150]. These studies have found that AMD3100 exceeded the classical AAT regarding tumor growth rate reduction [94,[149][150][151], blood vessel density [149,151] and other vasculogenic parameters [94,150,151]. Kioi et al found that radiotherapy, one of the pillars of the GBM standard-of-care therapy, triggers the recruitment of BMDCs into the tumors [94].…”

The role of tumor microenvironment in resistance to anti-angiogenic therapy

“…BMDCs play a crucial role in the progression of angiogenesis and resistance to anti-angiogenic therapy. Many studies have shown that recruitment of BMDCs in GBM can cause resistance to vatalanib treatment and correspondingly the depletion of BMDCs can potentiate the effects of vatalanib 95 – 97 . Hypoxia-regulated neuropilin-1 (Nrp1), a marker of pro-angiogenic macrophages, can regulate the infiltration of TAMs into tumor hypoxic regions, and loss of Nrp1 in macrophages reduced angiogenesis and tumor growth 98 .…”

Major Challenges and Potential Microenvironment-Targeted Therapies in Glioblastoma

“…In addition, our study found a significantly higher number of GFP+ bone marrow cells in close proximity to CD11b+ and F4/80+ cells [ 37 ]. In another study, we reported that the paradoxical growth of tumor following Vatalanib treatment was controlled by inhibiting the mobilization of BMDCs and disrupting the CXCR4-SDF-1α interaction using whole body irradiation and AMD3100, respectively [ 38 ]. BMDCs orchestrated the therapeutic resistance to AAT in a GBM model.…”