Validation of PDGFRβ and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1346-1356 ◽  
Author(s):  
Addolorata Maria Luce Coluccia ◽  
Teresa Cirulli ◽  
Paola Neri ◽  
Domenica Mangieri ◽  
Maria Cristina Colanardi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Tumor Growth ◽  
Tyrosine Kinases ◽  
Plasma Cells ◽  
Tumor Vessel ◽  
Synergistic Cytotoxicity ◽  
Vessel Growth ◽  
Endothelial Growth Factor

AbstractInhibition of multiple myeloma (MM) plasma cells in their permissive bone marrow microenvironment represents an attractive strategy for blocking the tumor/vessel growth associated with the disease progression. However, target specificity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)–receptor beta (PDGFRβ) and pp60c-Src as shared constitutively activated tyrosine-kinases (TKs) in plasma cells and endothelial cells (ECs) isolated from MM patients (MMECs). Our cellular and molecular dissection showed that the PDGF-BB/PDGFRβ kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Interestingly, pp60c-Src TK-activity was selectively induced by VEGF in MM tumor and ECs, and the use of small-interfering (si)RNAs validated pp60c-Src as a key signaling effector of VEGF loop required for MMEC survival, migration, and angiogenesis. We also assessed the antitumor/vessel activity of dasatinib, a novel orally bioactive PDGFRβ/Src TK-inhibitor that significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel antimyeloma drugs (ie, melphalan, prednisone, bor-tezomib, and thalidomide). Overall data highlight the biologic and therapeutic relevance of the combined targeting of PDGFRβ/c-Src TKs in MM, providing a framework for future clinical trials.

Dasatinib Inhibits Multiple Myeloma Growth by Blocking PDGF-Rb and c-Src Activity in Patient-Derived Tumor and Endothelial Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 550-550
Author(s):  
Addolorata M.L. Coluccia ◽  
Teresa Cirulli ◽  
Paola Neri ◽  
Franco Dammacco ◽  
Pierfrancesco Tassone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Plasma Cells ◽  
High Dose ◽  
Tumor Vessel ◽  
Angiogenic Switch ◽  
Synergistic Cytotoxicity

Abstract Multiple myeloma (MM) is characterized by a clonal proliferation of immunoglobulin-secreting plasma cells in the bone-marrow (BM) and remains an incurable disease, despite the use of high-dose chemotherapies. Since a marked (BM)-angiogenesis is the hallmark of MM, but not of monoclonal gammopathies of undetermined significance (MGUS), validation of novel agents targeting MM tumor cells and their permissive BM-stroma is crucial to improve patient outcome. Patients fulfilling the International Myeloma Working Group diagnostic criteria for MM (n = 21) and MGUS (n = 14) were studied. Healthy donors or patients with benign anemia (due to vitamin B12 deficiency) were also incuded as controls. In plasma cells and endothelial cells (ECs) isolated from BM-aspirates by anti-CD138 and Ulex Europaeus agglutinin-1 (UEA-1) coated-beads, we dissected the contribution of activity against individual targets such as platelet-derived growth factor (PDGF)-receptor beta (PDGF-Rb) and c-Src tyrosine kinases (TKs), to the anti-tumor/vessel efficacy of dasatinib (BMS-354825), a novel orally bioavailable TK inhibitor. The PDGF-BB/PDGF-Rb kinase-axis was found constitutively activated in plasma cells from patients with MM but not with MGUS or benign anemias, thus supporting its pathophysiological role in MM. PDGF-Rb activated, independently of vascular endothelial growth factor (VEGF)-receptors (VEGF-R1 and VEGF-R2), the mitogen-activated protein kinases (ERK1/2) and the phosphatidylinositol 3-kinase (PI3-K)/AKT-dependent cascade, thereby increasing MM plasma cell growth. Expression of PDGF-Rb, at both mRNA and protein levels, was also increased in MMECs compared to MGECs, correlating with AKT phosphorylation. Exposure to recombinant PDGF-BB or conditioned media from MM plasma cells triggered PDGF-Rb phosphorylation and MMEC migration and spontaneous sprouting in vitro (both being mandatory for angiogenesis). Dasatinib abrogated PDGF-elicited tumor/vessel growth and impaired VEGF-signaling via c-Src TK-inhibition (IC50=25–100nM) in both MM-patient tumor and ECs. The use of small-interfering (si)-RNAs validated c-Src as a key VEGF-downstream effector of MMEC proliferation, migration and capillarogenesis in vitro. Nevertheless, the inhibitory effect elicited by siSrc was partially rescued by recombinant PDGF-BB which sustained the expression of pro-angiogenic factors such as VEGF, interleukin (IL)-8, basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) in MMECs. Dasatinib reversed all these transcriptional effects, thereby abrogating MMEC angiogenesis in the CAM assay as well as the neovascularization and tumor growth of MM-xenografts in vivo. More importantly, low-dose dasatinib showed synergistic cytotoxicity in vitro when tested in combination with conventional MM drugs (i.e. bortezomib and thalidomide), thereby increasing therapeutic efficacy and overcoming drug resistance. These findings indicate that: the PDGF-BB/PDGF-Rb kinase-axis elicits direct effects on MM plasma cells and could promote the MM “angiogenic switch”, hence disease progression; the inhibition of this pathway could provide the rationale for clinical trials with dasatinib which interferes with shared growth-signaling cascades in MM-patient isolated plasma cells and ECs, involving PDGF-Rb and cytosolic c-Src TKs.

Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 350-357 ◽  
Author(s):  
Boris Lin ◽  
Laurence Catley ◽  
Richard LeBlanc ◽  
Constantine Mitsiades ◽  
Renate Burger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Efflux Pump ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Growth And Survival ◽  
Epothilone B ◽  
Endothelial Growth Factor

Abstract In this study, we investigated the in vitro and in vivo efficacy of patupilone (epothilone B, EPO906), a novel nontaxane microtubule stabilizing agent, in treatment of multiple myeloma (MM). Patupilone directly inhibited growth and survival of MM cells, including those resistant to conventional chemotherapies, such as the taxane paclitaxel. Patupilone induced G2M arrest of MM cells, with subsequent apoptosis. Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1), 2 known growth and survival factors for MM, did not protect MM.1S cells against patupilone-induced cell death. Proliferation of MM cells induced by adherence to bone marrow stromal cells (BMSCs) was also inhibited by patupilone and was paralleled by down-regulation of vascular endothelial growth factor (VEGF) secretion. Importantly, stimulation of cells from patients with MM, either with IL-6 or by adherence to BMSCs, enhanced the anti-proliferative and proapoptotic effects of patupilone. Moreover, patupilone was effective against MM cell lines that overexpress the MDR1/P-glycoprotein multidrug efflux pump. In addition, patupilone was effective in slowing tumor growth and prolonging median survival of mice that received orthotopical transplants with MM tumor cells. Taken together, these preclinical findings suggest that patupilone may be a safe and effective drug in the treatment of MM, providing the framework for clinical studies to improve patient outcome in MM. (Blood. 2005;105:350-357)

scholarly journals Split for the cure: VEGF, PDGF-BB and intussusception in therapeutic angiogenesis

2014 ◽  
Vol 42 (6) ◽  
pp. 1637-1642 ◽  
Author(s):  
Roberto Gianni-Barrera ◽  
Mariateresa Bartolomeo ◽  
Brigitte Vollmar ◽  
Valentin Djonov ◽  
Andrea Banfi
Keyword(s):  
Growth Factor ◽  
Therapeutic Angiogenesis ◽  
Therapeutic Benefit ◽  
Vascular Endothelial ◽  
Therapeutic Implications ◽  
Vascular Growth ◽  
Intussusceptive Angiogenesis ◽  
Vessel Growth ◽  
Endothelial Growth Factor

Therapeutic angiogenesis is an attractive strategy to treat patients suffering from ischaemic conditions and vascular endothelial growth factor-A (VEGF) is the master regulator of blood vessel growth. However, VEGF can induce either normal or aberrant angiogenesis depending on its dose localized in the microenvironment around each producing cell in vivo and on the balanced stimulation of platelet-derived growth factor-BB (PDGF-BB) signalling, responsible for pericyte recruitment. At the doses required to induce therapeutic benefit, VEGF causes new vascular growth essentially without sprouting, but rather through the alternative process of intussusception, or vascular splitting. In the present article, we briefly review the therapeutic implications of controlling VEGF dose on one hand and pericyte recruitment on the other, as well as the key features of intussusceptive angiogenesis and its regulation.

Wogonin Inhibits Angiogenesis Via a c-Myc/Hif-1α–dependent Pathway in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5238-5238 ◽  
Author(s):  
Rong Fu ◽  
Qinglong Guo ◽  
Yan Chen ◽  
Huihui Song ◽  
Baoan Chen
Keyword(s):  
Multiple Myeloma ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Conflicts Of Interest ◽  
Tumor Promotion ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Dependent Pathway

Abstract Wogonin, a plant-derived flavone, has been shown to inhibit tumor angiogenesis. Angiogenesis is associated with multiple myeloma (MM) progression. However, the mechanisms that Wogonin inhibits angiogenesis in MM microenvironment are not well known. In this study, we investigated Wogonin inhibited tumor angiogenesis that correlated with the inhibition the secretion of vascular endothelial growth factor (VEGF) in MM cells. The c-Myc/Hif-1α–dependent pathway was essential to regulate MM cell-mediated angiogenesis and contributed to tumor growth. Wogonin inhibited c-Myc activation and down-regulated the expression of c-Myc and Hif-1α. Functionally, based on transient knockdowns and overexpression, our data delineate Wogonin inhibited VEGF production and secretion mediating tumor angiogenesis via c-Myc/Hif-1α–dependent pathway. Our data, therefore, identify Wogonin as a novel anti-angiogenesis compound to inhibit tumor promotion in MM. Disclosures No relevant conflicts of interest to declare.

scholarly journals Anti-cancer effects of F16: A novel vascular endothelial growth factor receptor–specific inhibitor

Tumor Biology ◽  
2017 ◽  
Vol 39 (11) ◽  
pp. 101042831772684 ◽  
Author(s):  
Appu Rathinavelu ◽  
Khalid Alhazzani ◽  
Sivanesan Dhandayuthapani ◽  
Thanigaivelan Kanagasabai
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Growth ◽  
Growth Factor Receptor ◽  
Specific Inhibitor ◽  
Vascular Endothelial ◽  
And Migration ◽  
Endothelial Growth Factor

Vascular endothelial growth factor receptor-2 is a dynamic target for therapeutic intervention in various types of cancers. This study was aimed to explore the anti-angiogenic activity of a novel vascular endothelial growth factor receptor–specific inhibitor named F16 in both in vitro and in vivo experimental models. This compound effectively reduced cell proliferation, tube formation, and migration of human umbilical vein endothelial cells in a concentration-dependent manner by directly inhibiting vascular endothelial growth factor binding and subsequent vascular endothelial growth factor receptor-2 phosphorylation. The F16 was also able to inhibit the phosphoinositide 3-kinase/protein kinase B–mediated survival and migration pathways in cancer in addition to inhibiting the focal adhesion kinase and mitogen-activated protein kinases–mediated signaling in GI-101A cancer cells. The chorioallantoic membrane assay followed by tumor growth inhibition measurements with GI-101A breast cancer xenograft implanted athymic nude mice confirmed the in vivo tumor reductive effects of F16. It was interesting to observe a decrease in tumor burden after F16 treatment which correlated very well with the decrease in the plasma levels of mucin-1 (MUC-1). Our studies so far have confirmed that F16 is a specific inhibitor of angiogenesis in both in vitro and in vivo models. The F16 also works very efficiently with Taxol in combination by limiting the tumor growth that is better than the monotherapy with any one of the drugs that were tested individually. Thus, F16 offers a promising anti-proliferative and anti-angiogenic effects with better specificity than some of the existing multi-kinase inhibitors.

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