Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of pazopanib (GW786034)

Prince, H. Miles; Hönemann, Dirk; Spencer, Andrew; Rizzieri, David A.; Stadtmauer, Edward A.; Roberts, Andrew W.; Bahlis, Nizar J.; Tricot, Guido; Bell, Bill; DeMarini, Douglas J.; Suttle, A. Benjamin; Baker, Kristy Z.; Pandite, Lini

doi:10.1182/blood-2009-02-207209

Cited by 49 publications

(26 citation statements)

References 10 publications

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“…It is possible that Sunitinib increases BMI1 expression, or more likely, as reported with cytotoxic therapies, it preferentially targets the rapidly proliferating cancer cells and thus enriches the fraction of the cancer stem cells remaining. Nevertheless, our result is consistent with treatment failure, as the benefit of anti-angiogenic therapy is often short-lived and the majority of cancer patients eventually relapse and progress [Prince et al, 2009]. Indeed, increasing evidence indicates that better outcomes may be realized by targeting this chemo-resistant tumor cell fraction [Dean, 2009].…”

Section: Therapeutic Targeting Of Bmi1 For the Treatment Of Cancersupporting

confidence: 85%

BMI1 as a novel target for drug discovery in cancer

et al. 2011

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Growing evidence has demonstrated that clonogenic cancer stem (initiating) cells are responsible for tumor regrowth and disease relapse. Bmi-1 plays a critical role in the self-renewal of adult stem cells. The Bmi-1 protein is elevated in many types of cancers, and experimental reduction of Bmi-1 protein levels by small interfering RNA (siRNA) causes apoptosis and/or senescence in tumor cells in vitro and increases susceptibility to cytotoxic agents. The Bmi-1 protein has no known enzymatic activity, but serves as the key regulatory component of the PRC1 complex (polycomb repressive complex-1). This complex influences chromatin structure and regulates transcriptional activity of a number of important loci including the Ink4a locus which encodes the tumor suppressor proteins p16(Ink4a) and p14(Arf) . In this prospective study, we will discuss the implication of BMI1 in cancers, the biology of BMI1, and the regulatory control of BMI1 expression. The target validation and the future prospects of targeting BMI1 in cancer therapy are also discussed.

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Section: Therapeutic Targeting Of Bmi1 For the Treatment Of Cancersupporting

confidence: 85%

BMI1 as a novel target for drug discovery in cancer

et al. 2011

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“…In line with these results, we found also in nonresponders, lower A-values after therapy compared with the initial measurements, which might indicate that vessel regression alone does not automatically translate into reduction of tumor burden. Although this assumption needs to be clarified by further studies, recent clinical trials with antiangiogenic monoclonal antibodies or tyrosine kinase inhibitors as single agents or in combination with bortezomib as well as lenalidomide failed to show additional benefit in patients with relapsed or refractory multiple myeloma (24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Assessment of Antiangiogenic Treatment Effects in Multiple Myeloma

Merz

Ritsch

Kunz

et al. 2015

Clinical Cancer Research

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Purpose: To noninvasively assess bone marrow microcirculation before and after therapy in patients with newly diagnosed multiple myeloma with dynamic contrast-enhanced MRI (DCE-MRI).Experimental Design: Ninety-six patients received DCE-MRI before and after primary treatment for newly diagnosed multiple myeloma. For the 91 evaluable patients, treatment consisted of high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) in 82 patients and chemotherapy without ASCT in 9 patients. In addition, 33 healthy volunteers were imaged as the control group. Analysis of DCE-MRI was performed according to the two-compartment model by Brix to quantify amplitude A (associated with blood volume) and exchange rate constant k ep (reflecting vessel permeability and perfusion).Results: Nonresponders showed significantly higher A-values before the start of therapy compared with responders (P ¼ 0.02). In both responders and nonresponders to therapy, A-values dropped significantly (P ¼ 0.004 and <0.001, respectively) after primary therapy, whereas lower values for k ep were found only in responders (P < 0.001). Depth of remission was significantly correlated to decreased bone marrow microcirculation: Patients in near complete response (nCR) or complete remission (CR) after treatment showed significantly lower values for A compared with patients not achieving nCRþCR. The application of HDT or novel agents had no significant effect on DCE-MRI parameters after therapy, although patients treated with novel agents more often achieved nCRþCR (42%/12.5%; P < 0.002). Higher k ep -values at second MRI were positively correlated to shorter overall survival (HR 3.53; 95% confidence intervals, 1.21-10.33; P ¼ 0.02).Conclusion: Parameters from DCE-MRI are correlated to remission after primary therapy and outcome in newly diagnosed multiple myeloma.

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“…A notable array of compounds have been described in recent years to (partially) inhibit FGFR, next to other Tyrosine Kinase Receptor (TKR), including Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet Derived Growth Factor Receptor (PDGFR), Fms-like tyrosine kinase 3 (FLT-3), c-Kit (c-KIT), Rearranged during transfection (RET) and BCR-ABL. These compounds include Brivatinib (Cai et al, 2008), Lenvatinib (Yamamoto et al, 2014), Regorafenib (Wilhelm et al, 2011), Ponatinib (Gozgit et al, 2012), Dovitininb (Porta et al, 2015), Nintedanib (Dhillon, 2015), Pazopanib (Prince et al, 2009), Orantinib (Ohta et al, 2009), ENMD 2076 (Matulonis et al, 2013), Lucitanib (Bello et al, 2011), PBI 05204 (Hong et al, 2014), Sunitinib (Welti et al, 2011) and Cediranib (Wedge et al, 2005). Although some of them have achieved approval for use against several cancer types, this section only focuses on those multi-target inhibitors that have included a subset of patients with FGFR alterations (Table 1).…”

Section: Non-selective Fgfr Tkismentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

179

162

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of pazopanib (GW786034)

Cited by 49 publications

References 10 publications

BMI1 as a novel target for drug discovery in cancer

BMI1 as a novel target for drug discovery in cancer

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Assessment of Antiangiogenic Treatment Effects in Multiple Myeloma

FGFR a promising druggable target in cancer: Molecular biology and new drugs

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