A phase II clinical trial of the Vascular Disrupting Agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma

Nowak, Anna K.; Brown, Chris; Millward, Michael; Creaney, Jenette; Byrne, Michael; Hughes, Brett; Kremmidiotis, Gabriel; Bibby, David C.; Leske, Annabell F.; Mitchell, Paul; Pavlakis, Nick; Boyer, Michael; Stockler, Martin R.

doi:10.1016/j.lungcan.2013.05.006

Cited by 49 publications

(30 citation statements)

References 22 publications

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“…The majority of patients that experienced benefit from VDA treatment occurred in the form of disease stabilization, potentially attributable to the anti-proliferative effects that tubulin-binding agents also have on tumor parenchymal cells. 3,12,13 Phase II trials involving the combination of a VDA with platinum or taxane-based regimens have provided some encouraging data 9,21 but follow-on phase III trials did not support further development. 10 We have explored the notion that a way to harness the action of VDA agents is through combination with targeted therapeutics which exploit the adaptive responses of the tumors to a sudden depletion of vasculature.…”

Section: Discussionmentioning

confidence: 99%

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The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer

Inglis

Lavranos

Beaumont

et al. 2014

Cancer Biology & Therapy

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Abbreviations: HIF1a, hypoxia-inducible factor 1-alpha; GLUT-1, glucose transporter 1; mTOR, mammalian target of rapamycin; 4EBP1, eukaryotic translation initiation factor 4E binding protein 1; eIF2a, eukaryotic translation initiation factor 2a; VEGF, vascular endothelial growth factor; VDA, vascular disrupting agent; NSCLC, non-small-cell lung carcinoma; PERK, protein kinase-like endoplasmic reticulum kinase; PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor; PFS, progression free survival; IFNa, interferon a; H&E, hematoxylin and eosin.BNC105 is a tubulin targeting compound that selectively disrupts vasculature within solid tumors. The severe tumor hypoxia and necrosis that ensues translates to short term tumor growth inhibition. We sought to identify the molecular and cellular events activated following BNC105 treatment that drives tumor recovery. We investigated tumor adaptation to BNC105-induced hypoxia in animal models of breast and renal cancer. HIF-1a and GLUT-1 were found to be strongly upregulated by BNC105 as was the VEGF signaling axis. Phosphorylation of mTOR, 4E-BP-1 and elF2a were upregulated, consistent with increased protein synthesis and increased expression of VEGF-A. We sought to investigate the potential therapeutic utility of combining BNC105 with agents targeting VEGF and mTOR signaling. Bevacizumab and pazopanib target the VEGF axis and have been approved for first line use in renal cancer. Everolimus targets mTOR and is currently approved in second line therapy of renal and particular breast cancers. We combined these agents with BNC105 to explore the effects on tumor vasculature, tumor growth inhibition and animal survival. Bevacizumab hindered tumor vascular recovery following BNC105 treatment leading to greater tumor growth inhibition in a breast cancer model. Consistent with this, addition of BNC105 to pazopanib treatment resulted in a significant increase in survival in an orthotopic renal cancer model. Combination treatment of BNC105 with everolimus also increased tumor growth inhibition. BNC105 is currently being evaluated in a randomized phase II clinical trial in combination with everolimus in renal cancer.

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Section: Discussionmentioning

confidence: 99%

“…12 A number of patients receiving BNC105 as monotherapy experienced disease stabilization with one case of durable partial response. 13 Clinical evaluation of BNC105 in combination with standard of care treatments is currently being explored in renal and ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer

Inglis

Lavranos

Beaumont

et al. 2014

Cancer Biology & Therapy

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“…Results were disappointing with a median PFS of 1.5 months. These results did not warrant further research as a single agent [48].…”

Section: Immunomodulation and Other Pathwaysmentioning

confidence: 82%

Second line therapy in malignant pleural mesothelioma: A systematic review

et al. 2015

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a b s t r a c tAfter the implementation of standard first line chemotherapy with platinum and antifolates in pleural mesothelioma, patients are confronted with a need for second line treatment at relapse or progression. We conducted a systematic review of the literature for the activity, effectiveness and toxicity of second line treatment. The results are presented according to the class of drugs: chemotherapy and targeted or biological agent.

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“…Clinically, there is also limited evidence of tumor shrinkage using VDAs as single agents, although a complete response was observed in a patient with anaplastic thyroid cancer (ATC) treated in a Phase I trial (NCT00003768) with CA4P (102). The VDA BNC105 is a tubulin polymerization inhibitor that preclinically demonstrated an ability to inhibit tumor growth (124), but following a Phase II trial (no trial registration number) it was deemed ineffective as a monotherapy when used in mesothelioma (125). Furthermore, as discussed above, VDA monotherapy is unlikely to be curative as these agents are not able to eliminate residual cells at the tumor's edge (68,71).…”

Section: Vdas As Monotherapymentioning

confidence: 99%

Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer

Siemann

Chaplin

Horsman

2017

Cancer Investigation

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Vascular targeted therapies (VTTs) are agents that target tumor vasculature and can be classified into two categories: those that inhibit angiogenesis and those that directly interfere with established tumor vasculature. Although both the anti-angiogenic agents (AAs) and the vascular disrupting agents (VDAs) target tumor vasculature, they differ in their mechanism of action and therapeutic application. Combining these two agents may realize the full potential of VTT and produce an effective therapeutic regimen. Here, we review AAs and VDAs (monotherapy and in combination with conventional therapies). We also discuss the rationale of combined VTT and its potential to treat cancer.

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A phase II clinical trial of the Vascular Disrupting Agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma

Cited by 49 publications

References 22 publications

The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer

The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer

Second line therapy in malignant pleural mesothelioma: A systematic review

Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer

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