The Snark is a Boojum: the continuing problem of drug resistance in the antiangiogenic era

Miller, Kathy D.; Sweeney, C. J.; Sledge, George W.

doi:10.1093/annonc/mdg033

Cited by 37 publications

(15 citation statements)

References 77 publications

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“…Therefore, blocking just one signaling axis likely results in up-regulating or further escalating other pathways (18)(19)(20). This is one possible explanation for the lack of long-term efficacy of angiogenesis inhibitors, such as anti-VEGF antibodies, in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity

Eikesdal

Sugimoto

Birrane

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Tumstatin is an angiogenesis inhibitor that binds to ␣v␤3 integrin and suppresses tumor growth. Previous deletion mutagenesis studies identified a 25-aa fragment of tumstatin (tumstatin peptide) with in vitro antiangiogenic activity. Here, we demonstrate that systemic administration of this tumstatin peptide inhibits tumor growth and angiogenesis. Site-directed mutagenesis identified amino acids L, V, and D as essential for the antiangiogenic activity of tumstatin. The tumstatin peptide binds to ␣v␤3 integrin on proliferating endothelial cells and localizes to select tumor endothelium in vivo. Using 3D molecular modeling, we identify a putative interaction interface for tumstatin peptide on ␣v␤3 integrin. The antitumor activity of the tumstatin peptide, in combination with bevacizumab (anti-VEGF antibody), displays significant improvement in efficacy against human renal cell carcinoma xenografts when compared with the single-agent use. Collectively, our results demonstrate that tumstatin peptide binds specifically to the tumor endothelium, and its antiangiogenic action is mediated by ␣v␤3 integrin, and, in combination with an anti-VEGF antibody it exhibits enhanced tumor suppression of renal cell carcinoma.angiogenesis ͉ ␣v␤3 integrin ͉ bevacizumab ͉ tumstatin peptide

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Section: Discussionmentioning

confidence: 99%

Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity

Eikesdal

Sugimoto

Birrane

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Despite the promising results obtained using VEGF inhibitors, and as it occurs with other therapeutic approaches, tumors become resistant to the antiangiogenic drugs (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

The Absence of Pericytes Does Not Increase the Sensitivity of Tumor Vasculature to Vascular Endothelial Growth Factor-A Blockade

2010

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Recent progress with therapies targeting endothelial cells has drawn attention also to the pericytes as potential target cells for antiangiogenic therapy. Published data suggest that pericytes might confer resistance to vascular endothelial growth factor (VEGF) withdrawal in tumors. This hypothesis has been supported by experiments using tumors with reversible transgenic expression of VEGF-A as well as by individual pharmacologically targeting VEGF and platelet-derived growth factor receptor signaling in endothelial cells and pericytes using receptor tyrosine kinase (RTK) inhibitors with different specificities. However, the RTK inhibitors applied thus far are not entirely specific to the mentioned pathways, and therefore, the effects putatively attributed to pericyte targeting might reflect other antitumor effects. Here, we have reinvestigated the putative benefits of doubly targeting endothelial cells and pericytes in the treatment of experimental tumors. For this purpose, we used two highly specific tools, the pericyte-deficient pdgfb ret/ret mouse and the recently developed specific anti-VEGF-A antibody G6-31, which neutralizes both murine and human VEGF-A. We generated B16, Lewis lung carcinoma, and T241 subcutaneous tumors in both pdgfb ret/ret and control mice and treated these mice with G6-31. Our results fail to show any improved effect of VEGF inhibition, as measured by tumor growth or decrease in vascular density, in pericyte-deficient tumors compared with controls. Our observations suggest that additional targeting of pericytes does not increase the antitumor effect already generated by anti-VEGF drugs. Cancer Res; 70(12); 5109-15. ©2010 AACR.

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“…), and result in increased apoptosis of the endothelial cells as well as pericyte activation and vessel maturation. The single effects mentioned above can be and are actually achieved to some great extent by existing anti-VEGF drugs (at least transiently), the ultimate goal of antiangiogenic cancer treatment -the long-term control of tumour growth, however, is unfortunately out of easy reach at the moment (Broxterman et al, 2003;Ellis and Hicklin, 2008;Miller et al, 2003;Miller et al, 2005).…”

Section: Anti-vegf (Anti-sprouting) Approach and Its Efficacymentioning

confidence: 99%

Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again?

Hlushchuk

Makanya²,

Djonov

2011

Int. J. Dev. Biol.

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�nhi�itors of angiogenesis an� ra�iation in�uce compensatory changes in the tumor �as� �nhi�itors of angiogenesis an� ra�iation in�uce compensatory changes in the tumor �as� culature �oth �uring an� after cessation of treatment. �n numerous preclinical stu�ies, angiogenesis inhi�itors were shown to �e efficient in the treatment of many pathological con�itions, inclu�ing soli� cancers. �n most clinical trials, howe�er, this approach turne� out to ha�e no significant effect, especially if applie� as monotherapy. Reco�ery of tumors after therapy is a major pro�lem in the management of cancer patients. The mechanisms un�erlying tumor reco�ery (or therapy resistance)ha�e not yet �een explicitly eluci�ate�. This re�iew �eals with the transient switch from sprouting to intussuscepti�e angiogenesis, which may �e an a�apti�e response of tumor �asculature to cancer therapy that allows the �asculature to maintain its functional properties. Potential can�i�ates for molecular targeting of this angioa�apti�e mechanism are yet to �e eluci�ate� in or�er to impro�e the currently poor efficacy of contemporary antiangiogenic therapies. KEY WORDS: antiangiogenic therapy, anticancer therapy, protein tyrosine kinase inhibitor, tumor recovery, intussusceptive angiogenesis, escape mechanism Tumor angiogenesisAngiogenesis, the process of formation of new blood vessels from pre-existing ones, plays an essential role in the tumour growth and progression. New vascular segments are needed to supply the increasing tumour mass with oxygen and nutrients. Hence, the crucial step for tumour growth above the size of 1-2 mm 3 is the "angiogenic switch", when the tumour gains capability to produce angiogenic factors and induce angiogenesis (Hanahan and Folkman, 1996). Modes of angiogenesisTwo major modes of angio ge nesis have been described, namely sprouting and intussusception (often also called "non-sprouting" or splitting) (Burri et al., 2004). Sprouting angiogenesis was described more than 150 years ago and has been in the focus of research groups for many decades. This mode of angiogenesis occurs by outgrowth of abluminal sprouts which subsequently merge with existing capillaries. Degradation of endothelial basement membranes (obviously associated with increased vessel permeability) as well as proliferation of endothelial cells are essential for this process (van Hinsbergh and Koolwijk, 2008). This mode of angiogenesis Int.

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The Snark is a Boojum: the continuing problem of drug resistance in the antiangiogenic era

Cited by 37 publications

References 77 publications

Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity

Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity

The Absence of Pericytes Does Not Increase the Sensitivity of Tumor Vasculature to Vascular Endothelial Growth Factor-A Blockade

Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again?

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