A Phase II Study of ABT-510 (Thrombospondin-1 Analog) for the Treatment of Metastatic Melanoma

Markovic, Svetomir N.; Suman, Vera J.; Rao, Ravi A.; Ingle, James N.; Kaur, Judith S.; Erickson, Lori A.; Pitot, Henry C.; Croghan, Gary A.; McWilliams, Robert R.; Merchan, Jaime R.; Kottschade, Lisa A.; Nevala, Wendy K.; Uhl, Cindy B.; Allred, Jacob B.; Creagan, Edward T.

doi:10.1097/01.coc.0000256104.80089.35

Cited by 97 publications

(67 citation statements)

References 57 publications

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“…Although the results on overall survival were encouraging, insufficient response was seen to unambiguously promote this application. Additionally, 21 patients with stage IV (metastatic) melanoma were studied in a phase II trial of ABT-510 monotherapy (Markovic et al 2007). Similarly, this study failed to yield convincing evidence that ABT-510 alone resulted in improvement in clinical outcomes.…”

Section: Exogenous Thrombospondins and Their Derivativesmentioning

confidence: 99%

Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and -2

Lawler

2012

Cold Spring Harbor Perspectives in Medicine

416

335

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Thrombospondins TSP-1 and TSP-2 are potent endogenous inhibitors of angiogenesis. They inhibit angiogenesis through direct effects on endothelial cell migration, proliferation, survival, and apoptosis and by antagonizing the activity of VEGF. Several of the membrane receptor systems and signal transduction molecules that mediate the effects of TSP-1 and TSP-2 have been elucidated. TSP-1 and TSP-2 exert their direct effects through CD36, CD47, and integrins. Recent data indicate that CD36 and b1 integrins collaborate to transmit the signals that are initiated by TSP-1 and TSP-2. Furthermore, these receptors appear to associate with VEGFR2 to form a platform for the integration of positive and negative signals for angiogenesis. Cross talk between pro-and antiangiogenic signal transduction pathways may enable TSP-1 and TSP-2 to inhibit angiogenesis by antagonizing survival pathways while also activating apoptotic pathways. CD36 and CD47 are both involved in the suppression of nitric oxide (NO). Advances in understanding of the molecular regulation of angiogenesis by TSP have paved the way for innovations in experimental treatment of cancers and will likely continue to offer vast avenues for discovery in other disease processes as well.

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Section: Exogenous Thrombospondins and Their Derivativesmentioning

confidence: 99%

Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and -2

Lawler

2012

Cold Spring Harbor Perspectives in Medicine

416

335

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“…CD36 has been shown to mediate the anti-angiogenic activity of the TSRs [27]. The TSRs of THBS-1 and -2, as well as several other proteins, inhibit angiogenesis.…”

Section: Functional Sitesmentioning

confidence: 99%

“…The TSRs of THBS-1 and -2, as well as several other proteins, inhibit angiogenesis. Furthermore, an anti-angiogenic compound, designated ABT-510, which is based on the THSB-1 sequence, is currently in clinical trials as a treatment for cancer [27]. ABT-510 is a substituted derivative of the peptide GVITRIR, which is found in the second β strand of the second TSR of THBS-1 (Fig.…”

Section: Functional Sitesmentioning

confidence: 99%

Thrombospondins: from structure to therapeutics

Carlson

Lawler

Mosher

2008

Cell. Mol. Life Sci.

168

111

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Thrombospondins are large secreted, multi-modular, calcium-binding glycoproteins that have complex roles in mediating cellular processes. Determination of high-resolution structures of thrombospondins has revealed unique and interesting protein motifs. Here, we review this progress and discuss implications for function. By combining structures of modules from thrombospondins and related extracellular proteins it is now possible to prepare an overall model of the structure of thrombospondin-1 and thrombospondin-2 and discern features of other thrombospondins. (Part of a multi-author Review) KeywordsThrombospondin; extracellular protein structure; cartilage oligomeric matrix protein; calcium

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“…31 In a phase II clinical trial of ABT-510, which is a peptide mimetic of thrombospondin type 1 (yet another endogenous angiogenesis inhibitor), only 3 out of 21 latestage malignant melanoma patients showed stable disease, and no definite clinical efficacy was demonstrated. 32 Another phase II trial also showed only one objective response out of 88 patients with advanced soft tissue sarcoma. 33 The mechanisms of action for all the previously discussed drugs are poorly or only partially understood.…”

Section: Setbacks For Antiangiogenic Therapymentioning

confidence: 99%

From antiangiogenesis to hypoxia: current research and future directions

Huang¹,

Rice²

2010

CMAR

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Angiogenesis has long been recognized as an essential element in tumor growth. Since the conception of antiangiogenesis for cancer therapeutics, great strides have been made in understanding the molecular biology underlying angiogenesis, both in cancer and in physiology. By capitalizing on these advancements through bench-to-bedside research, potent antiangiogenic agents have been developed and tested. To date, the clinical results of most of these antiangiogenic agents have not met expectations. Even with the most successful agents, such as bevacizumab, used either as single agents or in combination with chemotherapy, gains in overall survival of cancer patients have been modest in most cases. In this article, the authors present the evolving views of antiangiogenic therapy, review recent experimental and clinical studies on antiangiogenesis, and address the fundamental role of hypoxia in tumor progression, which may be key to improving the efficacy of antiangiogenic therapy.

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A Phase II Study of ABT-510 (Thrombospondin-1 Analog) for the Treatment of Metastatic Melanoma

Abstract: ABT-510 therapy administered at 100 mg twice/day in patients with MM did not demonstrate definite clinical efficacy. Further dose escalation or combination with cytotoxic therapy may be more effective therapeutically.

Cited by 97 publications

References 57 publications

Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and -2

Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and -2

Thrombospondins: from structure to therapeutics

From antiangiogenesis to hypoxia: current research and future directions

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