CCI-779 in metastatic melanoma: A phase II trial of the California Cancer Consortium

Margolin, Kim; Longmate, Jeff; Baratta, Tracey; Synold, Timothy W.; Weber, Julien; Gajewski, Thomas F.; Quirt, Ian; Christensen, Scott; Doroshow, J. H.

doi:10.1200/jco.2004.22.14_suppl.7523

Cited by 38 publications

(43 citation statements)

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“…Inhibitors of mTOR are currently being tested clinically and have been somewhat disappointing as monotherapy in cancer. Although these compounds are cytostatic in many preclinical studies (Easton and Houghton, 2004;Takeuchi et al, 2005), mTOR inhibitors have failed to achieve similar cytostasis in clinical trials (Margolin et al, 2005), suggesting that the utility of these agents may be improved through combination therapy (Choo and Blenis, 2006). It has recently been proposed that selective mTOR inhibition may lead to PI3 kinase activation, thereby limiting the effectiveness of these agents (Hay, 2005).…”

Section: Discussionmentioning

confidence: 99%

A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma

et al. 2006

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The PI3 kinase family of lipid kinases promotes cell growth and survival by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate. To define targets critical for cancers driven by activation of PI3 kinase, we screened a panel of potent and structurally diverse drug-like molecules that target this enzyme family. Surprisingly, a single agent (PI-103) effected proliferative arrest in glioma cells, despite the ability of many compounds to block PI3 kinase signaling through its downstream effector, Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both PI3 kinase alpha and mTOR. PI-103 showed significant activity in xenografted tumors with no observable toxicity. These data demonstrate an emergent efficacy due to combinatorial inhibition of mTOR and PI3 kinase alpha in malignant glioma.

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Section: Discussionmentioning

confidence: 99%

A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma

et al. 2006

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“…Dolastatin 10 is a potent, promising agent with broad tumor specificity, yet the recent data from Phase II clinical trials indicate that it is not effective as a single agent. [11][12][13] We recently isolated a new cytotoxic dolastatin 10 derivative, symplostatin 1, from marine cyanobacteria. Studies were conducted to elucidate the mechanism of action of symplostatin 1 and to determine if it has properties that would indicate that it might provide advantages over dolastatin 10.…”

Section: Discussionmentioning

confidence: 99%

“…9 -13 The results of the Phase II studies in multiple tumor types suggest that dolastatin 10 is well tolerated but it did not exhibit clinical anticancer activity as a single agent. [11][12][13] Analogs of dolastatin 10 continue to be evaluated. TZT-1027 is a synthetic derivative of dolastatin 10 that appears to have a similar mechanism of action in that it disrupts microtubules, causes mitotic arrest and induces apoptosis.…”

mentioning

confidence: 99%

The molecular pharmacology of symplostatin 1: A new antimitotic dolastatin 10 analog

Mooberry

Leal

Tinley

et al. 2003

Intl Journal of Cancer

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Symplostatin 1, an analog of dolastatin 10, was recently isolated from cyanobacteria of the genus Symploca. Symplostatin 1 is a potent inhibitor of cell proliferation with IC 50 values in the low nanomolar range and it exhibits efficacy against a variety of cancer cell types. Symplostatin 1 caused the formation of abnormal mitotic spindles and accumulation of cells in metaphase at concentrations that had only minor effects on interphase microtubules. At higher concentrations, symplostatin 1 caused the loss of interphase microtubules. Cell cycle analysis revealed that symplostatin 1 caused G 2 /M arrest, consistent with its effects on mitotic spindles. Symplostatin 1 initiated the phosphorylation of Bcl-2, formation of micronuclei and activation of caspase 3, indicating induction of apoptosis. The cellular effects of symplostatin 1 are consistent with other antimitotic tubulintargeting drugs. Tubulin polymerization experiments indicated that symplostatin 1 potently inhibits the assembly of purified tubulin, suggesting that tubulin may be its intracellular target. Some microtubule-targeting agents are reported to have antiangiogenic activity and therefore the effects of symplostatin 1 on endothelial cell proliferation and invasion were evaluated. Symplostatin 1 was found to be a potent inhibitor of both endothelial cell proliferation and invasion. Because of its potent and broad activity in vitro, symplostatin 1 was evaluated in vivo. Symplostatin 1 was active against murine colon 38 and murine mammary 16/C; however, it was poorly tolerated and the mice were slow to recover from the toxicity. The data indicate that symplostatin 1 has a mechanism of action similar to dolastatin 10.

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“…Melanoma cells with genetic changes in the PI3K signaling pathway above mTOR are probably more sensitive to sirolimus than melanoma cells with genetic changes below mTOR . Monotherapy regimes with mTOR inhibitors have not yet shown sufficient antitumor activity in patients with metastatic melanoma and are thus mTOR inhibitors are to be tested in the future in combination with other drugs [33]. Tolerability appears on the whole to be good.…”

Section: Pi3k/akt Signaling Pathwaymentioning

confidence: 99%

Oncogenetics of melanoma: basis for molecular diagnostics and therapy

Held

Eigentler

Meier

et al. 2011

J Deutsche Derma Gesell

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SummaryOur understanding of oncogenetics and of the molecular mechanisms involved in melanoma development and signaling has dramatically changed in recent years. Today, melanomas are also classified based on molecular alterations. Emerging molecular therapies are targeted against specific mutations in melanoma. An example of targeted therapies is the successful treatment of KITmutant melanoma with the kinase inhibitor imatinib. Highly selective BRAF-inhibitors are likewise under clinical development and show encouraging clinical responses. An increasing number of targeted drugs will emerge in the coming years, based on molecular diagnostics and classification. The present article reviews signaling pathways in melanocytes and alterations in melanoma that are a prerequisite to understanding modern cancer therapies in melanoma.

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CCI-779 in metastatic melanoma: A phase II trial of the California Cancer Consortium

Cited by 38 publications

References 0 publications

A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma

A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma

The molecular pharmacology of symplostatin 1: A new antimitotic dolastatin 10 analog

Oncogenetics of melanoma: basis for molecular diagnostics and therapy

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