American Society of Preventive Oncology Distinguished Career Achievement Lecture 2006—Enjoy the Journey: The Long and Winding Road of Chemoprevention Agent Development

Meyskens, Frank L.

doi:10.1158/1055-9965.epi-06-0609

Cited by 3 publications

(2 citation statements)

References 34 publications

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“…Mutations in critical regulatory genes disrupt intracellular signaling in melanocytes, allowing them to produce autocrine growth factors and lose growth inhibitory signals and cell cycle regulation (5). Consequently, melanocytes with constitutive proliferative signal activation and loss of tumor suppressor genes often develop into melanoma lesions and progress to metastatic melanoma.…”

Section: Introductionmentioning

confidence: 99%

Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy

Yang

Zaja‐Milatovic

Thu

et al. 2009

Molecular Cancer Therapeutics

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The BRAFV600E mutation is common in human melano-ma. This mutation enhances IκB kinase (IKK)/nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase/activator protein signaling cascades. In this study, we evaluated the efficacy of targeting either B-Raf or IKKβ in combination with the DNA alkylating agent temozolomide for treatment of advanced metastatic melanoma. Xenografts of Hs294T human metastatic melanoma cells exhibiting the BRAFV600E mutation were treated with inhibitors of IKKβ (BMS-345541), B-Raf (BAY 54–9085), and/or temozolomide. Drug response was mechanistically analyzed in vitro and in vivo. In this study, we determined that the antitumor activity of all three drugs depends on inhibition of NF-κB. BMS-345541 inhibits IKKβ-mediated phosphorylation of IκBα and thus blocks the nuclear localization of NF-κB, whereas BAY 54–9085 inhibits activation of NF-κB through a mechanism that does not involve stabilization of IκBα. Moreover, BMS-345541, but not BAY 54–9085, activates the death pathways of p53 and c-Jun-NH2-kinase, contributing to the killing of melanoma cells. Temozolomide inhibits both NF-κB and extracellular signal-regulated kinase activity, conferring effective in vivo antitumor activity. Thus, temozolomide, but not BAY 54–9085, has a synergistic in vivo antitumor effect with BMS-345541. We conclude that the efficacy of antimelanoma therapy depends on inhibition of expression of antiapoptotic genes transcriptionally regulated by NF-κB. In contrast, drug targeting of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway alone in melanoma cells is ineffective for melanoma therapy in cases where NF-κB is not also targeted.

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Section: Introductionmentioning

confidence: 99%

Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy

Yang

Zaja‐Milatovic

Thu

et al. 2009

Molecular Cancer Therapeutics

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“…The topic of at-risk populations has been reviewed in detail elsewhere (50, 51, 54). From a practical and regulatory point of view, several levels of cancer risk are identifiable (Fig.…”

Section: Identifying a High Risk Of Cancer And Thus Appropriate Candimentioning

confidence: 99%

Regulatory Approval of Cancer Risk-Reducing (Chemopreventive) Drugs: Moving What We Have Learned into the Clinic

Meyskens

Curt

Brenner

et al. 2011

Cancer Prevention Research

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This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high (er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs.

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Combination chemoprevention

Zhou

Cheng²,

Yang³

et al. 2012

European Journal of Cancer Prevention

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Recent research has drawn attention to protective effects of chemopreventive agents that reverse, suppress, or prevent the carcinogenic progression using pharmacological or nutritional agents. Aspirin and celecoxib are the promising preventive agents to effectively reduce the risk of colorectal cancer, but such agents are associated with severe gastrointestinal and cardiovascular side effects in long-term administration at high doses. Recently, the strategy that combinational use with several chemopreventive agents at low doses induces greater inhibition of carcinogenesis has become the focus. The nonsteroidal anti-inflammatory drugs (NSAIDs) may combine with ornithine decarboxylase inhibitors, hydroxymethylglutaryl-CoA reductase inhibitors, epidermal growth factor signaling inhibitors, peroxisome proliferator-activated receptor-γ ligands, and tumor necrosis factor-related apoptosis-inducing ligand, to magnify the chemoprophylactic effect. It is noteworthy that the phase III trial of difluoromethylornithine combination with sulidac has shown greater and effective preventive roles, which pave the way for the use of combinations of other agents. The long-term statins and low-dose NSAIDs have also been associated with risk reduction in vitro, in vivo, and in retrospective studies; however, the data are inconsistent. Epidermal growth factor signaling inhibitors, peroxisome proliferator-activated receptor-γ ligands and tumor necrosis factor-related apoptosis-inducing ligand have been demonstrated to potentiate the preventive effects of NSAIDs in vitro and in vivo, but these combinational regimens have not yet been applied to clinical research. The major goal of this study was to review combination chemoprevention for colorectal cancer by means of combining low doses of potential preventive agents to increase their chemoprophylaxis efficacy and to minimize toxicity.

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American Society of Preventive Oncology Distinguished Career Achievement Lecture 2006—Enjoy the Journey: The Long and Winding Road of Chemoprevention Agent Development

Cited by 3 publications

References 34 publications

Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy

Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy

Regulatory Approval of Cancer Risk-Reducing (Chemopreventive) Drugs: Moving What We Have Learned into the Clinic

Combination chemoprevention

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