- Email: [email protected]
Cancer
Vol. 2, No. 4 2005
Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Issue 4
EDITORIAL
Cancer Tona M. Gilmer1, Michael J. Luzzio2 1 US Human Biomaker Labs, Translational Medicine and Genetics, GlaxoSmithKline, RCII 105, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Email: [email protected] 2 Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. Email: [email protected]
A recent article in Journal of the National Cancer Institute reported that death rates in the US have decreased by 1.1% annually from 1993 to 2002 for all cancer sites combined [J. Natl. Cancer Inst. 2005;97:1407–1427]. However, cancer as a disease state remains an area with tremendous unmet medical need. In one year, across just the developed world, approximately 3 million people are diagnosed with cancer, and approximately 1.5 million people die of this disease. Cancer is pleiotrophic in nature and therefore, is many diseases of the human body. The most prevalent cancers are prostate cancer, breast cancer, nonsmall cell lung cancer, colorectal cancer, ovarian cancer and pancreatic cancer. This disease and its treatments result not only in a physical toll on the person but also have a major psychological impact. Cytotoxic agents and hormonal therapies are expected to continue as the anchor of anticancer regimens. Many new genetic alterations associated with the pathology of a specific tumor type are being discovered and analyzed as potential drug targets. The recent performance of innovative therapies such as imatinib (Gleevec), trastuzamab (Herceptin), cetuxamab (Erbitux), bevicizamab (Avastin), gefitinib (Iressa) and erlotinib (Tarceva) signal the growing importance for targeted agents that improve upon the efficacy of cytotoxics or are efficacious when dosed alone. Strategies to combine these types of drugs with newer agents are a major focus of drug development. As cancer researchers, we strive to understand the genetics of the tumor, the pathways that regulate cell growth and proliferation, the dysregulation of normal cellular processes, and ultimately, how these changes and processes are relevant to cancer. This body of evidence leads to scientific deductions 1740-6773/$ ß 2005 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2005.11.008
to identify a ‘mechanism of action’ of key biological regulators in the tumor. Some of the challenges we face in cancer drug discovery are the following: (1) Are these targets amenable to small molecule or therapeutic protein approaches? If so, what approach should be used – small molecule, protein
Box 1. Section Editors Tona M. Gilmer Dr Tona Gilmer received her PhD in Microbiology from the University of Virginia, where she studied retroviruses in the laboratory of Dr Thomas Parsons. Dr Gilmer moved to the University of Colorado Health Sciences Center and, as a post-doctoral fellow with Dr Ray Erikson, identified the viral src oncogene as containing intrinsic protein kinase activity by expressing it in E. coli. She then spent a year as a post-doctoral fellow with Dr Steve Bachenheimer at University of North Carolina at Chapel Hill School of Medicine studying normal cellular src. Dr Gilmer joined the National Institute of Environmental Health Sciences as a Senior Staff Fellow working with Dr Carl Barrett and investigated the molecular basis for the genesis and progression of carcinogenesis. In 1988, Dr Gilmer joined the Department of Chemotherapy at Glaxo as Research Investigator and began working on kinase inhibitors for cancer. Since that time, she has held several positions, including Project Leader of the Phosphotyrosine Signaling Project, Cancer Forum Head, Director of Oncology Biology and is currently Director of Translational Medicine and Genetics at GlaxoSmithKline. She has been involved in numerous drug discovery programs in the areas of signal transduction, cell cycle regulation and apoptosis.
www.drugdiscoverytoday.com
297
Drug Discovery Today: Therapeutic Strategies | Issue 4
Michael J. Luzzio Michael Joseph Luzzio received his BA in Biochemistry from San Francisco State University in 1979 under Professor Daniel Buttlaire. He then worked as a chemist at Syntex in the laboratories supervised by Dr John Moffatt (1979–1981). Returning to S.F.S.U., Mike completed a MS in Biochemistry (1981–1982) under Professor Robert Lindquist. He received his MS and PhD in organic chemistry at the University of Rochester (1982–1986) under Professor Andrew Kende and was a National Institute of Health post-doctoral fellow at the University of California, Berkeley (1986–1988) under Professor William G. Dauben. In 1988, Mike was one of a small group of organic chemists recruited by Glaxo to establish Discovery Chemistry Laboratories of Glaxo in the United States. In 1999, Mike accepted a position with Pfizer in Groton, CT as an Associate Research Advisor. Since 1988, Mike has worked as a medicinal chemist contributing to the discovery of several anticancer drugs that have entered human clinical studies. When he is not being a chemist, Mike enjoys being with his family, cooking and playing an occasional game of pool.
298
www.drugdiscoverytoday.com
Vol. 2, No. 4 2005
therapeutic or a combination of both? (2) How do we evaluate these molecules preclinically giving the limitations of in vitro and in vivo models and their relevance to cancer in humans? (3) How do we optimize the pharmacokinetics? Ideally, the effectiveness of a potential drug therapy should be based upon the optimum interaction of that therapy with its intended target. A drug should not fail owing to poor drug-like physical properties. (4) Is the drug getting to the target and if it is, are we observing the desired effect based upon a defined biological mechanism of action? (5) Are the toxicities of therapies acceptable (i.e. manageable and/or reversible)? (6) Can we identify ‘predictive’ biomarkers for efficacy, lack of efficacy and response? Our ultimate challenge still remains to translate the knowledge we gain to discovering therapies that will have a significant impact on this disease and will result in sustainable cures. With best wishes, Tona M. Gilmer Michael J. Luzzio
Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Issue 4
EDITORIAL
Cancer Tona M. Gilmer1, Michael J. Luzzio2 1 US Human Biomaker Labs, Translational Medicine and Genetics, GlaxoSmithKline, RCII 105, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Email: [email protected] 2 Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. Email: [email protected]
A recent article in Journal of the National Cancer Institute reported that death rates in the US have decreased by 1.1% annually from 1993 to 2002 for all cancer sites combined [J. Natl. Cancer Inst. 2005;97:1407–1427]. However, cancer as a disease state remains an area with tremendous unmet medical need. In one year, across just the developed world, approximately 3 million people are diagnosed with cancer, and approximately 1.5 million people die of this disease. Cancer is pleiotrophic in nature and therefore, is many diseases of the human body. The most prevalent cancers are prostate cancer, breast cancer, nonsmall cell lung cancer, colorectal cancer, ovarian cancer and pancreatic cancer. This disease and its treatments result not only in a physical toll on the person but also have a major psychological impact. Cytotoxic agents and hormonal therapies are expected to continue as the anchor of anticancer regimens. Many new genetic alterations associated with the pathology of a specific tumor type are being discovered and analyzed as potential drug targets. The recent performance of innovative therapies such as imatinib (Gleevec), trastuzamab (Herceptin), cetuxamab (Erbitux), bevicizamab (Avastin), gefitinib (Iressa) and erlotinib (Tarceva) signal the growing importance for targeted agents that improve upon the efficacy of cytotoxics or are efficacious when dosed alone. Strategies to combine these types of drugs with newer agents are a major focus of drug development. As cancer researchers, we strive to understand the genetics of the tumor, the pathways that regulate cell growth and proliferation, the dysregulation of normal cellular processes, and ultimately, how these changes and processes are relevant to cancer. This body of evidence leads to scientific deductions 1740-6773/$ ß 2005 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2005.11.008
to identify a ‘mechanism of action’ of key biological regulators in the tumor. Some of the challenges we face in cancer drug discovery are the following: (1) Are these targets amenable to small molecule or therapeutic protein approaches? If so, what approach should be used – small molecule, protein
Box 1. Section Editors Tona M. Gilmer Dr Tona Gilmer received her PhD in Microbiology from the University of Virginia, where she studied retroviruses in the laboratory of Dr Thomas Parsons. Dr Gilmer moved to the University of Colorado Health Sciences Center and, as a post-doctoral fellow with Dr Ray Erikson, identified the viral src oncogene as containing intrinsic protein kinase activity by expressing it in E. coli. She then spent a year as a post-doctoral fellow with Dr Steve Bachenheimer at University of North Carolina at Chapel Hill School of Medicine studying normal cellular src. Dr Gilmer joined the National Institute of Environmental Health Sciences as a Senior Staff Fellow working with Dr Carl Barrett and investigated the molecular basis for the genesis and progression of carcinogenesis. In 1988, Dr Gilmer joined the Department of Chemotherapy at Glaxo as Research Investigator and began working on kinase inhibitors for cancer. Since that time, she has held several positions, including Project Leader of the Phosphotyrosine Signaling Project, Cancer Forum Head, Director of Oncology Biology and is currently Director of Translational Medicine and Genetics at GlaxoSmithKline. She has been involved in numerous drug discovery programs in the areas of signal transduction, cell cycle regulation and apoptosis.
www.drugdiscoverytoday.com
297
Drug Discovery Today: Therapeutic Strategies | Issue 4
Michael J. Luzzio Michael Joseph Luzzio received his BA in Biochemistry from San Francisco State University in 1979 under Professor Daniel Buttlaire. He then worked as a chemist at Syntex in the laboratories supervised by Dr John Moffatt (1979–1981). Returning to S.F.S.U., Mike completed a MS in Biochemistry (1981–1982) under Professor Robert Lindquist. He received his MS and PhD in organic chemistry at the University of Rochester (1982–1986) under Professor Andrew Kende and was a National Institute of Health post-doctoral fellow at the University of California, Berkeley (1986–1988) under Professor William G. Dauben. In 1988, Mike was one of a small group of organic chemists recruited by Glaxo to establish Discovery Chemistry Laboratories of Glaxo in the United States. In 1999, Mike accepted a position with Pfizer in Groton, CT as an Associate Research Advisor. Since 1988, Mike has worked as a medicinal chemist contributing to the discovery of several anticancer drugs that have entered human clinical studies. When he is not being a chemist, Mike enjoys being with his family, cooking and playing an occasional game of pool.
298
www.drugdiscoverytoday.com
Vol. 2, No. 4 2005
therapeutic or a combination of both? (2) How do we evaluate these molecules preclinically giving the limitations of in vitro and in vivo models and their relevance to cancer in humans? (3) How do we optimize the pharmacokinetics? Ideally, the effectiveness of a potential drug therapy should be based upon the optimum interaction of that therapy with its intended target. A drug should not fail owing to poor drug-like physical properties. (4) Is the drug getting to the target and if it is, are we observing the desired effect based upon a defined biological mechanism of action? (5) Are the toxicities of therapies acceptable (i.e. manageable and/or reversible)? (6) Can we identify ‘predictive’ biomarkers for efficacy, lack of efficacy and response? Our ultimate challenge still remains to translate the knowledge we gain to discovering therapies that will have a significant impact on this disease and will result in sustainable cures. With best wishes, Tona M. Gilmer Michael J. Luzzio