Drug Discovery Today: Therapeutic Strategies
Vol. 6, No. 2 2009
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
Molecularly targeted cancer therapy Robert A. Copeland Epizyme Inc., 840 Memorial Drive, Cambridge, MA 02139, United States. Email: [email protected]
This year, 2010, marks the centennial anniversary of the first marketed chemotherapeutic agent, Salvarsan, developed by Professor Paul Ehrlich and Dr. Sahachira¯ Hata for the treatment of syphilis. Over the course of the 20th century the use of the term chemotherapy has largely been limited to small, organic molecules that are used for the clinical treatment of cancers. Cancer chemotherapies have, until recently, been discovered and developed in an empirical fashion, using antiproliferative activity in cells and organisms as the main metric of success. This approach has led to life-saving and lifeprolonging therapeutics, at the cost of severe side effects attributable to the nonspecific nature of the molecular basis of therapy. Beginning in the last quarter of the 20th century, researchers began to take a more rational approach to cancer therapy, focusing on the design and/or discovery of selective modulators of specific molecular targets. This approach was expected to yield therapeutic agents with greater pathobiological specificity, resulting both in efficacy and improved tolerability for patients. Indeed, all indications are that this approach is working, albeit with plenty of room for continued improvements in terms of safety, tolerability and overall effectiveness of today’s cancer treatments. The ability to select specific targets for intervention was enabled by a voluminous literature of detailed information on the genetic dysregulation of intracellular growth and other pathways in cancers. Thus, it became clear that the protein kinases were key enzymes of intracellular signal transduction that were themselves genetically altered in cancers, or were catalytically associated with dysregulated pathways in cancers. Not surprisingly, many of the first molecularly targeted cancer therapeutics to reach the clinic were designed as selective inhibitors of protein kinases. The four articles contained within this special edition of Drug Discovery Today: Therapeutic Strategies extend and expand the repertoire of molecularly targeted cancer therapies. While 1740-6773/$ ß 2010 Elsevier Ltd. All rights reserved.
the protein kinases have been exploited broadly as targets for drug discovery, there remains much untapped potential in this target class. This is exemplified in the article by Gray and co-workers that focuses on novel inhibitors of the mTOR Robert A. Copeland holds a PhD and is Executive Vice President and Chief Scientific Officer at Epizyme, Inc. He joined Epizyme in September, 2008, from GlaxoSmithKline, where he was Vice President, Biology, Oncology Center of Excellence in Drug Discovery. Dr. Copeland is also Adjunct Professor of Biochemistry and Biophysics and a Fellow of the Eldridge Reeves Johnson Foundation at the University of Pennsylvania, School of Medicine. Additionally, he serves on the Scientific Advisory Board of Sigma–Aldrich, on the American Chemical Society Committee for Professional Training and on the Editorial Board of the Journal of Biological Chemistry. Before joining GSK he held scientific staff positions at Merck Research Laboratories, DuPont-Merck and Bristol-Myers Squibb and a faculty position at the University of Chicago, Pritzker School of Medicine. Dr. Copeland received his BS in chemistry from Seton Hall University, his doctorate in chemistry from Princeton University and did postdoctoral studies as the Chaim Weizmann Fellow at the California Institute of Technology. His research interest is in elucidating the determinants of drug recognition by their biological targets, and the use of this information in the discovery and design of new medicines. He has contributed to drug discovery and development efforts across a wide range of therapeutic areas leading to numerous drug candidates entering human clinical trials and the approval of Altabax (Retapamulin), a novel antibiotic. Dr. Copeland has contributed over 150 publications to the scientific literature, holds 8 issued US patents and has authored 4 books in the areas of protein science and enzymology. His latest book, Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (Wiley, Hoboken, NJ), published in March 2005.
Drug Discovery Today: Therapeutic Strategies | Cancer
complexes. The two mTOR complexes are central regulators of several signal transduction cascades. Most notably, mTOR complex 2 (mTORC2) is the effecter kinase that initiates the AKT/Pi3K signaling pathway; a pathway that is often genetically altered in human cancers. The authors present the latest data on small molecule, ATP-competitive inhibitors of the mTOR kinases and describe the potential of these compounds as therapeutic agents. A critical issue for the clinical utilization of kinase inhibitors and other targeted therapeutics is the cellular contextdependency of response to target modulation. That is, some cells are phenotypically responsive to treatment with a specific kinase inhibitor and other cells are insensitive to the same compound, despite similar levels of intracellular target engagement. The molecular basis for this differential sensitivity is not always clear. To treat patients effectively, it is critical to have a rational basis for determining what tumors are likely to respond to specific treatments. The article by Huang and co-workers explores the use of comprehensive gene expression signatures of signaling pathways as a means of enabling better predictions of drug response. These authors exemplify this approach with application to the Pi3K, RAS and EMT pathways, showing how the pathway activity signatures can be used to guide treatment choices. The success of targeted therapies against the protein kinases has spurred continued interest in extending the molecularly targeted cancer therapy approach to new protein classes that have heretofore been unexplored, or under-explored as drug targets. Numerous examples of novel target classes are beginning to emerge as potential modes of cancer treatment. The article by Shelton and Gilmartin, for example, describes recent efforts to antagonize protein/peptide receptors within the hedgehog pathway. The smoothened receptor has been successfully targeted by a number of antagonists that are progressing through preclinical and clinical development for cancer indications. Other receptors involved in hedgehog signaling, including Shh, Ihh and Dhh are also described as potential targets for antagonist discovery. Finally, the article by Pollock
Vol. 6, No. 2 2009
and Richon describes an exciting development in cancer therapy: the targeting of enzymes involved in epigenetic regulation of gene transcription. Several classes of enzymes are involved in the methylation of chromosomal DNA and in the post translational modification of the histone protein core around which chromosomal DNA is wound in chromatin. These various modifications effect conformational changes in chromatin that impact specific gene transcription; multiple examples of enzymes from several of these classes have been demonstrated to be dysregulated in human cancers. Inhibitors of the DNA methyltransferases and the histone deacetylases are already marketed drugs for cancer indications. The article by Pollock and Richon goes on to describe preclinical efforts aimed at discovery of inhibitors of other epigenetic enzymes, such as the histone methyltransferases, the histone demethylases and other enzyme families. The articles presented in this issue provide the reader a sense of the breadth of targeted therapeutic approaches that are being explored for new cancer therapies. Yet, this issue merely scratches the surface with respect to the plethora of novel target classes that are currently under exploration for cancer drug discovery. Enzymes, receptors, chaperones and other protein classes – many of which had previously been deemed ‘undruggable’ – are beginning to yield interesting starting points for drug discovery and development. These exciting advances, coupled with similarly exciting advances in biomarker-driven patient stratification and rational, clinical approaches to drug combination therapies are truly heralding an era in which cancer patient care will be more tailored to the genetic and biochemical uniqueness of the disease at hand. Surely, this strategy will have unintended regulatory and financial consequences on health care, and may also impose unintended burdens on physicians. Novel, well-thought-out solutions to these issues will clearly be required. Yet, the promise of greater effectiveness and safety that this approach offers should, I believe, engender optimism in researchers, physicians and cancer patients as we continue to progress in the 21st century.