Selecting the right targets for cancer therapy

Abstract

Molecular Oncology can be defined as that branch of medical science that looks at cancer from a molecular point of view. For several reasons, outlined in all of the chapters of this book, and globally reviewed in this first and initial chapter, "molecular oncology" represents the "heart of the matter" of cancer, and our best hope for developing more rational and safer new therapies for cancer throughout the multiple stages of cancer development, including its "pre-clinical" natural history, also known as "carcinogenesis." These new anticancer drugs based on molecular oncology are also called "targeted therapies," for it is precisely the "molecular targets" relevant to the cancer phenotype that are aimed at. But the impact of molecular oncology is not restricted to the development of new therapies. As I shall briefly review, and as is explained also in other chapters of this book, molecular oncology is helping us to define new methods for primary cancer prevention (for example, effective vaccines against carcinogenic viruses, like Hepatitis B virus and human papilloma viruses), or for secondary cancer prevention (like inhibitors of cyclo-oxygenase 2 (COX-2), to prevent colonic adenomas or carcinomas, or new antiestrogen molecules for breast cancer prevention, or antiandrogens for prostate cancer prevention). It is also allowing powerful new "molecular imaging" methods, that promise to detect and measure some of the key properties of malignant cells "in vivo," as well as their response to therapy. In this first chapter, we shall try to see "the wood, rather than the individual trees," even if, in light of present knowledge, it remains difficult to bridge the vast gulfs that open up on closer examination, and that cannot yet be spanned by the most audacious hypothesis. The evolution of most human cancers can be viewed as the operation of Darwinian selection, the processes among competing populations of dividing cells and the sequential accumulation of relevant genetic and epigenetic events. There are different types of tumor markers: (1) genetic markers in both hereditary tumors and nonhereditary tumors; (2) cellular and tissue markers; (3) epigenetic markers, usually in nonhereditary tumors; and (4) circulating cancer markers. Some of these markers are already used routinely in clinical practice (e.g., several circulating cancer markers are useful for the diagnosis, prognosis, and follow-up of some cancer types), others are being investigated as a source of important prognostic information or even as predictors of response to chemotherapy or radiotherapy (e.g., several cellular and tissue markers), and others still are being explored, in the context of genetic counselling, as potentially useful in screening for hereditary cancer predisposition. Some epigenetic markers (see chapter on Epigenomics and Cancer by Manel Esteller and colleagues) promise to be useful in detecting premalignant changes, for example in the bronchial epithelium of heavy smokers. Regulatory pathways involved in the complex regulation of cell growth, differentiation, senescence, and cell death are being gradually understood. Although we are still largely unable to draw schematically precise cell-type-specific regulatory pathways, current knowledge and research efforts will be updated. In contrast, the classical metabolic regulatory pathways have been known for many years. Pathways such as, for example, the "citric acid cycle" (postulated by Krebs in 1937), the central role of ATP in the energy-transfer cycles (postulated mainly by Lipmann in 19391941), or the intriguing Mitchells hypothesis (1961) to explain the mechanism of oxidative and photosynthetic phosphorylation, to name but a few examples, have been part of biochemistry textbooks for decades. Some 29 years ago, the structure of DNA had already been known for over 2 decades and yet eminent scientists were pessimistic about real therapeutic progress in oncology. This book is a good demonstration that things have changed. Although there is still no treatment for any of the major lethal cancers that is as effective as the antibiotics are for infections, the knowledge that has accumulated on the fine regulatory mechanisms that are deranged in cancer cells is vast and undoubtedly promises new therapeutic insights. The introduction into routine clinical use of selective (though not entirely specific) tyrosine kinase inhibitors, for example for chronic myeloid leukemia or some solid tumors, like gastrointestinal stromal tumors (GIST), nonsmall cell Edited by: Miguel H. Bronchud et al. Humana Press Inc., Totowa, NJ lung cancer, renal cell carcinomas, and others, and the development of specific monoclonal antibodies for breast cancer or some lymphomas, are good examples. In contrast to the situation some 20 years ago, not only do we know many molecular targets to design new drugs for the chemoprevention or treatment of cancer, but, paradoxically, we have an apparent excess of targets for our current resources of drug development worldwide. The Human Genome Project has completed its first basic human genome map well ahead of schedule, and it is likely to give us further insights and more potential targets. It is now estimated that the human genome contains some 30,000 genes, less than originally thought by most researchers. Because of alternative splicing and other mechanisms these genes can code for up to 300,000 different proteins in human cells. Many of these genes and proteins are well characterized and their functions in various pathways are known. But the real function of the majority of these human genes and proteins remains speculative. In other words, the rate-limiting step in true progress against cancer is the amount of resources we can spend and the optimization and coordination of this huge research process, rather than a shortage or lack of therapeutic targets. Selecting the right targets for cancer therapy can make a big difference. If, for example, we were clever or lucky enough to correctly guess the right targets for the main human cancers, and if large multinational pharmaceutical companies agreed to focus their efforts and enormous resources on these targets, then revolutionary new cancer treatments might become available for clinical testing within 5 to 10 years. But, if we were wrong, or not enough importance was given to this war against cancer, then it might take another 20 or 30 years, or even more. The object of all cancer research is simply to stop cancer from being a major cause of death and human suffering, and it is in this light that all new research must ultimately be judged. In spite of progress there is still ample room for improvement, and many practicing oncologists still believe that new cancer drugs often deliver less than they promise. The problem may not only lie in the drugs themselves, but also in the way they are tested and used. The methodology of clinical development of new targeted drugs, coupled with new molecular imaging tools and a more precise understanding of what these drugs are actually doing in different cancers, will also need to improve if we want to reduce total costs for each new drug, still estimated to be between 600 and 800 million US dollars, and the overall time "from bench to regulatory approval" for clinical use, still around the 10 years mark. For example, it is commonly accepted that targeted drugs are generally very much less harmful and toxic than conventional cytotoxic agents, which probably means less need for phase- I studies (many trials are now directly coupling the phase I to a single phase-I/II study), but also more in-depth phase-II studies, with pharmacodynamics in well-defined populations of cancers, and ideally combination studies with two or more agents to hit the cancer-specific targets in the most efficient and intelligent way. These methodological changes will need the support and adaptation of regulatory bodies, as well as new mathematical, imaging, and biochemical tools to assess response. In this initial chapter we review some new prospects in the prevention, early detection, and treatment of cancer, based on four basic truths of oncology: 1. cancer can be revented; 2. cancer can be diagnosed, and the earlier the diagnosis the higher the chances of curative treatment; 3. cancer can be cured (by local or systemic therapies, or a combination of both), but the impact on mortality of present therapies is often limited; 4. cancer cannot always be cured, and it seems reasonable to predict that even in the year 2040 there will still be many cancers incurable at the time of clinical presentation. © 2008 Humana Press Inc.