THE THERAPEUTIC PROMISE OF CANCER GENOMICS

Just as it is the objective of basic cancer research to understand the fundamental basis of malignancy, so it is the goal of modern molecular therapeutics research to develop drugs that exploit this basic knowledge (Workman and Kaye 2002; Workman 2003a,b; Bronchud et al. 2004). The last five years in particular have seen the translation of our understanding of genomics and molecular biology of cancer into new treatments targeted to pathways responsible for malignancy. In contrast to the drugs developed in the cytotoxic era, the new molecular therapeutics that are being developed in this second golden era of cancer drug development are designed to attack the oncogenic players and pathways that are deranged in cancer: Hence, there is an expectation that these agents will be more efficient and have fewer side effects compared to conventional cytotoxic drugs (Workman 2005). Although our comprehension of the molecular processes that propel malignancy remains very much incomplete, there is no doubt that the accumulation of genetic and epigenetic abnormalities is critical for cancer progression (Balmain et al. 2003; Vogelstein and Kinzler 2004). These abnormalities in turn produce the hallmark characteristics of cancer, including uncontrolled cell cycle progression and proliferation, inappropriate survival, immortalization, invasion, angiogenesis, and metastasis (Hanahan and Weinberg 2000). It is believed that selection for alterations providing a growth advantage occurs, according to the model of clonal evolution (Nowell 1976). The contribution of various genes to malignant progression is illustrated schematically in Figure 1A, and the exploitation of this knowledge for the development of new therapeutics is depicted alongside in Figure 1B. We now understand very well that the engine of cancer is fueled by the activation oncogenes (which are the “accelerators” of cancer) and the inactivation of tumor suppressor genes (which are the “brakes” on malignancy). In addition, tumor development is encouraged by the mutation and loss of genes involved in DNA repair. Furthermore, the oncogenic process seems to be strongly supported by genes that had been considered previously to play “housekeeping” roles, such as histone deacetylases and the molecular chaperone Hsp90. The ultimate aim must be to identify and understand all of the genes and pathways that are involved in all cancers and to develop drugs that are active in each case. The choice of molecular targets for cancer drug development is now rooted very firmly in the identification of new cancer genes and the functional pathways that they hijack. High-profile articles in the lay press have helped to fuel public debate about the extent to which the massive investment in cancer research since Richard Nixon’s famous “war on cancer” in the 1970s, together with the much-hyped genomic revolution, have already delivered the goods in terms of benefit to patients (Anonymous 2004; Leaf 2004). The clinical activity and regulatory approval of small-molecule drugs like imatinib (Gleevec), gefitinib (Iressa), and erlotinib (Tarceva; see Fig. 2 for structures), and also the therapeutic antibodies trastuzamab (Herceptin), cetuximab (Erbutix), and bevacizumab (Avastin), have provided some reassurance that we are now on the right track. An article published in Business Week while the Symposium meeting was in progress argued that “medical care is reaching a tipping point” and pointed to the 400 cancer drugs that are now in clinical trial, many of which are directed to cancer genome targets (Arnst 2005). In this paper, I provide a personal perspective on drug development based on cancer genomics, with particular emphasis on “drugging the cancer kinome. ” I summarize the considerable challenges that face us, as well as the remarkable progress that has been made. I start by discussing cancer kinome targets and focus particularly on the impact of human genome and cancer genome sequencing. I then illustrate many of the issues with examDrugging the Cancer Kinome: Progress and Challenges in Developing Personalized Molecular Cancer Therapeutics