Shifting from the cell-kill paradigm to pharmacogenomics

Delineation of cancer genomes on a comprehensive scale and large-scale translational applications will require the concerted efforts of the research community as well as substantial public support. The initial phases of this elaborate and massive undertaking has already benefited from the efforts and vast human and financial resources of the public and private sectors. However, given their divergence in goals and motives, the molecularly targeted drug development phase, an endeavor dominated by private industry, is likely to favor profit-driven tracks. In such a scenario, targeted drugs likely to be pursued vigorously will be those with the highest financial return on investment. Thus, the focus, at least initially, will be on drugs for cancers with high incidence rates and those relatively inexpensive to bring to market. Cancers with genetic defects not easily druggable or with low incidence rates among the population will be shunned or disfavored. Another area of concern is whether the medical community and the public are prepared to abandon the notion of cancer as an “invader” to be eradicated at all cost and to embrace the view that it results from genetically dysfunctional cells that can be brought back to a normal life cycle ending in apoptosis. Likewise, assessment of the efficacy of gene-targeted drugs and of treatment response must shift from the cancer cell-kill paradigm to biological surrogates of tumor response. As suggested by experience with Imatinib mesylate, molecularly targeted cancer drugs are likely to have a low toxicity when compared to current cytotoxic cancer drugs, which commonly lead to life-threatening myelosuppression and immunosuppression. This and their modulating rather than cytotoxic mechanism of action should help focus clinicians' attention on patient outcome rather than tumor outcome, as is currently the case under the cell-kill paradigm. However, a new cancer management strategy that emphasizes the functional control rather than the destruction of cancer cells is such a radical departure from the current cancer-eradication dogma that its implementation will require re-educating clinical researchers, community physicians, patients, and the public at large.