Biomarkers measure drug-induced changes in a patient's blood or tissue. Such changes can confirm drug activity and thereby help select patients more likely to respond to treatment. These biochemicals are revolutionizing cancer drug development.
It's a revolution sorely needed. A recent
After 20 years of study, we have begun to see clinical benefits for patients from drugs that were designed to exploit cancer gene-based targets. These drugs cannot be optimally developed using approaches designed for the more traditional cytotoxic chemotherapies: Maximum tolerated dose may not indicate optimal dose; dose-limiting toxicity may not be proliferation-linked; and myelosuppression side effects cannot be used as surrogate markers of cytotoxicity, as many of these effects do not deplete blood cells.
These facts highlight the need to find and develop pharmacodynamic and prognostic markers to confirm that new agents have their desired biochemical effects as well as to establish optimal dosing. A biomarker that reveals apoptosis in tumor cells, for example, can demonstrate that an experimental agent is killing tumor cells without costly imaging techniques or the long delays required to reach a clinical endpoint.
At present, biomarkers are used approach, using prognostic markers through DNA microarray chips, could match new classes of drugs with the molecular profile of individual tumors. If a drug is targeted specifically against cells that have a particular mutation, translocation, or gene overexpression, then testing tumor tissues to determine whether that molecular profile is present in a tumor should help clinicians avoid prescribing an ineffective treatment.
The second approach, pharmacodynamic (PD) markers, tells us whether a drug is having its intended biochemical effect, and if so, how extensive it is. In the long term, these PD effects could be used as surrogate markers for clinical response. The industry hopes regulators would accept validated surrogate markers for clinical response, as they do with other diseases.
Measuring protein markers in plasma by enzymatic assays or mass spectrometry is preferred, as these techniques are sensitive, minimally invasive, and in particular do not require tumor biopsies. PD markers also may be used to monitor treatment progress, provide early warnings of relapse, or monitor patient compliance. The latter can be a particular problem with new anticancer drugs because patients take them at home, by mouth. Clinical trial protocols could specify that patients who miss their drug dosing would be ineligible for evaluation, thus improving integrity of clinical data and cost-efficiency of clinical trials.
Additional hurdles must be overcome to develop biomarker-based drugs. Markers need to be identified early in a drug's life cycle, since their use spans preclinical and clinical phases of evaluation. Also, in many cases it will help to develop and validate a diagnostic agent in parallel with a therapeutic agent, although this would increase the complexity of the development process.
The Food and Drug Administration is recognizing biomarkers' growing importance in oncology, although its views and their eventual impact on regulatory requirements are still evolving. For now, the agency has invited companies to submit their biomarker data, and ain particular specific data from individual drug trials. The FDA has offered to act as a clearinghouse for pooling and sharing this information under safe-harbor provisions, intended to address industry concerns about potential market fragmentation. This is a bold and visionary policy because it will accelerate knowledge.
Using biomarkers based on proteomic and pharmacogenomic tools allows targeted drug development, a revolution that builds on the successes of targeted drug design, in particular computer-aided design tools used together with X-ray crystal structures of novel target proteins.
Biomarkers can lead to development of less toxic drugs as well as drugs that are more suitable for specific patients. Biomarkers can pave the way for a new vision of cancer therapy, where cancer could be controlled for life. This new era promises drugs that can better meet patients' needs than the current armamentarium.
Athos Gianella-Borradori is director, Medical Affairs; Robert Jackson is executive director, Research and Development; and Spiro Rombotis is CEO of Cyclacel in Dundee, Scotland.