By Richard Just, MD
The explosion of information in molecular oncology has identified a seemingly infinite number of targets for novel therapeutic agents. This has spawned the concept of personalized oncology, which has “gone viral.” However, a disconnect between the very large number of possible targets and the very small number of treatments is now apparent. In addition, most (85%) of drugs thought to be beneficial in Phase II clinical trials cannot be validated when other labs and institutions attempt to reproduce these results. And it is still taking up to 10 years and costing over $1 billion to bring a single new agent from the bench to the bedside. A postulated major roadblock is that Clinical Trial design has not adapted to these new developments.
Maitland and Schilsky addressed this topic in a comprehensive article entitled: Clinical Trials in the Era of Personalized Oncology; CA, A Cancer Journal for Clinicians; vol 61 no 6, Nov/Dec 2011: pp 365-381. Table 1, pg 366 summarizes “Oncology Care and Clinical Trials in the Eras of Population Oncology, Transition, and Personalized Oncology.” In the areas of Screening, Diagnosis, Staging, Treatment determination, and Assessment intervals, we are headed for molecular-based and individual-based decision making, but we’re still in the transition phase. As far as early phase clinical trials are concerned, the Population Oncology Era was oriented to maximum tolerated dose (MTD); the Transition Phase is oriented to “optimum biologic dose” and the Personalized Oncology Era to determine the range of tolerable and active doses. Mid-phase clinical trials use histology and prior treatment-based eligibility in typically single-arm, non-comparator trials in the Population Oncology Era; the addition of some marker-based screening and some randomized controlled trials in the Transition Phase and some trials, histology, and prior treatment-based eligibility with rapid, serial assessments in the Personalized Oncology Era, many with eligibility restricted to tumor marker subsets. Obviously, the trend is to stratify patients according to their biomarkers and to serially assess for response or lack of it at more frequent intervals to accelerate the conduct of trials.
Another issue is the complexity of the diseases we’re dealing with. Weinberg and Hanahan proposed 6 “rules” that define the behavior of cancers, the so-called hallmarks of cancer:
- Self-sufficiency in growth signals: cancer cells acquire an autonomous drive to proliferate, so-called pathological mitosis, by virtue of the activation of oncogenes
- Insensitivity to growth-inhibitory (antigrowth) signals: cancer cells inactivate tumor suppressor genes that normally inhibit growth.
- Evasion of programmed cell death (apoptosis): cancer cells suppress and inactivate genes and pathways that normally enable cells to die.
- Limitless replicative potential: cancer cells activate specific gene pathways that render them immortal even after generations of growth.
- Sustained angiogenesis: cancer cells acquire the capacity to draw out their own supply of blood and blood vessels-tumor angiogenesis.
- Tissue invasion and metastasis: cancer cells acquire the capacity to migrate to other organs, invade other tissues, and colonize these organs, resulting in their spread throughout the body.
A Cancer Genome Atlas is currently in process of development for the major cancers to map all these mutations and pathways to hopefully identify targets important in the causation of these cancers.