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An interesting conversation with this year's AACR president, Frank McCormick, PhD, on the next big area of interest in cancer research, and what the future holds for cancer research progress.
Frank McCormick, PhD
The American Association for Cancer Research (AACR) advocates that research is the best defense against cancer. In its 2012 Cancer Progress Report, the AACR outlines important advances in cancer research, as well as the challenges the AACR is facing regarding funding. We had an interesting conversation with this year’s president, Frank McCormick, PhD, president and director of the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, and gained some insight into the coming year regarding what’s the next big area of interest in cancer research, and what the future holds for cancer research progress.
McCormick notes that one of the strategic priorities of the AACR is to expand its presence in the grass roots community, to increase awareness not only about the issues related to funding for cancer research, but also to include things people can do in terms of prevention, such as avoiding tobacco use and maintaining a healthy diet. Awareness, he advises, is to a greater extent legislative and involves policy issues, which most researchers can’t influence as effectively as they would like.
In addition to educational material for the public about cancer prevention, diagnosis, and treatment interspersed with stories from cancer survivors, the Cancer Progress Report also includes discussions of some of the important recent advances in the development of targeted therapies, anti-hormone therapies, immunotherapies, patient stratification, and genomic medicine.According to McCormick, one of the many challenges involved with cancer research is financial. The impact of the impending automatic spending cuts or “sequestration” proposed to occur in early 2013 would result in an approximate $400 million decrease in funding for the National Cancer Institute. First-time investigators just getting started would be severely hit hard by this slash in cuts, impeding significant future innovation.
Moreover, the impact of sequestration on the National Institutes of Health would reduce funding by approximately $2.52 billion, resulting in about 2300 fewer grants receiving awards in the fiscal year 2013. According to McCormick, “This would be a disaster and is something that is of major concern to the whole community, not just because of all the careers of people who will be affected, but also the fact that this is a moment in the history of cancer research when we are really getting a good bead on how complicated things are and how many opportunities there are to make progress.”
Sequestration would also severely affect the Centers for Disease Control and Prevention, the Food and Drug Administration, the Agency for Healthcare Research and Quality, and the National Science Foundation.McCormick identified three of the hottest areas of interest in cancer research for 2013:
McCormick prefers the term precision medicine to personalized medicine. The objection to personalized medicine is that physicians feel they have always practiced personalized medicine. Precision medicine captures the precision of new technologies. “We are all talking about same thing,” says McCormick, “that is, identifying who is likely to benefit from specific drugs and who should be excluded, and tailoring drugs to individual patients.” A good example of this would be non-small cell lung cancer, which has had a very poor prognosis. Today, several subtypes of the disease have been identified that respond fairly well to targeted therapies. Therefore, physicians are obliged to run companion diagnostics to determine if patients have mutations in EGFR, translocations in ALK, or mutations in KRAS to identify the appropriate therapy.
McCormick believes that sooner or later it will be faster and cheaper to sequence the whole genome and make decisions based on that rather than by using dozens of tests. He anticipates that every large medical center will one day be able to sequence every gene in every tumor, and notes that the FDA is aware that this is on the horizon. In the era of the $1000 genome, this would yield 105 times the information obtained from one gene mutation test, and at a much lower cost.
Patients who come to the clinics at UCSF are already seeking to have their tumor genome sequenced. McCormick acknowledges that the computer power to store and analyze this amount of data is an area of technology that’s struggling to keep up with all of the information. McCormick thinks it’s possible that polymorphisms in normal, healthy tissue may predict the response to targeted therapies, conventional chemotherapy, and radiation therapy. This means that a future complete workup would include completely sequencing normal tissue, tumor tissue, and, ideally, metastases. “It’s mind-bogglingly complicated and expensive, but that’s the future of predictive medicine,” he says.In the next year or so, McCormick predicts, the big breakthrough discoveries that will affect patients directly by providing a survival benefit will be in immunotherapy. He expects to see results from secondgeneration approaches to affecting immune checkpoint genes or proteins that normally suppress the immune response in cancer patients, and looks forward to reports of benefits from relieving those checkpoints. He notes that in cancers with poor prognoses such as malignant melanoma, and possibly lung and renal cancer, some patients are surviving long enough that they might be considered cured. The challenge here is to figure out why 20% of patients respond and 80% don’t, and how survival can be increased by understanding the molecular basis of the responses and the nonresponses. That is a research field that wasn’t even possible until a few years ago because there weren’t enough responders to generate enough data to be analyzed. Now, the focus will be on biomarkers of responders and how they can be used to predict who is going to respond, and how the potency of antitumor agents can be increased so more patients have a long-term response. “It’s a fantastically fruitful area of research which wasn’t even thinkable a few years ago,” says McCormick.
For immunotherapy, it’s not clear whether differences in response are due to differences in the tumors themselves or in the host immune system or other aspects of the host makeup. Here, too, genes involved in the whole immune system and its regulation and expression, as well as genes actually in the tumor, will eventually be sequenced to try to determine who is likely to respond best.Epigenetics is a field of study McCormick finds hard to deal with. He likes the concept that mutations lead to changes in proteins, which then may lead directly to the development of specific therapies. It is more difficult to figure out how changes or modifications to histones and chromatin structure translate into effects on tumor cells. As more and more sequencing is carried out on tumor genomes, more and more mutations in genes that affect these pathways are being identified, giving this area of research a more genetic underpinning. This is also resulting in a better sense of an epigenetic code and the impact this has on treatment. McCormick speculates that after the current first wave of cancer targets from the kinome, one of the next waves of drug targets might come from analysis of proteins involved in regulating the epigenome. Although drugs are being developed based on chromatin remodeling, genome plasticity, and methylation, the biology is complicated, and it will require a lot more validation and biological understanding, but it is definitely going happen.McCormick expects therapies based on targets from the epigenome to be featured in the next year or two in the Cancer Progress Report. Another aspect of cancer therapy that will play out over the next several years will be the results of combination treatments using targeted therapies. This will require a very sophisticated level of understanding to figure out how to make these pathways work together. “We can expect to see a whole range of discoveries there,” McCormick says, “I’ve been around a long time, and every few years some major innovation comes along which completely changes the way we think about how we do research and how we see therapies in ways which nobody previously anticipated, such as recombinant antibodies, cloning, PCR, siRNA, and so on.
“Those game-changing technologies keep on coming as long as the research world is well funded and supported. It may be difficult to predict the future, but I am confident that innovations will keep on coming, and that as long as that momentum is maintained, we will have a much more dramatic impact than what we can foresee by extrapolating from today,” concludes McCormick.