Personalized Medicine in Action
Personalized medicine is becoming increasingly important in all aspects of clinical care, but oncology is where some of the major developments have taken off.
In studies published in The New England Journal of Medicine and The Lancet Oncology, D. Ross Camidge, MD, PhD, Director of the Thoracic Oncology Clinical Program, was instrumental in describing the importance of anaplastic lymphoma kinase (ALK)-positive lung cancer. The studies showed that patients with this abnormality, present in 5% of lung cancers, responded to a specific ALK-inhibitor drug called crizotinib. He and his colleagues including Dara Aisner, MD, PhD, in Pathology and Marileila Varella-Garcia, PhD, in medical oncology, described the diagnostic tests used to identify this molecular subset of lung cancer with the goal that everyone who might benefit from drugs targeted to specific molecular changes in a cancer actually receive them.
By subdividing lung cancer in the clinic not just into ALK and non-ALK but into multiple different molecular subgroups (see below), Dr. Camidge and colleagues were then able to start to observe patterns that had never been seen before. In essence, they were discovering and describing new diseases in the clinic that had been overlooked when all patients were grouped together.
As each of the mutations and gene rearrangements alters the underlying biology of the cancer, the Cancer Center team was able to note distinct patterns of metastatic spread in the body and different reactions to even some standard chemotherapy drugs, opening up large new fields for study. Until just a few years ago, lung cancer was lumped into two gross categories: adenocarcinoma or squamous. Instead, with all these developments, lung cancer is turning out to be a collection of many different rare diseases.
Subtyping Across the U.S.
With a ringside view of the ALK discoveries that were showing that amazing control of specific cancers could be achieved when molecular subtyping was used to direct patients to drugs targeted to their individual genetic abnormalities, the Cancer Center team was well placed to move molecular subtyping in lung cancer to the next level. Dr. Bunn again took the lead and created the Lung Cancer Mutation Consortium (LCMC) with initial funding from an American Reinvestment and Recovery Act Grand Opportunities grant, which helped establish the standard molecular profiling of 10 different oncogenes in 1,000 cases of lung cancer across 13 major U.S. academic centers.
New Subtypes Being Discovered
Cancer Center researchers continue to make remarkable discoveries, identifying even more molecular subtypes of lung cancer – diseases within one disease. A study recently published in Nature Medicine and led by Robert C. Doebele, MD, PhD, in the division of Medical Oncology, has revealed a gene fusion – NTRK1 – that spurs cells to divide rapidly, causing another subset of non-small cell lung cancers. Dr. Varella-Garcia, who co-developed the original and still most widely-used test for ALK-positive lung cancer, designed a new test using fluorescence in situ hybridization (FISH) to detect NTRK1 fusions. Having this precise knowledge of what is driving each patient’s cancer should enable researchers to conduct clinical trials to find more precise (and thus more effective) drugs to treat and turn off the genes.
Novel Side Effects
Cancer drugs are licensed more and more quickly and drugs that interfere with molecules involved in cancer may also have, as yet, unknown functions in normal physiology. As such, physicians are challenged to become better diagnosticians to spot novel side effects of these sophisticated targeted drugs. In recent collaborations with Michol Rothman, MD, in the division of endocrinology and Michel Chonchol, MD, in the division of nephrology, Dr. Camidge and the CU lung cancer team became the first to describe how the first licensed ALK inhibitor crizotinib also dropped men’s testosterone and interfered with glomerular filtration. By identifying these side effects, patients on these drugs can be managed for long periods of time much more effectively.
With all of this fragmentation of one disease into many smaller subsets of disease, how cancer clinical research is being conducted is now also being re-examined. The National Cancer Institute (NCI) Master Protocol Task Force in Lung Cancer is harnessing collective knowledge and research. The master protocol concept builds on the principles of the Lung Cancer Mutation Consortium and guides clinical studies in lung cancer using personalized therapy based on the biomarker profile of the patient’s tumor to determine therapy. Patients, no matter where they live in North America, enroll in clinical trials tailored to their specific molecular pattern.
Serving on the master protocol’s Multi-Sector Oversight Committee is Fred R. Hirsch, MD, PhD, in medical oncology. He is well known for his work in developing potential predictive biomarkers for the Epidermal Growth Factor Receptor (EGFR) antibody cetuximab, a treatment approved for colorectal cancer that may also have a role in lung cancer. In addition, Dr. Hirsch was also recently named CEO for the International Association for the Study of Lung Cancer, the longest established international research organization in lung cancer, which is headquartered in Colorado.
It is perhaps a tribute to the University’s powerhouse role in the study and treatment of lung cancer, that the next biannual World Conference on Lung Cancer, the “Olympics of Lung Cancer” in a sense, will be held in Denver in 2015, with Dr. Hirsch serving as the conference president.