Cancer—few other words incite such fear and confusion as this pervasive disease.Yet, nearly 1.7 million Americans hear this devastating diagnosis every year. Those with advanced-stage disease face an arduous future and a bleak prognosis. Some of the deadliest cancer types, including colorectal, lung, and pancreatic, remain undetected until they reach these advanced stages, leaving aggressive chemotherapy as the only option to slow the disease’s growth, abate symptoms, and improve quality of life. Add to that, very few cancers respond consistently to chemotherapy, and oftentimes a positive response lasts only weeks or months. Until very recently, advanced cancer treatment followed a “one-size-fits-all” approach that based standard treatments on cancer type alone. As a research scientist and assistant professor in APU’s Department of Biology and Chemistry, I have seen the results of hundreds of clinical trials and their chemotherapy success rates and side effects, and can only conclude that one size clearly does not fit all, and any positive impact on tumors proves only marginally effective. But this may all be about to change.
Cancer differs from many other treatable human diseases in that it originates from cells that were originally normal, but acquired genetic mutations that grew and spiraled out of control over time. Unfortunately, because these cancer cells retain features and functions similar to normal cells in the body, chemotherapy takes on the nearly impossible task of targeting and isolating these cancer cells while sparing healthy cells. Further confounding the situation, as cancer develops, it continually acquires more mutations and abnormalities that drive more aggressive growth, promote spreading, and dramatically increase resistance to chemotherapy, rendering cancer a constantly evolving, moving, and elusive target. The complexity of the issue does not stop there. Although all people possess the same basic genetic makeup, natural variations occur within those genes that make each person unique. This leads to major differences in how each patient tolerates and metabolizes chemotherapy, as they would other types of medications such as antibiotics. We now realize that these subtle differences can have a profound impact on the success of their chemotherapy. This new era of cancer treatment abandons the “one-size-fits-all” approach, opting instead for rigorous genetic analyses of patients and their tumors to tailor an effective and safe treatment with the highest possible likelihood of success.
A Fresh Approach
Until recently, personalized medicine existed more as a concept than a reality because of the difficulty in pinpointing the reasons for the success or failure of chemotherapy. Identifying those few key genetic mutations or proteins that can make the difference between chemotherapy success and failure represents a monumental task, quite literally like searching for a needle in a haystack. The University of Southern California Norris Comprehensive Cancer Center (USC/Norris) stands at the forefront of personalized cancer medicine with a translational research program that begins at the research bench and continues to the patient’s bedside.
I have been fortunate to participate in an ongoing research program that maintains strong ties with USC/Norris, where I earned my doctorate in 2010 and completed a postdoctoral fellowship in 2010 and 2011 with Heinz-Josef Lenz, MD, one of the world’s foremost experts in gastrointestinal cancers.
During that time, I focused on a new class of chemotherapeutic drugs called histone deacetylase inhibitors (HDACi), which disrupt cancer growth in several ways, including restructuring the tumor cells’ DNA and altering the genes that are switched on and off. HDACi also cause the premature breakdown of some key proteins that tumor cells rely on to fuel their growth and withstand chemotherapy. One of these proteins, thymidylate synthase (TS), accounts for the failure of an important type of chemotherapy in colorectal cancer. My husband, Peter Wilson, Ph.D., an adjunct professor in APU’s Department of Biology and Chemistry and researcher at USC/Norris, and I researched this phenomenon and showed that it may be possible to integrate HDACis into chemotherapy treatments for colorectal cancer to improve the overall effectiveness and prevent treatment failure—specifically in patients whose tumors contain high levels of TS protein and whose chance of responding positively to chemotherapy is extremely low.
Colorectal cancer remains one of the toughest cancers to treat and is the third-most-deadly cancer in the U.S., after lung and breast cancers. The American Cancer Society projects that 143,000 Americans will be diagnosed in 2013, and approximately 51,000 patients will die of this disease. Despite advances in technology and promising new drugs, improvements to colorectal cancer patient survival rates over the last 10 years have only been incremental, and the chances of responding positively to chemotherapy remain at about 40 percent. The aggressive and resistant nature of advanced colorectal cancer means that less than 10 percent of patients diagnosed survive five years. We urgently need new ideas and treatment options to remedy this sobering statistic.
A Hopeful Prognosis
USC/Norris performed a phase one clinical trial with the most promising HDACi drug, vorinostat, to determine the safety of combining these agents with standard chemotherapy. Although the trial proved the combination safe, only a few patients showed improvement in their disease. This disappointment prompted a return to the research bench. At this juncture, in an APU-USC collaboration, Peter and I used information gleaned from the clinical trial to better inform our laboratory experiments. In our manuscript published in Investigational New Drugs in January 2013, assisted by APU research students Shelby Martin ’13 and Stephanie Kuwahara ’13, our team used simulated experiments to show that the body broke down vorinostat at a rate faster than it could exert its anticancer effects in most patients. We then used a new HDACi called panobinostat, which the body breaks down approximately four times slower than vorinostat. Panobinostat proved to be much more effective at inducing numerous anticancer effects, including the faster breakdown of TS at lower doses than vorinostat, and USC/Norris is now evaluating this research in another phase one clinical trial with seven patients recruited thus far.
This multidisciplinary collaborative effort between USC/Norris’ Departments of Gastrointestinal Oncology and Pathology and APU’s Department of Biology and Chemistry highlights the pivotal need for understanding the underlying reasons that so many cancer drugs fail, and the importance of the research bench in informing and ensuring the future development and success of cancer drugs. This move toward personalized cancer treatment will take much of the guesswork out of chemotherapy and gives the patient the best chance at receiving a successful therapy from the onset of treatment. While this may not change the overall prognosis for patients whose cancer has progressed too far, we are confident it will provide them with precious time while improving their quality of life. Most important, a significant number of cancer patients who receive effective personalized therapy delivered the first time around will undoubtedly become cured and lead cancer-free lives.