Colon Cancer: Research Highlights

The Society's support for research on colorectal cancer (commonly called colon cancer) includes 114 current grants totaling approximately $76.3 million as of January 1, 2011.  In fiscal year 2008, the Society spent $26.1million on colon cancer research.  The Society also supports research in a multitude of areas that are not specific to colon cancer, but are known to impact the understanding of this disease, such as DNA repair, DNA instability, apoptosis, genetics, drug resistance, metastasis, and immunology, among others.

Research highlights
Genetics is a very hot area in colon cancer research.  In March 1997, a team of scientists that included former American Cancer Society Research Professor Bert Vogelstein, MD, announced the discovery of a genetic change in a protein called beta-catenin that appears in 15% of familial colon cancers and perhaps 60% of all colon cancers.  The beta-catenin gene product interacts with the product of another gene discovered by Dr. Vogelstein--the familial adenomatous polyposis gene.  Increasing knowledge of this pathway may lead to new ways to treat the disease.

Significant developments in colon cancer research related to diet have occurred recently.  The Society's epidemiologic studies are contributing to progress in the prevention, detection, and treatment of colon cancer. Cancer Prevention Study II (CPSII) is a compilation of lifestyle data gathered from more than 1 million Americans since 1982.  Society epidemiologists use these data in a number of ways, and several important findings pertaining to colon cancer have emerged from this research.

Focusing on dietary risk factors, researchers learned from their study of CPSII data that diets rich in fruits, vegetables, and high-fiber grains were associated with a lower risk of fatal colon cancer. 

When Society epidemiologists analyzed data on aspirin use among certain segments of the CPSII study participants, they found that the risk of fatal colon cancer among persons using aspirin 16 or more times a month was approximately half that of nonusers. The trend of decreasing risk with increasing dose was statistically significant in both men and women. Other studies subsequently have reported similar results. While these results are encouraging, further studies are needed before scientists and physicians can make firm recommendations on the use of aspirin to reduce the risk of developing fatal colon cancer.

In 2010, Lin Zhang, PhD, a Society-supported researcher, reported that NSAIDs help prevent colorectal cancer by inducing apoptosis (cell death) in the small subset of cells known as cancer stem cells.  Importantly, he provided evidence that a gene known as SMAC is involved regulating this process.  These findings are an important advance in understanding the regulation of death in cancer cells, and may provide new avenues for prevention of this disease.

Years of basic research, much of it conducted on organisms such as yeast and bacteria, paid off with the discovery of three genes responsible for inherited colon cancer. Richard Kolodner, PhD, of the Dana-Farber Cancer Institute in Boston, and Bert Vogelstein, MD of the Johns Hopkins Oncology Center in Baltimore, led teams that independently discovered the first gene in late 1993. The same groups also were involved in subsequent discoveries of other genes that influence susceptibility to colon cancer.

The discovery of these genes has several implications for colon cancer patients and their families. The first is that a blood test has been developed that can identify people genetically predisposed to colon cancer. Members of families in which there have been multiple cases of colon cancer can be tested to see if they carry one of the susceptibility genes. If they do, they can lessen their risk of developing the disease by making changes in their diet and lifestyle.  They should also be encouraged to undergo more frequent screening via colonoscopy so that if colon cancer does develop, it can be detected and treated early.  Some patients may be advised to have a prophylactic, surgical removal of the colon, which is, fortunately, not as drastic a procedure as it once was.

A second implication is that much of the information accumulated during the research that led to isolation of the genes can be used to develop new forms of therapy.  The information also may help scientists find ways to prevent colon cancer.

American Cancer Society Research Professor, Wafik El-Deiry, MD, PhD, has recently made a number of important contributions to the discovery and evaluation of a new therapeutic agent for colorectal cancer, and in developing new means of imaging colorectal cancer cells and cancer stem cells for evaluating their response to therapy.

One of the most common drugs used to treat colon cancer, 5-flurouracil (5 FU) was synthesized by longtime Society grantee Charles Heidelberger, PhD, in 1958.  For 40 years, 5-fluorouracil (5 FU) has been the first line treatment for colon cancer.  In the early 1990s, the response to 5-FU was found to be enhanced by leukovorin, a compound first used in the treatment of leukemia by Society Professor Joseph Bertino, MD, Memorial Sloan-Kettering Cancer Center.  But for advanced, stage IV colon cancer there has been no effective treatment.

Recently, the drug irinotecan (Camptostar), the patent for which cites research supported by American Cancer Society  grants to Milan Ptomesil, MD, PhD, New York University,  was approved in 2000 by the FDA for the treatment of advanced colon cancer.  Former Society Career Development Awardee Leonard Saltz, MD, Memorial Sloan Kettering Cancer Center, now reports that a combination of all three of these drugs--5-FU, leukovorin, and irinotecan - elicits a 39% response in advanced colon cancer compared to ~21%  with irinotecan alone, or the dual combination of 5 FU and leukovorin.  The mean survival time for the three drug regimen was 14.8 months compared with 12.6 months with the other two treatments.

"That doesn't sound like much, but it is a big deal for the person who gets that extra two months," said Dr. Saltz. "For someone with incurable cancer, every bit of time is important. These results are exciting not only because of what this treatment can offer right now to our most advanced patients, but also because this combination may be able to improve the cure rate when used in the post-operative setting for patients with earlier stage colon cancer."  Based on these results, a clinical trial of the three drug combination in earlier, stage III patients has begun.