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Under the Microscope: Fighting Colorectal Cancer and Cancer Disparities

Cancer takes many forms, but even cancers that on the surface appear to be the same disease can be different on the molecular level.

Case in point: colorectal cancer. While colorectal cancer can be devastating for anyone, African Americans bear the heaviest toll, contracting colorectal cancers more frequently than Caucasians and dying from them more often.

With support from the V Foundation, Stanford Markowitz, MD, PhD, Markowitz-Ingalls Professor of Cancer Genetics at Case Western Reserve School of Medicine and a medical oncologist at University Hospitals Seidman Cancer Center in Cleveland, OH, leads an ambitious research project to unravel the tangled web of genes and environmental factors at the heart of this disparity.

“Right now, African Americans have a 50 percent greater chance of dying from colorectal cancer,” says Markowitz. “We see these disparities all the time, and this project is a chance to explore what’s going on and do something that could have impacts right in our own backyard. The more we understand, the more likely it is we will be able to develop targeted treatments.”

In addition to Markowitz, key members of the research team include Joseph Willis, MD, vice chair of Case and University Hospitals pathology department; Kishore Guda, DVM, PhD, a cancer geneticist at Case Comprehensive Cancer Center; and Vinay Varadan, PhD, a computational biologist at Case Comprehensive Cancer Center.

A different—and more deadly—disease

To get started, Markowitz and his colleagues wanted to find out whether colorectal cancers in African Americans and Caucasians show differences at the genetic level. The V Foundation provided funding for the team’s genetic sequencing work through the foundation’s Stuart Scott Memorial Cancer Research Fund, a fund that honors ESPN sportscaster Stuart Scott and his dedication to addressing cancer disparities.

Comparing DNA from samples of colorectal tumors from 103 African American patients with samples from Caucasian patients, the research team zeroed in on a group of 15 genes. “We found that certain genes were much more mutated in African Americans and that those individuals with the mutations had more relapses and died more frequently,” says Markowitz.

The mutations, found in about 40 percent of the samples from African American patients, were significant enough to rightly call the mutated cancer a biologically different disease.

Further research on samples from 66 African American patients with stages 1 – 3 colorectal cancer found that those with one of the 15 mutations were nearly three times more likely to have metastatic cancer and also three times more likely to suffer relapses. The work confirmed that colorectal cancer varies on the molecular level among individuals and between ethnic and racial communities.

Environment vs. genetics

Markowitz and his team are now looking to learn whether the mutations seen in African American patients arise due to genetic vulnerabilities or if environmental factors play a role. They have partnered with Vanderbilt University to repeat their genetic analyses with data from colorectal cancer patients who participated in the Southern Community Cohort Study, a long-term effort to understand the causes of cancer disparities. That work should show whether the genetic mutations can be generalized to African American colorectal cancer patients across the U.S. and whether common environmental factors—such as smoking, diet and exposure to environmental carcinogens—are implicated in the development of the mutations.

Additionally, Markowitz is collaborating with Funmi Olopade, MD, a cancer expert at the University of Chicago, to determine whether similar mutations occur in colorectal patients in Africa. The researchers will compare their data to colorectal patient data from a hospital in Lagos, Nigeria, to determine whether the mutations are hardwired into the biology of people of African descent.

“Ultimately, we want to know how to target these cancers that are different on the molecular level,” says Markowitz. “We want to know what causes the mutations, how we can target them and whether they are sensitive to drug therapies.”

Moving toward better therapies

In addition to investigating the causes of the mutations, Markowitz’s team studies their effects. In studies led by Willis, the team showed that colon cancers with the mutations were more lethal than those without them. The team hopes this observation will lead to a clinical trial to determine if using more intensive chemotherapy might translate into better survival rates for patients whose tumors carry the mutations.

“If you can identify these aggressive cancers early on, and if you know that they need to be treated differently or more aggressively, that is good news,” he says. In studies led by Guda, the team is investigating how the mutations affect tumor growth and metabolism, with an aim to identify drugs that may be particularly suited for treating these molecularly distinct tumors. Markowitz and his team hope that a better understanding of how the mutations promote cancer will ultimately lead to developing new treatments. For example, if researchers discover that the mutated genes turn on specific signaling pathways that cancer cells use to multiply, they could also be sensitive to new classes of cancer drugs that shut down those signaling pathways and cause cancer cells to die.