Colorectal cancer is the fourth most common cancer and the second leading cause of cancer death in the United States. Current approved treatments for colon cancer include surgery and chemotherapy, but these can be unsuccessful against the more serious stages of the disease.
CRI postdoctoral fellow Jeffrey Chou, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center, with his sponsor Edus Warren, M.D., Ph.D., is focusing on developing a new treatment approach that combines low-dose chemotherapy with immunotherapy. Combining these treatment modalities, Dr. Chou hypothesizes, may improve their effectiveness in patients. If proven true, Dr. Chou’s work could provide new hope for the more than 655,000 people worldwide who are expected to die from colorectal cancer each year.
Making cancer an easier target
One of the most promising and most thoroughly studied targets for cancer immunotherapy is the tumor antigen NY-ESO-1, a cellular marker that flags danger to the immune system.
Clinical and laboratory studies have shown that NY-ESO-1 is present in many different cancers—including melanoma, lung, breast, and ovarian cancers—and not in most healthy tissue. Tumor immunologists are therefore able to design immunotherapies that target only cancer cells while leaving normal cells unharmed.
The level of NY-ESO-1 expression in colorectal and several other tumor types, however, is very low, limiting the efficacy of treatments that target NY-ESO-1 in patients with these cancers. Dr. Chou has shown that the drug decitabine (DAC), a chemotherapy that is currently approved to treat a form of pre-cancerous leukemia, can induce the expression of NY-ESO-1 in colorectal and other types of cancers.
"The danger flags that weren’t there before now appear," Chou says, "and that could make the cancer cells much easier targets for immune attack." With the danger flags in place, following DAC with an immunotherapy designed to enhance the anti-cancer immune response could be a winning combination for patients.
Taking down the cancer ringleaders
Dr. Chou is focusing on DAC’s ability to induce the immune system to target and attack colorectal "cancer stem cells." Like normal stem cells, cancer stem cells are thought to possess the ability to self-renew and differentiate into multiple cell types. This can be a particular challenge for cancer therapy, because the persistence of cancer stem cells following treatment may allow tumors to re-propagate, leading to recurrence and spread of the cancer to other organs.
According to Dr. Chou, cancer stem cells may be the cells that are responsible for initiating and maintaining the growth of all the cells in a tumor. "The theory is that if we can eliminate these cells we may be able to eradicate a patient’s cancer indefinitely at the root," says Chou.
It is Dr. Chou’s hope that, by treating colon cancer stem cells with DAC and then exposing them to immune cells that have been primed to recognize NY-ESO-1, he can generate a targeted and durable immune response against these cells without harming healthy cells.
If successful, these studies could lay the foundation for new treatment approaches combining chemotherapy with immunotherapy to maximize the body’s ability to fight cancer.
"We anticipate," says Dr. Chou, "that this research will provide important pre-clinical data to support clinical trials using DAC and similar drugs combined with immune therapies targeting antigens like NY-ESO-1 to treat advanced colorectal cancer and potentially other common cancers."