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Lisa Dubow Research Fellows Grant 2009

Epigenetic modulation of colorectal cancer stem cells for immunotherapy

As the recipient of the 2009 Lisa Dubow Research Fellows Grant, Jeffrey Chou, M.D., Ph.D. will study ways to make colorectal cancer stem cells more vulnerable to the body’s own immune system.

He will be working with both cell cultures and specially-bred mice to see if the drug decitabine can increase levels of a specific protein that induces a strong immune response.  If so, a combination of decitabine and a vaccine against that protein might be an effective treatment for advanced colorectal cancer.

In his proposal, Dr. Chou writes,

Despite advances in surgery, radiation, and chemotherapy, the majority of patients with advanced or metastatic disease ultimately die from their cancer. Treatment failures in colorectal cancer may be due to incomplete elimination of the colorectal cancer stem cell which can initiate and sustain tumor growth. Thus, an urgent need exists for the development of better systemic therapies which target the colorectal cancer stem cell.

Colorectal tumors are composed of different cell types. A small number of tumor cells have the ability to move from where they first developed to new sites in the body to establish new tumors. Cells with this property are called cancer initiating stem cells. These cells are particularly resistant to chemotherapy. Even if 99 percent of a tumor is killed by chemo or other therapy, but cancer stem cells remain, the tumor will grow back and continue to spread.

Find new ways of targeting and destroying colorectal cancer stem cells may lead to new and more effective treatment for colorectal cancer.

One way to destroy cancer stem cells is to harness the body’s own immune system to recognize them as a threat and eliminate them.  Ordinarily, the immune system accepts the proteins in cancer as a normal part of the body and basically ignores them.

However special proteins known as cancer/testis antigens (CTAs) stimulate an immune response in many cancers.  CTAs are only found in cells in the testicles, where they are invisible to the immune system, and in some cancers.  Because they are not found in normal tissue outside of testes, an immune system attack on cells with CTA can target cancer and leave healthy cells alone, ideal for cancer treatment.

Unfortunately, colorectal cancer cells have very low levels of CTAs so treatments for advanced colorectal cancer that evoke immune response (immunotherapy) haven’t been very effective. However, preliminary data show that the drug decitabine increases CTA levels in many types of cancers allowing  immune system cells to recognize and kill them.

One cancer/testis antigen (NY-ESO-1) induces strong immune responses in cancer cells.  Immune cells called cytotoxic T lymphocytes (CTLs) that can specifically recognize and kill cells producing NY-ESO-1 have been discovered.  When colorectal cancer cells are treated with decitabine in the laboratory NY-ESO-1-specific CTLs kill the cancer cells but not normal or untreated cells.

Dr. Chou is planning to build on this knowledge in his research, asking three questions:

• Will treating colorectal cancer stem cell cultures with decitabine increase the levels of NY-ESO-1 in those cells?
• If colorectal cancer cells are treated with decitabine and immunotherapy (cytotoxic T lymphocytes) and transplanted into mice, will the mice develop cancer?
• Can treating mice who already have cancerous tumors with decitabine slow tumor growth or destroy those tumors completely?

If successful, Dr. Chou’s basic research with colorectal cancer cells and mice may lead to effective vaccine therapies for colorectal cancer, killing the stem cells that keep it from being completely eliminated by conventional treatments.

The choice of Dr. Chou’s proposal for the 2009 award was made in collaboration with the American Association for Cancer Research (AACR) as part of its Fellows Grants Program for talented young investigators.

Lisa Dubow dreamed of a day when even the most dangerous and deadly colorectal cancer could be cured. You can help C3 make those dreams come true by supporting the work of Jeffrey Chou and other imaginative young cancer researchers by investing in the Lisa Fund.

Last Update: April 7, 2009