Adrenal Cancer Stem Cell Research
Adrenal cancer: rare but deadly
Adrenocortical carcinoma (ACC) is rare, but very deadly. This type of cancer develops in the outer layer, called the cortex, of the two small adrenal glands that sit on top of each kidney. About 600 new cases are diagnosed each year in the United States, or about one to two cases per million people.
The adrenal glands are part of the body's endocrine system. They make hormones that regulate the activity of other organs in the body. Among other things, these hormones help control blood pressure and how the body reacts to stress. Sex hormones produced by adrenal glands trigger physical changes in the body during puberty as boys and girls develop into men and women.
Adrenocortical cancer is most common in either the first or fifth decade of life. Because it produces symptoms in children, pediatric adrenal cancer is often diagnosed and treated at an early stage. Five-year survival rates in children are greater than 50%.
Adults rarely have obvious symptoms, so they often are not diagnosed until the cancer is large and has spread to other parts of the body. Although adrenal cancer can be treated in adults, it usually comes back. Once it recurs, it is almost always fatal.
U-M scientists in the Cancer Center's adrenal cancer program are studying primitive cells, called stem or progenitor cells, found in the outer cortex of the adrenal gland. They believe defects in these stem cells and the genes that regulate them could be the cause of adrenal cancer. Discovering what goes wrong early in the development of adrenal cancer is the vital first step toward finding better treatments and a cure for this fatal disease.
Does the adrenal gland have stem cells?
Like every other organ in the body, adrenal glands contain a small number of what scientists call adult stem cells or progenitor cells. Their job is to generate a continuous supply of new adrenal cells to replace old ones that wear out and are destroyed. The adrenal gland continually regenerates itself, so without stem cells, it wouldn't last long. In the adrenal gland, stem cells are located just under the outer capsule that surrounds adrenal tissue like the skin on a grape. These rare stem cells are the only cells in the adrenal gland that can make new adrenal cells.
Has anyone found an adrenal cancer stem cell?
Not yet. The U-M Cancer Center is one of the few research institutions working on the genetics and cell biology of adrenal cancer, so there's still a great deal of work to be done in this field.
How does the U-M Cancer Center approach research on stem cells in adrenal cancer?
U-M researchers are studying genes involved in the biology of normal stem or progenitor cells in the adrenal cortex, as well as the genetics of adrenal cancer. They think the same genes that regulate normal stem cells could be responsible for adrenal cancer. This is consistent with the cancer stem cell hypothesis that defective stem cells are the root cause of cancer.
Scientists in the Cancer Center are particularly interested in three genes that are associated with familial pediatric adrenal cancer and are similar to mutated genes found in adult adrenal cancer. All three of these genes are known to be involved in normal stem cell biology. When we induce mutations in those genes in mice, they get adrenal cancer.
By understanding exactly how these genes and others work - both in normal and malignant adrenal cells - researchers hope to use that knowledge to create new treatments targeted at these genetic defects.
What are the goals of this research?
The scientific goal of Dr. Hammer's laboratory research is to define normal stem cell biology in the adrenal gland. Understanding what's normal will help researchers figure out what happens when stem cells act abnormally. This will allow them to complete the circle from normal to pathologic, from mouse to human, and the signaling pathways that link them.
Does research on adrenal cancer have applications to other types of cancer?
The signaling pathways researchers are studing in adrenal cancer are very likely to be involved in other types of cancer, too. Specifically, what we learn about the development of adrenal glands in an embryo will have direct applications to ovarian and testicular cancer. This is because the adrenal glands, ovaries and testes all develop from the same tissue in the embryo. In Dr. Hammer's laboratory, they have shown in mice that inducing mutations in the stem cell regulatory genes they study can turn an adrenal gland into an ovary. It's an example of the plasticity of stem cells.
Because the adrenal gland is most like the testes and ovary and because the same genes affect the development of all these organs, scientists believe that research on adrenal cancer will have broad implications for the more common and deadly diseases of ovarian and testicular cancer.
Are clinical trials underway for new treatments for adrenal cancer?
Based on evidence from laboratory research and animal studies, researchers believe shutting down the insulin-like growth factor (IGF) signaling pathway could be a promising treatment approach for adrenal cancer. Research on the IGF signaling pathway has led to two new clinical trials in adrenal cancer:
The National Cancer Institute is sponsoring a phase II trial of a monoclonal antibody that inhibits the IGF2 signaling pathway. The antibody is given in combination with mitotane - the only drug approved by the FDA to treat adrenal cancer. The trial began in 2010 in patients with advanced or metastatic adrenal cancer at the U-M Comprehensive Cancer Center and other research institutions nationwide.
Another phase III trial of an oral drug called OSI-906 targeted at the IGF signaling pathway is underway at the U-M Cancer Center and other research institutions. The trial, which opened in 2009, is aimed at patients with locally advanced or metastatic adrenal cancer and is sponsored by OSI Pharmaceuticals. If this drug is approved by the FDA, it will be the first drug approved for adrenal cancer since mitotane was approved in 1959.
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