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NEWS TIPS ON CANCER THERAPY TARGETS - 08/15/2006

NEWS TIPS ON CANCER THERAPY TARGETS

Researchers Find Clues to Disease Spread and Origin
Release Date: August 15, 2006

Aug. 15, 2006 - The following studies by Johns Hopkins researchers describe two new potential targets for cancer drugs, one that takes aim at the beginning of the tumor growth process and origins of cancer cells and the other at the process of tumor spread.  Reports on the work, published in the August 1 issue of Cancer Research, describe experiments with mice and cell cultures that could lead to new treatments for childhood brain tumors and adult prostate cancers.

RESEARCHERS TARGET CELLS THAT CAUSE BRAIN CANCER

Building on previous research linking a common childhood brain cancer called medulloblastoma with high levels of the Notch2 gene, a team led by Charles Eberhart, M.D., Ph.D., is exploiting Notch2 gene products known to regulate brain stem-cell growth and survival.

The new studies provide the first hint that a class of drugs, called gamma secretase inhibitors, which block Notch proteins and currently are being developed for Alzheimer's disease, specifically kills stem cells responsible for creating and sustaining a brain tumor.

"Drugs that we typically use to treat cancer don't seem to kill tumor stem cells," says Eberhart, associate professor of pathology and oncology, and after the stem cells survive an onslaught of chemotherapy and radiation, they are left to regrow new tumors. 

Gamma secretase inhibitors appear to overcome this barrier. Eberhart and postdoctoral fellow Xing Fan, M.D., Ph.D., treated medulloblastoma cell cultures for 48 hours with a gamma secretase inhibitor and found that tumor growth slowed.  Closer inspection of the types of cells in the culture revealed that the cancer's stem cells were almost completely eliminated by the drug, but remained in drugless cultures.

Intrigued, the researchers injected the drugged and drug-free cultured cells into mice.  All 24 control mice with cells not treated with the Notch-blocking drug grew large tumors.

Mice that received cells previously treated with the drug fared much better. Only two of eight mice in this group grew very small tumors - less than one-tenth the size of control tumors.

"Medulloblastoma stem cells have much higher Notch gene activity than other cells in the tumor, which may be why the stem cells die first. They are more dependent on the Notch pathway, and blocking it causes severe problems," Eberhart explains.

Although the stem cells are a very small percentage of the entire tumor - approximately 1 percent - other researchers have identified heavy-duty transporters on their cell surfaces that may pump out chemotherapy drugs and cause cancers to become treatment-resistant.

Eberhart and Fan are continuing laboratory studies to select an appropriate gamma secretase inhibitor for clinical trials.

This study was funded by the Children's Cancer Foundation of Baltimore, Md.

Additional authors include William Matsui, Leila Khaki, and Duncan Stearns of Johns Hopkins; and Jiong Chun and Yue-Ming Li of Memorial Sloan-Kettering Cancer Center.

ENZYME LINKED TO PROSTATE CANCER SPREAD

Johns Hopkins Kimmel Cancer Center scientists have found that an enzyme, normally associated with the nervous system, appears to control deadly spread in prostate cancer.  Blocking the enzyme, called CDK5, could prevent disease spread in high-risk patients and make metastatic cells more susceptible to chemotherapy.

"Cancer cells must be able to 'crawl' out of the primary tumor in order to spread," says Barry Nelkin, Ph.D., professor of oncology, who notes that the cell's mobility is controlled by activation of the CDK5 enzyme.

The enzyme alters a cell's inner skeleton, allowing it to change shape and move to invade other tissues. Says Nelkin, cancer cells also activate CDK5 to reduce the number of "sticky" molecules coating its surface and loosen the bonds to neighboring cancer cells.

Once a cancer cell pulls free, it can migrate to other areas of the body via the bloodstream and establish potentially lethal spread. High levels of active CDK5 were found in prostate cancer cells, as well as melanoma and thyroid, adrenal, pancreatic and small cell lung cancers.

Using mice with a form of prostate cancer that spreads to the lung, the researchers implanted genetically modified tumors that blocked the CDK5 enzyme. Mice with CDK5-free tumors had a 79 percent reduction in the number of metastatic lung lesions.

The researchers will continue studies to determine the role of CDK5 in other cancers and development of a CDK5 enzyme-blocker suitable for humans.

This research was funded by the National Cancer Institute and Patrick C. Walsh Prostate Cancer Research Fund.

Authors include Christopher J. Strock, Jong-In Park, Eric K. Nakakura, G. Steven Bova, John T. Isaacs, and Douglas W. Ball of Johns Hopkins.   

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