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Stem Cell Studies from Johns Hopkins Featured at Cancer Research Meeting - 04/10/2008

Stem Cell Studies from Johns Hopkins Featured at Cancer Research Meeting

Release Date: April 10, 2008

The following summaries are based on abstracts scheduled for presentation at the American Association for Cancer Research (AACR) Annual Meeting, April 12 - 16 in San Diego, CA.


-Laboratory studies refine method of finding the cells

Abstract #5000

Johns Hopkins Kimmel Cancer Center scientists have refined methods used in a previous study to reveal rare pancreatic tumor stem cells thought to fuel cancer growth and predict shortened survival.  Pancreatic cancer remains one of the deadliest cancers and most difficult to treat.

To sift away mature cancer cells from the rarer stem cell versions, the Johns Hopkins scientists applied two filters to human pancreatic tumors transplanted into mice.  One filter was first used by University of Michigan researchers to catch cells marked with protein flags called CD44 and CD24.

The next filter screened for cells containing high levels of an enzyme called aldehyde dehydrogenase, also found in normal bone marrow stem cells.  The Johns Hopkins scientists previously used the enzyme filter to identify stem cells in multiple myeloma, a cancer of the bone marrow.

The investigators say that using both filters resulted in a stem cell population that was two to 10 times more concentrated than using either filter alone.  Only about 1 in 500 pancreatic cancer cells has stem cell features.

“Purifying this stem cell population even further is key to identifying the ultimate pancreatic cancer stem cell and eventually identifying the processes that control it,” says William Matsui, M.D., assistant professor of oncology.  Investigators could use the information to create drugs that attack stem cell-specific gene products and track stem cell populations as the drugs take effect.

Further analysis revealed that pancreatic cancer stem cells marked with aldehyde dehydrogenase were found in patients who survived on average four months less than patients whose cells lacked the enzyme.

Cancer that spreads is the main culprit in cancer deaths, and the Johns Hopkins researchers believe stem cells have a role in this.  “These stem cells have physical properties similar to the types of cells that are invasive and likely to spread to distant sites,” says Zeshaan Rasheed, M.D., Ph.D., clinical fellow at the Johns Hopkins Kimmel Cancer Center.

In addition to new drug targets, the investigators are planning studies to tease out stem cells’ role in cancer metastasis and disease outcome.
The study was funded by the National Institutes of Health.  Additional participants include Jie Yang, Qiuju Wang, Irwin Freed, Daniel Laheru, Xiaobing He, David Berman, Manuel Hidalgo, Antonio Jimeno, Hansbart Koorstra, Seung-Mo Hong, and Anirban Maitra from Johns Hopkins.



Abstract # LB-87

Preliminary data from one of the first clinical trials to test a stem cell-targeting drug in cancer patients shows that while the drug did not prolong survival, its suppressing effect on patients’ stem cells was impressive enough to send investigators looking for a better drug to try.

As an emerging field of study in cancer research, stem cells are believed to sprout cancer much like the hidden roots of weeds that elude efforts to get rid of them.

Rituximab, a drug currently approved to treat B-cell lymphomas, plus a common chemotherapy agent, cyclophosphamide, were given to 21 patients whose multiple myeloma, a cancer of the bone marrow, had relapsed or was defined as high-risk first remission.  A previous study using the drug alone in multiple myeloma patients suggested that the disease in some participants progressed more slowly.

During the study, the Johns Hopkins team examined the stem cells under the microscope.  “We found cancer stem cells coated with rituxumab, but the drug wasn’t killing them,” said Carol Ann Huff, M.D., assistant professor of oncology.  “We think the idea is correct, but the drug itself wasn’t the right one.”  Rituximab is sold under the trade name Rituxan.

Huff and her team believe that several therapies are required to kill cancer - one to get rid of the bulk of the tumor, like mowing the lawn, and another to hit the root of the cancer, its stem cells.  “We think one reason that cancer comes back is because stem cells, which are resistant to chemotherapy, repopulate the body with new cancer cells,” says William Matsui, M.D., assistant professor of medicine at the Johns Hopkins Kimmel Cancer Center.

Their test of the rituximab-cyclophosphamide combo showed up to a 1000-fold reduction in cancer stem cells during the initial treatment.  However, stem cell quantities eventually crept back up and led to a progression of disease.  Investigators were able to predict when patients’ disease would recur by tracking the number of stem cells they had.  The average advance notice was two months.

Since the study began in early 2005, four patients have died from their disease, three remain progression-free, and the rest have disease that has progressed.

Matsui and Huff are currently testing drugs that block an enzyme called telomerase, which may give cancer stem cells longevity, and other drugs that block a stem cell-signaling pathway called hedgehog.  Other promising therapies, according to the scientists, include a combination of the drugs interleukin-6 and interferon-alpha, which may prematurely age stem cells.

Funding for the study was provided by the National Cancer Institute, American Society of Clinical Oncology, the Commonwealth Foundation, and Genentech.  In addition to Matsui and Huff, these Johns Hopkins scientists participated in the study: Q Wang, K Rogers, M Jung, Javier Bolanos-Meade, Ivan Borrello, and Richard Jones.

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