Breast Cancer; New type of drug shrinks primary breast cancer tumors significantly in just 6 weeks
2008 APR 28 - (NewsRx.com) -- A drug that targets the cell surface receptors that play an important role in many types of cancer can bring about significant tumour regression in breast cancer after only six weeks of use, a scientist told the 6th European Breast Cancer Conference (EBCC-6) today (Thursday 17 April). Dr. Angel Rodriguez, from the Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, USA, said that the work demonstrated for the first time that the tyrosine kinase inhibitor lapatinib could decrease tumour-causing breast cancer stem cells in the primary breast cancers of women receiving neoadjuvant treatment (treatment given before the primary surgery for the disease) (see also Breast Cancer).
Dr. Rodriguez and colleagues studied 45 patients with locally advanced breast cancer in which the gene HER-2 was over-expressed. The patients received lapatinib for six weeks, followed by a combination of weekly trastuzumab and three-weekly docetaxel, given over 12 weeks, before primary surgery. Biopsies were performed at the time of diagnosis and also after six weeks of lapatinib and cells from the tumours were obtained and analyzed.
"We saw significant tumour regression after six weeks of single agent lapatinib," said Dr. Rodriguez. "Bi-dimensional tumour measurements showed a median decrease of minus 60.8%. We had previously showed that tumour-causing breast cancer stem cells were resistant to conventional preoperative chemotherapy; indeed, residual cancers that were exposed to such chemotherapy showed an increase in tumour-causing cells and enhanced tumour initiation by the formation of mammospheres, small tumours that form when tumour-causing cells are cultured in a test tube, which reflect the capacity of the cells to self-renew. So we were excited to see that the results with lapatinib were different."
Dr. Rodriguez's results suggest that specific signalling inhibitors of the pathways responsible for stem cell self-renewal could provide a possible therapy for eliminating tumour-causing cells in order to achieve the long-term eradication of cancer.
Cancer stem cells help maintain the malignant tissue in the tumour by regenerating the tumour after attack from chemotherapy drugs. "This indicates that the stem cells themselves should be the specific target of chemotherapy drugs," said Dr: Rodriguez. "Rather than the broad brush approach, in which cells are killed indiscriminately, targeting the stem cells may be more effective and also prevent some of the unpleasant side effects associated with conventional chemotherapy treatment."
Scientists believe that cancer stem cells come into being through damage to their own DNA, which affects the regulation of their self-renewal. Other cells divide into two 'daughter' cells, but a stem cell can divide into a new stem cell and a 'progenitor' cell. The progenitor cell loses the power of self-renewal, but can still change into the cell type of the tissue served by the stem cell. The stem cell population then continues to renew itself as it generates new cells for the tissue. "This means that, unlike other cells, the stem cell has lost control over its own population size," said Dr. Rodriguez.
Lapatinib has few side effects, and those that exist are minimal, including diarrhoea and acne. But it is expensive. "In the US it costs between $2000 and $3000 a month," he said.
"This is an exciting finding, and we will be starting further studies on stem cells in order to confirm it. We will also look into its applicability in testing novel agents targeting tumour-initiating cells. This finding should also apply to other types of cancers and research of tumour-initiating stem cells in other cancers is ongoing," said Dr. Rodriguez.
"International studies are currently underway looking at the effect of lapatinib in lung, colon, head and neck, gastric, oesophageal, and bladder cancer and lymphoma, among others," he said.
This article was prepared by Stem Cell Week editors from staff and other reports. Copyright 2008, Stem Cell Week via NewsRx.com.
Cancer; Georgetown researchers find stem cell marker controls 2 key cancer pathways
2008 APR 28 - (NewsRx.com) -- Researchers at Georgetown University Medical Center have discovered that a gene associated with human breast stem cells can stimulate development of mammary cells by activating two critical cancer pathways. They say this finding, reported at the annual meeting of the American Association for Cancer Research (AACR), provides new evidence that breast cancer can arise from stem cells and that targeting this gene might provide a new way to treat cancers of the breast as well as other tumor types (see also Cancer).
"This is the first time any role has been attributed to this gene, and it turns out to be one that is surprisingly powerful," says the study's lead author, Xiaoyang Wang, Ph.D., Postdoctoral Fellow at Georgetown's Lombardi Comprehensive Cancer Center.
Specifically, Wang and the researchers show for the first time that this gene, Musashi1 (Msi1), switches on Wnt and Notch cell signaling. Both of these pathways help control stem cell growth, and are known to be critically important to the development of many cancers.
Msi1 was named after a famous 17th century Japanese swordsman, Miyamoto Musashi, by Japanese researcher Hideyuki Okano, Ph.D., who identified it in fruit flies in 1994. Okano currently collaborates with the Georgetown scientists.
Recent studies have shown Msi1 to be a marker of human stem cells in general because it has been found in human breast, colon, brain, skin, and other cells, says Robert Glazer, Ph.D., a professor of Oncology and Pharmacology and the study's senior author.
So Glazer and Wang decided to probe the gene's function. "Msi1 is known to be a marker of stem cells, but no one knows what it does. We wanted to see if it had a function in the mammary gland," Glazer says.
They were especially interested in whether Msi1 is associated with cancer development because recent studies have suggested that stem cells may be the causative root of some cancers – a notion that is vigorously debated among cancer researchers.
"It is really critical to understand if stem cells are involved in cancer development because a lot of therapies used to treat cancer don't target stem cells," he says. "That may explain why tumors come back."
In laboratory experiments, the scientists found that, in mammary cell development, Msi1 drives mammary cells along different lineages – in other words, it can decide what type of cell develops in the breast, be it muscle cells or cells that line milk ducts, etc.
In cancer, the Wnt and Notch pathways are often activated, and the researchers found that Msi1 is expressed in particularly aggressive tumors. The researchers then tested whether Msi1 regulates these pathways in mammary cells and found that it did.
The researchers then studied how Msi1 drives the Wnt and Notch pathways found that when Msi1 was over-expressed, there was an increased secretion of a growth factor known as proliferin, and reduced secretion of the Wnt pathway inhibitor, Dickkopf-3. Additionally, Msi1 programmed the expression of a number of genes that have a concerted effect on the cell cycle, Wang says.
"We believe that while Msi1 may contribute to cell proliferation, it is not the single gene that controls cancer development," Glazer says.
"This work suggests, but does not prove, that stem cells drive breast cancer formation," he says. "Msi1 might make a good therapeutic target, and we are currently testing ways to interfere with its function in cells to see if it disrupts cancer cell proliferation."