Herceptin Targets Breast Cancer Stem Cells
Main Category: Breast CancerAlso Included In: Stem Cell Research
Article Date: 10 Jul 2008 - 1:00 PDT
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A gene that is overexpressed in 20 percent of breast cancers increases the number of cancer stem cells, the cells that fuel a tumor's growth and spread, according to a new study from the University of Michigan Comprehensive Cancer Center.
The gene, HER2, causes cancer stem cells to multiply and spread, explaining why HER2 has been linked to a more aggressive type of breast cancer and to metastatic disease, in which the cancer has spread beyond the breast, the researchers say.
Further, the drug Herceptin, which is used to treat HER2-positive breast cancer, was found to target and destroy the cancer stem cells. Results of the study appear online in the journal Oncogene.
"This work suggests that the reason drugs that target HER2, such as Herceptin and Lapatanib, are so effective in breast cancer is that they target the cancer stem cell population. This finding provides further evidence for the cancer stem cell hypothesis," says study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center.
The cancer stem cell hypothesis says that tumors originate in a small number of cells, called cancer stem cells, and that these cells are responsible for fueling a tumor's growth. These cells represent fewer than 5 percent of the cells in a tumor. Wicha's lab was part of the team that first identified stem cells in human breast cancer in 2003.
In the current study, researchers found that breast cancer cells overexpressing the HER2 gene had four to five times more cancer stem cells, compared to HER2-negative cancers. In addition, the HER2-positive cells caused the cancer stem cells to invade surrounding tissue, suggesting that HER2 is driving the invasiveness and spread of cancer.
The researchers then looked at the drug Herceptin, which is used to treat HER2-positive breast cancer. They found Herceptin reduced the number of cancer stem cells in the HER2-positive breast cancer cell lines by 80 percent, dropping it to the same levels seen in HER2-negative cell lines.
When HER2 was not overexpressed in the cell cultures, the researchers found, the cancer stem cell population did not increase. Nor did Herceptin have any effect on the HER2-negative cells, which is consistent with how Herceptin is used in the clinic.
"We are now studying what pathways are activated by HER2 overexpression. Our hope is that we could develop inhibitors of these pathways that might be effective in targeting cancer stem cells in women whose tumors do not overexpress HER2 or those who are resistant to Herceptin," says study author Hasan Korkaya, Ph.D., a U-M research fellow in internal medicine.
Breast cancer statistics: 184,450 Americans will be diagnosed with breast cancer this year and 40,930 will die from the disease, according to the American Cancer Society. About 20 percent of breast cancers are considered HER2-positive.
Additional authors: Amanda K. Paulson, a U-M undergraduate student, and Flora Iovino, a U-M research fellow in internal medicine
Funding: National Institutes of Health, National Cancer Institute, A. Alfred Taubman Medical Research Institute at the U-M Medical School
Reference: Oncogene, advance online publication June 30, 2008; doi: 10.1038/onc.2008.207
U-M Cancer AnswerLine, 800-865-1125 Cancer's Stem Cell Revolution, http://www.mcancer.org/stemcells
University of Michigan Health System
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Ann Arbor, MI 48109-2435
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http://www.med.umich.edu
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True Pharmacological Innovation
posted by Dan on 10 Jul 2008 at 10:50 amInnovation in Pharmacology?
Beginning in the 1970, biopharmaceuticals were being researched for production in those places once called academic institutions. The first biopharmaceutical was a synthetic insulin called Humulin made by Genetech in 1982. Later the rights were sold to Eli Lilly for this insulin. Biopharmas are distant and covert relatives of big pharma, yet become intimate with them more often now than ever before due to dry pipelines of big pharma- GSK and Roche in particular, yet most big pharma examine acquisition of biopharma companies. Over 20 biopharma drugs were approved in 2005, I believe. They are overall very effective treatments for very difficult diseases to manage, as they target specific aspects of certain diseases, which limits side effects experienced by the patient on therapy with a biopharma drug. There are about a dozen of different classes or mechanisms of action of biopharmaceuticals that have about a half of dozen different types of uses that is always increasing, as lablel alterations of biopharmas are requested soon after the approval of a particular medication by ths method. Some cause apoptosis, or cell death of specific tumor cells. Some cause angiogenesis to occur, which means they cut off the blood supply to tumors. Then some biopharmaceuticals have multiple modes of action that benefit certain patient types and their diseases greatly.
Some biopharmas are more noteworthy than others, such as Enbrel, which was originally created for the many forms of RA- arthritis caused by the patient’s immune system attacking their bodies. At one point, demand exceeded supply for this drug greatly, as the efficacy was evident and demand was unexpected by the manufacturer, so Enbrel was sought out by doctors and patients both due to the clinical data verifying the efficacy and benefits of the drug. Enbrel was approved in 1998 and produced from what are called monoclonal antibiodies. In fact, some call the 1990s the biopharmaceutical decade.
Partnering of biopharmaceutical companies and larger pharmaceutical companies began during this decade- however has become more often recently due to the apparent dry pipelines of big pharma. It’s a symbiotic relationship in that big pharma can provide the resources and connections necessary to launch and grow a particular biopharmaceutical drug. Typically, big pharma just buys or acquires a biopharmaceutical company of interest to them.
Some biopharmaceutical drugs are more profitable than others as well. Biopharmas compose 10 percent of the pharmaceutical market presently, I understand. And with the government health care programs being the largest U.S. payers for pharmaceuticals, Medicare pays 80 percent of the cost of biopharmaceuticals. One profitable biopharma class is known as EPOs, with names like Procrit and Epogen, and are for anemia that is experienced in patients on dialysis or who have cancer in particular. Doctors are monetarily incentivized to exceed dosing requirements of these agents, but this causes premature deaths and accelerated cancer progression for the patients that are over-dosed in this way. Once this tactic was exposed, there are now limitations regarding the amounts used of these EPOs. They are hormone biopharmaceutical drugs, which is one of several classes of biopharmaceuticals.
While biopharmaceuticals are very efficacious and safe, as well as having therapeutic and diagnostic benefits for the very sick, the cost of them is outrageous. Genzyme has one biopharma that costs a half a billion dollars a year. Yet most biopharmaceuticals cost around 100 grand a year for therapy that provides limited life extension of only a few months. Furthermore, with cancer drugs, they are used with chemotherapy, so there is no real improvement in the quality of life of some patients on biopharmaceuticals, considering the devastating side effects of chemo treatmet. Co-pays financially drain such patients and their families, yet there is no other choice for therapy because of the avoidance in the creation of biosimiliars. Oncology, by the way, is the primary commercial focus of biopharmaceutical companies, so maybe competition will be a cost advantage to such patients.
How do these drugs differ from typical drugs that have been made before this advent? Unlike the small molecule, synthetic, carbon based pharmaceuticals of yesterday, biopharmaceuticals, classified under what is called Red biotechnology due to this being a medical process in the biotechnology world, are larger and very complex modified proteins derived from living biological materials that vary depending on what is manufactured and for what disease state. In fact, it is difficult to identify the clinically active component of a biopharma drug. A transformed host cell is developed to synthesize this protein that is altered and then inserted into a selected cell line. The master cell banks, like fingerprints are each unique and cannot be entirely duplicated, which is why there are no generic biopharmas, yet biosimilar drugs are possible, yet not available yet. After this insertion, the molecules are then cultured to produce the desired protein. These proteins are very complex and are manufactured from living organisms and material chosen for whatever biopharma may be desired to be created. It is difficult to identify the clinically active component of biopharma drugs. So manufacturing biopharmas is a difficult process, and a small manufacturing change could and has raised safety issues of a particular biopharma. It takes about 5 years to manufacture a biopharmaceutical. And each class has a different method of production and alteration of life forms to create what the company intends to develop.
Another difference is that biopharmas are regulated under what is called the Public Health Service Act, and unlike the FDA, they authorize the marketing of biopharmaceuticals. The Act’s role in monitoring the promotion of biopharmaceuticals is unknown. Safety protocols are a mystery to me as well.
Presently, there are about 200 biopharmaceutical companies, with maybe a little over 10 percent of them are actually profitable presently. The cost of developing a biopharmaceutical exceeds a billion dollars, with about a third actually making it to market. The market size of biopharmaceuticals is rapidly approaching 100 billion dollars a year, with average annual growth between 10 and 20 percent. Between 20 and 30 biopharmaceuticals make over a billion dollars a year presently. As cancer is the disease focus of biopharma companies, between70and 80 percent of cancer drugs are prescribed off-label.
Regardless of the challenges that are and will be faced by biopharmaceuticals, I’m pleased to see the results of true innovation in pharmacology, and I believe others should behave in a similar manner.
“The progressive development of man is vitally dependent on invention.” --- N. Tesla
Dan Abshear (what has been written is based upon information and belief)
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