Hope For Cancer

Researchers at Mayo Clinic in Arizona and the University of Georgia (UGA) have developed a vaccine that dramatically reduces tumors in a mouse model that mimics 90 percent of human breast and pancreatic cancer cases — including those that are resistant to common treatments.

The vaccine, described this week in the early edition of the journal Proceedings of the National Academy of Sciences, reveals a promising new strategy for treating cancers that share the same distinct carbohydrate signature, including ovarian and colorectal cancers.

When cells become cancerous, the sugars on their surface proteins undergo distinct changes that set them apart from healthy cells. For decades, scientists have tried to enable the immune system to recognize those differences to destroy cancer cells rather than normal cells. But since cancer cells originate within the body, the immune system generally doesn’t recognize them as foreign and therefore doesn’t mount an attack.

The researchers used unique mice developed by Sandra Gendler, Ph.D., the David F. and Margaret T. Grohne Professor of Therapeutics for Cancer Research at Mayo Clinic in Arizona and co-senior author on the study. Like humans, the mice develop tumors that overexpress a protein known as MUC1 on the surface of their cells. The tumor-associated MUC1 protein is adorned with a distinctive, shorter set of carbohydrates that set it apart from healthy cells.

“This is the first time that a vaccine has been developed that trains the immune system to distinguish and kill cancer cells based on their different sugar structures on proteins such as MUC1,” Dr. Gendler says. “We are especially excited about the fact that MUC1 was recently recognized by the National Cancer Institute as one of the three most important tumor proteins for vaccine development.”

“This vaccine elicits a very strong immune response,” says study co-senior author Geert-Jan Boons, Ph.D., Franklin Professor of Chemistry and a researcher in the UGA Cancer Center and its Complex Carbohydrate Research Center in Athens.

Dr. Gendler says MUC1 is found on more than 70 percent of all cancers that kill. Many cancers, such as breast, pancreatic, ovarian and multiple myeloma, express MUC1 with the shorter carbohydrate on more than 90 percent of cases.

She explains that when cancer occurs, the architecture of the cell changes and MUC1 is produced at high levels, promoting tumor formation. A vaccine directed against MUC1 has tremendous potential to prevent recurrence or as a prophylactic in patients at high risk for particular cancers, Dr. Gendler says. A vaccine also can be used together with standard therapy such as chemotherapy in cancers that cannot be cured by surgery, such as pancreatic cancer.

For the immune system to recognize MUC1 on the tumor cells, it required a special vaccine that had three parts. One part tricks the body into thinking that the cancer cell is a bacterial infection, one part stimulates an antibody response, and one part stimulates a lymphocyte response. If any of the three components were omitted, the vaccine did not work as well.

Dr. Boons notes that MUC1 is also overexpressed in 90 percent of the subset of patients who are not responsive to hormonal therapy, such as tamoxifen or aromatase inhibitors, or the drug Herceptin. These so-called triple-negative tumors are extremely aggressive and difficult to treat, Dr. Boons says, and a new treatment option is urgently needed.

“In the U.S. alone, there are 35,000 patients diagnosed every year whose tumors are triple-negative,” Dr. Boons says. “So we might have a therapy for a large group of patients for which there is currently no drug therapy aside from chemotherapy.”

Dr. Gendler and her colleagues are currently testing the vaccine’s effectiveness against human cancer cells in culture and are planning to assess toxicity. If all goes well, phase I clinical trials to test the safety of the vaccine could begin by late 2013.

Co-first authors on the paper are Vani Lakshminarayanan, Ph.D., at Mayo Clinic in Arizona, and Pamela Thompson at the University of Georgia. Additional authors include Margreet Wolfert, Ph.D. and Therese Buskas, Ph.D., both from UGA; and Judy Bradley, Latha Pathangey, Cathy Madsen and Peter Cohen, M.D., all from Mayo Clinic in Arizona.

The research was funded by the National Cancer Institute, the Mayo Breast Specialized Program of Research Excellence (SPORE) Grant and the Mayo Pancreas SPORE Grant. …source …more about breast cancer

Research on the same protein that was a primary mediator of the birth defects caused by thalidomide now holds hope in the battle against multiple myeloma, says the study’s senior investigator, Keith Stewart, M.B., Ch.B. of Mayo Clinic in Arizona. Dr. Stewart presented the results at the 53rd annual meeting of the American Society of Hematology in San Diego.

The drug thalidomide achieved infamy in the early 1960s as the cause of severe birth defects after being given to pregnant mothers for morning sickness. However, this drug, along with the highly related compounds lenalidomide and pomalidomide, also help to treat blood cancers, and are used worldwide as a cornerstone of therapy for the bone marrow cancer multiple myeloma. These drugs modulate the immune system and together are called immunomodulators or IMiDs.

The exact mechanisms and targets through which these therapies work to enhance immune response or kill cancer cells have been largely unknown. As a result, knowing which patients to treat and how to separate out the positive properties of these drugs from side effects has been impossible.

After recent research identified a protein known as cereblon as a primary mediator of the birth defects caused by thalidomide, researchers theorized that cereblon may also orchestrate the anti-tumor properties and be the primary therapeutic target for multiple myeloma.

In this study, researchers tested the theory and found a possible link between resistance to IMiDs and presence of cereblon. The researchers then found that lowering the level of cereblon allows the IMiDs to work properly.

“Interestingly, some resistant patients had normal cereblon levels, suggesting that while cereblon may be an absolute requirement for response, there are likely other mechanisms present that play a role in drug resistance,” says Dr. Stewart. “These findings help us understand which patients may be more or less likely to respond to therapy and allow us to focus on other ways we can target cereblon as a possible biomarker to improve treatment and patient outcomes in multiple myeloma. This work also suggests that we can begin to dissect out the cause of birth defects from the anti-cancer properties and develop safer drugs in the future.” …source …more about multiple myeloma

Researchers at the Johns Hopkins Kimmel Cancer Center have demonstrated during their work with breast cells that breast cells become vulnerable to cancer if a single copy of the breast cancer gene BRCA1 is inactivated. It causes genetic instability in the cells through reducing their ability to repair DNA damage.

The leading risk factor for hereditary breast cancer is an inherited mutation in the BRCA1 gene which requires close monitoring or prompt preventive mastectomy.

The breakthroughs might help researchers develop a drug that prevents hereditary breast cancer, as well as tools to identify those who benefit most from prophylactic treatments. The study is published in the Proceedings of the National Academy of Sciences Oct. 25.
BRCA1 Is Thought To Be A Tumor Suppressor Gene

Exactly how BRCA1 inactivation increases the risk of cancer has remained a mystery. BRCA1 is believed to be a “tumor suppressor” gene. Usually, cancer is not caused by the loss of one copy of such genes, as each individual is born with two copies of each gene (one from each parent), and the second copy is sufficient in keeping cells healthy in a similar way that a car can stop safely after losing control of the front brakes as the rear brakes are still working.

According to the researchers, cancer seems to develop in such cases only after the second copy of the gene is damaged, i.e. random mutation during cell division, resulting in uncontrolled cell growth.

Mouse models of BRCA-related cancers have demonstrated that damage to genes, such as TP53, occurred prior to damage to the second copy of BRCA.

Ben Ho Park, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center, explained:

“In theory, this process would take a long time and BRCA-related breast cancers occur at an early age.”

For the investigation, the team used novel technology in order to insert a single copy of a typical BRCA1 mutation into normal breast cells.

The main theory has been that the original inactivation of a single copy of BRCA1 produces additional DNA mutations to expand more rapidly than normal – a condition called “genomic instability.”

Park explains:

“The protein coded by BRCA1 is involved in repairing major DNA breaks, so it would make sense that its inactivation could weaken a cell’s resistance to DNA mutations.”

However, Park adds that the consequence of losing a single copy of BRCA1 was hard to model and difficult to investigate. Results from prior attempts to produce mice with single-copy BRCA1 mutations were uncertain as the mice were unable to demonstrate the pattern of human cancers. Furthermore, it has been hard for investigators to create human cell lines in which the only flaw is a single mutated copy of BRCA1.

In order to test their theory, the team first selected cell lines obtained from non-cancerous human breast epithelial cells – where BRCA1 breast cancers originate. An advanced gene-targeting method was then used to generate novel cell lines that have a typical cancer-associated BRCA1 mutation in just one copy of the gene.


Following this, tests were conducted on both cell types – cells with the BRCA1 mutation, and the original cells with two healthy copies of BRCA1 – to compare their DNA repair activity. The team demonstrated that cells with BRCA1 mutations were not as effective at carrying out the type of DNA repair known to involve the BRCA1 protein.

They found that when exposed to a DNA-damaging chemotherapy medication or radiation the BRCA1-mutated cells were more likely to die. In addition, BRCA1-mutated cells that were allowed to divide for many weeks were more likely to lose additional genes, includes those frequently mutated in breast tumors. Similar genetic losses were observed on non-cancerous breast cells taken from women with BRCA1 mutations.

Park said:

“What this shows is that having only a single working copy of BRCA1 really does bring about changes in a cell that would be expected to give rise to cancer.

We hope to use this new system to introduce other known BRCA1 mutations, to get a better idea of the relative cancer risk each individual mutation represents, because right now there are few good ways to do that. In the future, we hope to further define risk so that family members with one type of BRCA1 mutation may be advised to get preventative treatment or surgery, and those with other BRCA1 mutations could rely on careful screening.”

In addition, the cell models might be helpful in determining the susceptibility of various BRCA1 mutations to drugs, Park adds. At present, anti-cancer medications known as PARP inhibitors are in clinical trials against tumors with BRCA1-mutations.

The lifetime risks of developing breast cancer has been shown among women born with a mutated copy of BRCA1 to range between 50% to 90%. In addition, they have high, but variable risks of ovarian and other cancers. …source …more about breast cancer