Mayo Clinic researcher Sandra Gendler, Ph.D., has studied a large molecule, inside and out, for 25 years. Now she plans to go after it in human clinical trials with a new vaccine in the fight against breast cancer.

Mayo Clinic physicians diagnose and treat more than 1,300 new patients with breast cancer each year. Nationwide, an estimated 40,00 women will die this year from the disease -- the most common cancer diagnosed in women, especially as they age.

The molecule that Dr. Gendler is focusing on is a naturally occurring protein known as MUC1, a heavily sugarized mucin. It already has been the target of drugs aimed at breast cancer in recent years. Dr. Gendler, who was the first scientist to successfully clone the protein, and Mayo colleague Pinku Mukherjee, Ph.D., say they've made significant improvements in how MUC1 is approached and are poised to deliver a stimulus that tricks the immune system into killing cancer cells that express MUC1.

Dr. Gendler describes MUC1 as a "protein similar to a bottle brush, covered with sugar." It sits on many cell surfaces, including those lining body organs such as the breast, lung, stomach, intestines and reproductive tract. When cancer strikes, cell architecture collapses, more MUC1 with modified sugars are produced, and the protein becomes an antigen that sometimes triggers weak immune activity.

To reach their heightened understanding, Dr. Gendler and colleagues created a line of mice that express a human version of the MUC1. This protein "senses the environment of the cell" and then sends signals about that environment to the nucleus -- "the brain" -- of the cell, Dr. Gendler says. "Making MUC1 transgenic mice allowed us to determine that MUC1 itself is oncogenic; its expression resulted in tumors in the mammary glands of mice. The transgenic mice that express human MUC1 enabled us to test vaccines in a very suitable host -- a mouse with a functional immune system.”

Dr. Gendler's approach is to feed that immune response by manipulating the immune response to the protein. MUC1, with its abnormal sugars, appears on more than 90 percent of breast cancers and played a role in about 70 percent of human breast cancer deaths in 2007.

A Career of Research

A professor of biochemistry and molecular biology and the David F. and Margaret T. Grohne Research Professor of Therapeutics for Cancer Research, Dr. Gendler knows MUC1 intimately. In 1987, she led a team in the United Kingdom that cloned the protein. In 2001, she detailed what was known about it, calling MUC1 "the renaissance molecule" because of its multiple functions and roles in several diseases in a paper published in a journal devoted to breast cancer research.

Dr. Gendler was born in the northern Great Plains city of Minot, North Dakota. She once worked in Boston as a technician for DNA-discoverer James Watson. She then went to the University of Illinois at Urbana-Champaign, where she completed a master's degree in the Classics, studying Greek and Latin -- subjects, she says, that had given her great joy while earning bachelor's degrees in both microbiology and chemistry from the University of Minnesota.

Sandra Gendler dove full time into breast cancer research while a doctoral student at the University of Southern California. From there, she went to London to pursue work on MUC1 at the Imperial Cancer Research Fund, a facility located off the popular public square Lincoln's Inn Fields. Mayo Clinic was her next stop.

The Team Approach

Dr. Gendler, Dr. Mukherjee, both at Mayo’s Scottsdale, Ariz. campus, and Svetomir Markovic, M.D., Ph.D., of the Rochester, Minn. campus, have teamed to create a vaccine of specially crafted synthetic peptides based on MUC1. They've combined it with another synthetic peptide derived from another molecule, HER-2/neu, that is overproduced in 25 percent of breast cancers. These peptides will be delivered with adjuvants -- ingredients that help trigger the production of white blood cells and other immune responses.

"Preclinical studies in the mouse showed that a vaccine consisting of peptides and adjuvants, similar to what is being tested in our clinical trial, can prevent formation of tumors and slow the growth of established tumors," Dr. Gendler says.

Beginning this fall, with funding from the Department of Defense, the vaccine enters Phase 1 clinical trials at all three Mayo campuses. Normally this initial stage tests for optimum dosage and potential toxicity in human patients. However, in this case, the hopes are higher based on the long line of animal studies in which Dr. Gendler and colleagues have fine-tuned their research. In recent experiments using mice, they have seen definite immune responses, little or no signs of toxicity and 100-percent success in preventing tumor growth of colon cancer cells.

"In our upcoming clinical trials, patients will have been treated with surgery to remove tumors and other therapy, either chemo or radiation," Dr. Gendler says. "They will be free of detectable disease for three to 12 months post treatment so that their immune systems will have recovered. We expect to see our vaccine be more effective, and we should be able to see an immune response. That’s what we really will be looking for in our trials, since we don’t believe toxicity will be an issue."

The trials will be coordinated by, Donald Northfelt, M.D., in Arizona, Edith Perez, M.D. (a 2007 Mayo Clinic Distinguished Investigator) in Florida, and Dr. Markovic in Minnesota. The way the new vaccine has been formulated, Dr. Markovic says, makes it a potentially effective tool for generating the body's anti-tumor immune response.

"The nice thing about MUC1's being a target is that it is expressed in just about all breast cancers," says Dr. Markovic, whose specialty is the development and clinical testing of cancer vaccines and immune boosting agents. "If this vaccine works, it will help most patients. Based on our laboratory data, this should work better than prior efforts."

Breast cancer is second only to lung cancer as a killer of women. In 1998-2002, according to the American Cancer Society, 95 percent of new cases and 97 percent of deaths occurred in women 40 and older in the United States. However, early diagnosis and treatment have led to increasing survival rates in the last 25 years. There are more than two million breast cancer survivors in the United States today.

Potentially, this vaccine could be used as a complementary tool with tamoxifen, a widely used estrogen therapy used as a temporary post-treatment approach to prevent the return of tumors, Drs. Gendler and Markovic said.

“Ultimately, if things went well, we could have a preventative vaccine that could be used to vaccinate high-risk patients earlier," says Dr. Gendler. "That’s not here at the present time, but if we are able to see immune responses then this could become possible. Our goal is to prevent and treat spontaneous tumors and keep cancer from spreading."

Markovic heartily agreed, but with the same caution: "This will take a while," he said. "First, we need to see if the vaccine will produce an immune response. If it does, then we do another trial and ask whether that immune response will protect patients from cancer relapses. It will take at least five to seven years before we know."

- Jim Barlow, July 2008