Understanding Cancer: U-M researcher chases the reasons breast cancer cells metastasize.



On any given day, there are 50-100 cell culture dishes assembled on the countertops of Dr. Sofia Merajver’s lab at the University of Michigan Cancer Center. Together with measuring instruments, flasks, computers and other devices for growing and testing cancer cells, each piece of equipment has its own function in a space managed by one of the 10 research scientists working in the lab.

This is the heart of the Merajver Breast Cancer Research Program, which is dedicated to understanding the metastasis process of breast cancer when the cancer spreads from an organ in one part of the body to another.

Dr. Sofia Merajver examines tissue from animals treated with a novel compound against triple negative breast cancer.

“Too frequently, a patient with an early diagnosis of breast cancer increases her odds of successful treatment only to later discover the cancer has returned after a few years,” says Sofia Merajver, M.D., Ph.D., medical oncologist and professor of internal medicine at U-M Medical School. She’s also the director and founder of the U-M Breast and Ovarian Cancer Risk Evaluation Program and scientific director of the Breast Oncology Program at the U-M Cancer Center.

“Over two-thirds of women who die every year of breast cancer had received an early diagnosis in the past.”
According to the Centers for Disease Control and Prevention (CDC) in Atlanta, about 40,000 women and 400 men in the U.S. die from breast cancer annually.

Research in the lab focuses on understanding the molecular and metabolic regulators of very aggressive breast cancer types. The primary areas of attention are systems biology, mathematical oncology, biophysics, cell biology, genetics and drug development. Merajver works in the lab and in the clinic, making recent interventions and clinical trials available to her patients as the research progresses through rigorous testing.

For years, only a few therapies were available to treat all cancer patients. If the cancer is found outside the breast and axillary lymph nodes, it is called metastatic and designated as Stage IV. Today, new technologies enable research resulting in specific and personalized therapies to prevent metastasis of the original cancer.

“I want to know what goes on in cancer cells, why they spread, what changes take place in the cells that allow them to spread, and why the cells travel and attack other organs,” Merajver says.

Research has changed since she began her career as a scientist. At one time, scientists worked in their own “siloed” disciplines, hardly ever venturing outside. Now they increasingly tend to work in multidisciplinary teams to solve complex issues. Merajver has been a true pioneer in this team approach, stemming from her background in physics.

“I’m convinced my education in physics, math and medicine were very helpful in assembling and stewarding these teams,” says Merajver, who focuses on translating scientific findings into treatments, particularly in the molecular genetics of breast cancer.
“One of our research groups developed an inexpensive device [out of glass or plastic] that allows us to study the breast cancer cells from an individual patient to determine if the cells were likely to spread to other parts of the body such as the brain, bones, liver or lungs.

“By placing live cancer cells from breast cancer patients inside these devices, we can study which cells are able to spread to distant sites even before a tumor is clinically detectable,” Merajver says. “Using this device, I can separate small numbers of live cancer cells to observe and analyze so we can verify the characteristics of these cells and understand their potential to metastasize. We then separate these living cells into two groups — cells that move fast from the ones that don’t — then inject different drugs and combinations of drugs into each group and study how the groups respond to these substances without subjecting patients to any negative reactions.

“Compared to animal models used to study cancers, these devices are inexpensive and easy to reproduce, which allows scientists to quantify the measure of the cellular properties that aren’t accessible in animal models,” Merajver says. “Cells can also be analyzed more quickly, eventually making it possible to test hundreds of different drugs and personalized therapies.

“A primary tumor is not what kills patients,” she says. “Metastases are what cause much suffering and eventually shorten the lives of patients. Understanding which cells are likely to metastasize or spread helps us direct more targeted therapies to patients.”

To any observer it is obvious Merajver is passionate about her research. Her sense of urgency to continue her work is reflected in the energetic conversations among the members of her research teams.

Laboratory and clinical investigators at the Breast Oncology Program work together to improve evaluation and treatment for patients at risk for or with breast cancer.

Aggressive Breast Cancers
Merajver is also well known for her continuing research on the aggressive inflammatory breast cancer (IBC) in the United States, Africa and the Middle East.

“The proportion of IBC relative to the total number of breast cancers is eight to 10 times greater in some parts of the world, such as Egypt, than it is for women in the U.S.,” she says. “We are trying to find out the reason for this and also improve the meager medical treatment these women receive.

Merajver and Dr. Rabia Gilani, Ph.D., a post-doctoral research fellow in the Merajver Laboratory

How cancer cells use energy is very different from normal cells. Identifying those molecular and metabolic changes that promote metastasis may lead to the development of new drugs that prevent disease progression. Researchers at the Merajver Lab and collaborators at the University of Michigan are studying the cellular energy balance in different cell lines to establish an in vitro model (outside the body) of tumor progression.

“We are looking for metabolic changes that correlate with the switch between cell proliferation and motility, the ability to move spontaneously and actively, consuming energy in the process,” she says. “This switch is expected to be important because it relates to primary tumor formation, where rapid proliferation is crucial, and to secondary metastasis, where motility to new sites is essential.”

Merajver’s lab also has studies on HER2-positive breast cancer, a breast cancer that tests positive for a protein called human epidermal growth factor receptor (HER2), which promotes the growth of cancer cells. These cancers tend to be more aggressive than other types of breast cancer.

However, treatments specifically targeting HER2 are very effective and several new medications targeting HER2 are being tested in clinical trials.

Family Background
Born and raised in Argentina, the Merajver family lived in a small apartment in metropolitan Buenos Aires surrounded by a rich cultural environment and a strong Jewish community. She is an avid reader and her father’s library of 20,000 volumes was her primary source of literature and poetry as well as scientific and mathematical topics that piqued her interest.

“One of my earliest memories of practicing Judaism was attending the Passover seders at my grandparent’s home,” she recalls. “We weren’t a religious family, but I acquired a strong Jewish identify at age 6 after attending an exhibition portraying the Holocaust, and I extended that identity throughout my life.”

By the time she left Argentina at age 19 to attend the University of Maryland in College Park, the Argentinian Jewish population had diminished considerably because of the ruling military government and the appearance of anti-Semitism.

With a major in math and a minor in physics, Merajver finished her bachelor’s degree in under a year and pursued further physics studies with a biological focus.

She received her master’s and doctorate degrees from the University of Maryland and pursued a post-doctoral fellowship in biological physics at the U.S. Naval Research Laboratory in Washington, D.C. Her project was to devise membranes to encapsulate hemoglobin protein so artificial blood could be produced for the military.

Inspired by her work in medical problems, Merajver pointed her career to work on scientific problems that help humanity. She saw how the future of physics could be applied in medicine and spent the next 12 years getting medical training, specializing in internal medicine and oncology at U-M Medical School. Her connection in breast cancer research began when she was asked to work as a junior clinician on the breast cancer unit.

Meravjer is a firm believer in the power of student teams from partnering institutions throughout the world as a training model for future generations of researchers.

“The best tools we have to study the complex changes that take place in breast cancer require fairly advanced mathematics and biostatistics,” Merajver says. “In addition to descriptions of biologic phenomena, mathematics permits us to explore the patterns and principles underlying a biological phenomenon and to make predictions. We need to make these predictions available to clinicians.

“More importantly, if we can map the real-time activity of cancer cells taken from a patient, using mathematical modeling and other technologies, we can make better decisions about a patient’s treatment, helping us decide which drugs to give her in a particular sequence. We’ve moved much closer toward personalized medicine.

“The ultimate cure and prevention for all types of breast cancer is still somewhere in the future, but we’re close to turning most breast cancer into a chronic illness,” she says. “We also know more about nutrition and how changes in lifestyle can limit cancer occurrence.”

When asked what it would take to get where she wants to go with her research, without hesitation Merajver responds she’d like to complete all her ongoing research as well as finish those projects waiting to be researched.

“That would take about $10 million dollars over a period of five years to add additional lab space and hire additional researchers,” says Merajver, who spends close to two-thirds of her time raising funds from the government and individual donors to carry on her work.

“Understanding the basic biology and physics of cancer so that the genetic vulnerabilities of cancer cells can be discovered and targeted with better drugs is an overarching purpose of our research,” says Merajver, who enjoys spending time with her three grandchildren. Her three children, now adults, celebrated their bar mitzvahs at Temple Beth Emeth in Ann Arbor.

During her approaching sabbatical, Merajver will stop teaching her undergraduate class in global health and relinquish caring for patients so she can focus on her various research projects and accelerate their progress.

“Sofia Merajver is a great mother, incredibly smart, cares deeply about her patients and is energized by her research,” says Larry Baker, collegiate professor, Cancer Development Therapeutics and professor of internal medicine and pharmacology at the U-M Health Center. Although he lives in Ann Arbor, he maintains his longtime membership at Temple Beth El in Bloomfield Township.

“During the 20-plus years I’ve known her, Sofia, like most scientists, maintains a high level of curiosity she uses to discover how cancer cells differ from normal cell so they can be targeted and treated.” *

— Ruthan Brodsky | Contributing Writer

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