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Targeting a Surprisingly Common Cause of Cancer

By Gary Goldenberg
Thanks to one family’s philanthropy, researchers are moving closer to new treatments for Lynch syndrome
Male scientist in white lab coat at desk, female scientist looks into microscope. Winfried Edelmann, Ph.D., and Einstein colleague Elena Tosti, Ph.D., study the mechanisms underlying colon cancer development caused by defective DNA mismatch repair. (Photo by Jason Torres)

In 2009, Lori Feinberg Kany of Short Hills, New Jersey, was diagnosed with breast cancer, joining millions of other women with this dreaded disease. However, her case was different from most.

After learning of her family’s medical history, including a brother diagnosed with colorectal cancer at age 29, an astute genetic counselor advised her to get tested for Lynch syndrome, a heritable disorder that raises one’s risk for a host of cancers, especially colorectal cancer, typically beginning in middle adulthood. The test came back positive, profoundly changing her life in more ways than one.

Since that fateful day, Lori has undergone a double mastectomy and colon cancer surgery. She has persevered through a series of health crises and would tell you that they have motivated her and her family to commit to promoting Lynch syndrome research, mainly at Montefiore and Einstein.

Lynch syndrome is a heritable disorder that raises one’s risk for a host of cancers, especially colorectal cancer, and typically begins in middle adulthood.

People with Lynch syndrome inherit a mutation in one member of a pair of genes controlling a vital process called DNA mismatch repair (MMR). During cell replication, MMR corrects any typos in the DNA bases that spell out our genetic code.

For people with Lynch syndrome, their remaining “good” copy of the MMR gene can still handle mismatch errors for a while. But by the time people reach their 30s or 40s, that good copy is likely to suffer damage—allowing DNA errors to go uncorrected.

As a result, Lynch syndrome sufferers have up to an 80% risk of developing colorectal cancer during their lifetimes—20 times the usual risk. MMR defects also cause some 20% of sporadic (noninherited) colorectal cancers as well as a subset of breast, gynecological, and urological cancers.

Dr. Edelmann holds a slide containing sections of the liver and spleen of a mouse model of Lynch syndrome. (Photo by Jason Torres)

Supporting Lynch Syndrome Research

For a decade now, Lori’s family—including her mother (Betty Feinberg), her brother (Peter Feinberg), and two sisters (Jami Simons and Randi Feinberg)—has underwritten the research of Winfried Edelmann, Ph.D., professor of cell biology and of genetics and the Joseph and Gertrud Buchler Chair in Transgenic Medicine at Einstein. Dr. Edelmann is a leading authority on MMR. He is best known for creating the first mouse model that closely mimics the key molecular, genetic, and clinical aspects of Lynch syndrome in humans.

Thanks to this advance, the National Institutes of Health recently awarded Dr. Edelmann and his colleagues a five-year, $3.1 million grant to study how genetic and dietary interactions in their mouse model affect signaling and regulatory pathways in intestinal stem cells, problems which give rise to colorectal cancer. Findings from this research could lead to advances in detecting, preventing, and treating Lynch syndrome in particular and colorectal cancer in general.

“The Feinberg family helped us greatly in our efforts to develop our mouse model,” Dr. Edelmann says. “More importantly,” he adds, “they initiated my collaboration with Dr. Eduardo Vilar-Sanchez,” a physician-scientist and Lynch syndrome specialist at MD Anderson Cancer Center in Houston.

When we treated our Lynch syndrome mouse model with rapamycin plus a drug that inhibits MDR1, rapamycin was able to almost completely wipe out one type of cancer stem cell.

— Dr. Winfried Edelmann

Together, Drs. Edelmann and Vilar-Sanchez discovered that colorectal cancer cells in Lynch syndrome are highly sensitive to rapamycin, a drug commonly used to prevent organ-transplant rejection and to treat certain cancers. In one mouse study, treatment with rapamycin nearly eliminated Lynch syndrome tumors within two to three weeks—a response that stunned the researchers.

They are now working with Sanjay Goel, M.B.B.S., professor of medicine at Einstein and gastrointestinal oncologist at the Montefiore Einstein Center for Cancer Care, to set up a clinical trial to assess rapamycin’s use in Lynch syndrome patients.

Drs. Edelmann and Vilar-Sanchez are also trying to make rapamycin therapy last longer, since the tumor returns once treatments are stopped. “We have since learned that cancer stem cells have a membrane protein called MDR1 (multi-drug resistance 1), which pumps out any toxins (including rapamycin) that get into them,” Dr. Edelmann says. “When we treated our Lynch syndrome mouse model with rapamycin plus a drug that inhibits MDR1, rapamycin was able to almost completely wipe out one type of cancer stem cell. We don’t know yet if these results will be long-lasting, though this is a promising step toward a new treatment.”

Partial credit for this fruitful collaboration belongs to Peter Feinberg, who knew of Dr. Vilar-Sanchez’s work at MD Anderson and thought it would be beneficial to put the two researchers in touch. “I wanted to do something that could leverage their respective knowledge and bring two renowned institutions together,” he explains. “I pinch myself. It’s a dream turning into a reality.”

“I’m president of the Winfried Edelmann Fan Club,” jokes Lori, a retired lawyer and active philanthropist. “But seriously, I wish I had so much more to give. His brain is limitless, but his funds are not. Our goal is that somebody sees this article and they tell a friend about his work, and then they tell a friend.”

Woman in blue dress and white necklace. Betty Feinberg, a longtime Einstein trustee, helps fund Einstein’s research on Lynch syndrome and hopes to raise awareness of the condition.

The Way of the Feinbergs

In addition to supporting Lynch syndrome research, the Feinbergs hope to raise awareness of the condition, which affects about 1 in 370 people in the United States. “I’m amazed at how few people know about the syndrome,” says Jami Simons, a retired teacher and active community volunteer. “When people hear about breast cancer, they think ‘BRCA,’ the so-called breast cancer gene. But anyone with a family history of breast or ovarian or colon cancer ought to find out if they have one of the Lynch syndrome genes. All it takes is a simple blood test.”

While there’s no cure for Lynch syndrome, people who test positive can undergo regular cancer screenings to catch growths before they turn cancerous or when they’re still treatable. “I live by the creed that what I have won’t necessarily kill me, but ignoring it might,” Lori says.

Philanthropy was what we knew growing up. Our parents instilled in us a tremendous sense of obligation to help make the world a better place. We’d like to think we’re doing that.

— Randi Feinberg

he siblings’ philanthropic work was inspired by their parents: Betty, a longtime Einstein trustee, and her late husband, Sheldon, a prominent business leader in the second half of the 20th century.

“Decades ago, my parents recognized the need to fund brilliant researchers in the embryonic stages of their careers, when money is so tight,” says Peter, a former banker whose work now focuses on “impact investments” that help put medical and social innovations into everyday practice.

“Philanthropy was what we knew growing up,” Randi Feinberg adds. “Our parents instilled in us a tremendous sense of obligation to help make the world a better place. We’d like to think we’re doing that.”

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