In today’s smartphone era, just about everyone has an “autocorrect” story to tell, where an innocuous word or phrase was erroneously spellchecked into an embarrassing gaffe. Our phones are smart but not infallible.
The same could be said of our cells. A replicating cell makes a copy of its genetic material, which is proofread by DNA mismatch repair (MMR), a mechanism that automatically corrects typos in the DNA bases that spell out our genetic code. Unfortunately, nature’s autocorrect mechanism is itself prone to errors, leading to genetic mutations—some of which can turn a cell cancerous, explains Winfried Edelmann, Ph.D., a leading authority on MMR and professor of cell biology and of genetics and the Joseph and Gertrud Buchler Chair in Transgenic Medicine at Einstein.
We are all susceptible to replication errors. As we age, toxins, X-rays, and other environmental exposures further increase the incidence of these errors and if MMR gets corrupted, the DNA mutation rate increases by up to 1,000-fold.
Individuals with a hereditary condition called Lynch syndrome are especially vulnerable to MMR errors. They are born with a defect in one copy of an MMR gene, leaving the corresponding copy to take up the slack.
“People with Lynch syndrome can do just fine if the second copy is still functional,” Dr. Edelmann says. “But by the time they reach their 30s or 40s, that copy is likely to suffer damage, setting the stage for mismatch repair errors.”
Such errors, in turn, set the stage for a variety of malignancies, particularly in the intestines. They are the body’s most proliferative tissues, which regenerate every three to four weeks. Lynch syndrome sufferers have up to an 80% risk of developing colorectal cancer during their lifetimes—20 times the usual risk. Recent estimates suggest that 1 in 370 people in the United States could have Lynch syndrome. In addition, some 20% of sporadic (non-inherited) colorectal cancers are also caused by MMR defects
I think in the future we could be able to manage cancer like we can now manage HIV, and allow patients to live a normal life
Winfried Edelmann, Ph.D.
Build a Better Mouse Model
Over the last 25 years, Dr. Edelmann has created a variety of mouse models of Lynch syndrome by systematically knocking out, or disabling, each of the genes known to be involved in MMR. Those models greatly increased our understanding of both inherited and sporadic colorectal cancer. But they had fallen short in mimicking the key molecular, genetic, and clinical aspects of Lynch syndrome in humans, which limited progress towards new therapies.
About eight years ago, Dr. Edelmann successfully induced an Msh2 mutation (one of the most common MMR mutations) in intestinal cells while sparing all other cells, moving one step closer to a faithful model of the human disease. The mice developed cancer, but mostly in the small intestine rather than the large intestine that is primarily affected in Lynch syndrome. “The model still wasn’t ideal,” he says.
What was the model missing? It turns out that in Lynch syndrome, the gene TgfbRII in human colorectal cancer cells often contains errors in a repeat sequence of DNA also known as a coding microsatellite. Mice don’t have this particular microsatellite, Dr. Edelman explains. When he introduced the human microsatellite into the TgfbRII gene in his mouse model, the tumors became more aggressive.
“These and other new characteristics made tumors in the mouse model very similar to human colorectal tumors,” he says. The tumors, however, were still confined to the small intestine.
The final piece of the puzzle was provided by Dr. Edelmann’s longtime colleague, Leonard Augenlicht, Ph.D., professor of medicine and of cell biology, whose research focuses on the interactions between diet and genetics in causing cancer. “If you look back at the first cases of Lynch syndrome [recognized in 1913], most of their cancers occurred in the stomach or small intestine,” he says. “Colorectal cancers were the exception for Lynch syndrome back then but today they are the rule.”
“What had changed?” Dr. Augenlicht asks—and answers: “The environment. More specifically, the introduction of the modern Western diet.”
“I said to Winfried, we should put the mice on a higher-risk Western diet [high in fat and low in fiber, vitamin D, and calcium], instead of their standard healthy mouse chow,” Dr. Augenlicht recalls. “When we did that, the incidence of colorectal tumors soared.”
“For the first time,” Dr. Edelmann says, “we had a mouse model of Lynch syndrome that faithfully reflected the genetic and dietary influences of human disease.”
Thanks to this new the model, the National Institutes of Health awarded Einstein a five-year, $3.1 million grant to study colorectal cancer associated with Lynch syndrome.
Drs. Augenlicht and Edelmann and co-investigator Mathew Gamble, Ph.D., associate professor of molecular pharmacology and of cell biology, are studying how genetic and dietary interactions in their Lynch syndrome mouse model affect signaling and regulatory pathways in intestinal stem cells. They will also look for aberrant stem-cell signaling pathways that cause normal stem cells to change into cancer stem cells and will investigate ways to reverse pathways involved in cancer initiation or progression. Findings from this research could lead to advances in detecting, preventing and treating Lynch syndrome in particular and colorectal cancer in general.
New Treatments in Progress
The Lynch syndrome mouse model is already paying dividends. With a colleague, Eduardo Vilar-Sanchez, M.D., Ph.D., at The University of Texas MD Anderson Cancer Center, Dr. Edelmann found 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 almost completely eliminated Lynch syndrome tumors within two to three weeks—a response that stunned the researchers. They are now working with Sanjay Goel, M.D., M.S., professor of medicine at Einstein and gastrointestinal oncologist at Montefiore Einstein Center for Cancer Care, to set up a clinical trial to assess the use of rapamycin in Lynch syndrome patients.
One problem with rapamycin was that tumors returned in the Lynch syndrome animal model once treatment with the drug was stopped. The rapamycin was eliminating the bulk of the cancer cells but failing to get rid of the cancer stem cells implicated in Lynch syndrome, which then regenerated the tumor.
“We have since learned that those cancer stem cells have a membrane protein called MDR1 (multi-drug resistance 1), which pumps out any toxins that get into them,” says Dr. Edelmann. “When we treated our Lynch syndrome mouse model with a drug that inhibits MDR1, rapamycin almost completely wiped out one type of cancer stem cell within three weeks. We don’t yet know if those results will be long-lasting, but this is a promising step toward a new treatment approach.”
Dr. Edelmann is also working with researchers at Weill Cornell Medicine to develop an immunotherapy for MMR-deficient tumors. The idea here is to identify cell-surface proteins that are unique to the cancer cells and then induce the immune system to attack cancer cells displaying those proteins.
“Any cell that becomes MMR deficient would eventually express one of the cell-surface proteins, making those cells a target of the immune system,” he says. “The nice thing is that we can test this principle with our mouse systems.”
This approach won’t eliminate the cancer, but it may control it. “I think in the future we could be able to manage cancer like we can now manage HIV, and allow patients to live a normal life,” says Dr. Edelmann.
Posted on: Thursday, July 11, 2019