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Tumors

Alexander Krasnitz. Photo from CSHL

By Daniel Dunaief

If homeowners could find insects in their home, confirm that they were termites and locate nests before the termites damaged a house, they’d save themselves numerous problems. The same holds true for cancer.

Using the latest molecular biology techniques, researchers at Cold Spring Harbor Laboratory including Associate Professor Alexander Krasnitz and Professor Michael Wigler have explored ways to detect cancer earlier.

Unlike other scientists, who have created tests that reveal the genetic probability of developing cancer, Krasnitz and Wigler developed a blood test to reveal the presence of a tumor that might be hard to spot. Such a test could be particularly valuable for cancers such as ovarian and pancreatic cancer, which can be inoperable by the time they present clinical symptoms.

Urging what Wigler described as a “call to arms,” Krasnitz said they created a blood test, called copy number variation, that they hope will be economically feasible. In copy number variation, sections of genes are repeated. While healthy cells have copy number variation, cancer cells use them like a Jack Nicholson mantra in “The Shining,” where the repetition of “all work and no play makes Jack a dull boy” becomes a calling card for a killing spree.

In cancer, chromosomes or chromosome arms are duplicated or deleted. Sometimes, a narrow region of the genome undergoes amplification, creating multiple copies of the region. Other times, a region of the genome may be lost. Genome-wide copy number variation is a hallmark of cancer. Copy number variation occurs often amid the disruption of DNA repair mechanisms and the breakdown in the way DNA separates into daughter cells during division.

In a recent article in Trends in Molecular Medicine, Krasnitz, Jude Kendall, Joan Alexander, Dan Levy and Wigler — all scientists at CSHL — suggest the potential for single-cell genomic analysis that searches for the presence of copy number variations could raise the alert level for cancer, signaling the need to search more closely for developing tumors.

In most massive cancers in the population, including breast, ovarian and prostate cancer, copy number variation is “ubiquitous,” Krasnitz said. Screening for these changes could provide “evidence for the presence of something abnormal,” which can be validated through other tests, Krasnitz said.

Copy number variation, on its own, is not sufficient to detect cancer, Krasnitz said. Researchers need evidence of similar abnormal copy number profiles in multiple cells. For this test to have clinical relevance, it would need to minimize false positives, which could create alarm and lead to future tests that might not be warranted, while also avoiding false negatives, which would miss the presence of cancer.

The main sources of false positives could come from copy number variation that’s already in cells in the blood that randomly look like a tumor. Cells with partially degraded DNA can have high copy number variation, which the researchers have observed. These profiles, however, arise from random processes and typically look different from each other. Cells from a cancer clone, however, have similar copy number profile.

Cancers with low copy number variation were a minority among the 11 cancers the scientists studied and include a type of colorectal cancer called microsatellite-unstable. If these CSHL researchers developed a preclinical test, they would look for additional ways to detect such cancers.

While numerous technological innovations required for the test exist, including copy number profiling of single cells and methods to enrich specimens from blood for suspected tumors, Krasnitz explained that considerable work remains before its clinical use, including establishing tumor cell counts in the blood of early patients, making single-cell profiling cheaper and finding optimal ways to identify the tissue of origin.

They are planning to study newly diagnosed patients to observe the presence of circulating cells from tumors. Once the scientists prove that the test has some predictive value, they need to ensure that it is economical and that they can follow up with patients to find tumors.

At this point, it’s unclear what the presence of copy number variation might reveal about the type of tumor, which could be a slowly growing or an aggressive type. Additionally, an abnormal indication from this type of analysis wouldn’t reveal anything about the type of cancer. Further tests, including on RNA, would help direct doctors to a specific organ or system.

Apart from his work with Wigler, Krasnitz also has numerous collaborations, including one with CSHL Cancer Center Director David Tuveson.

In his work with Tuveson, Krasnitz is ensuring that the organoid models Tuveson’s lab creates, which are living replicas of tumors taken from patients, faithfully reflect the genetic make up of the tumors. That, Tuveson said, is a significant undertaking because it can validate the organoid model for exploring the biology of tumors.

“This is a deliverable that many people are waiting for,” Tuveson said. The researchers want to make sure “what we grew is what the patient had in the first place.” So far, Tuveson said, the data looks good and the scientists don’t have any examples of the genetics of the organoids differing from that of the tumor.

Krasnitz also attempts to predict an organoid’s response to drugs that haven’t been tested yet based on the organoid’s reaction to other drugs. Tuveson reached out to Krasnitz to work with his group. He said Krasnitz is “a major player” and is “very skilled” in the type of analysis of big data his group generates through the genome, the transcriptome and drug screens. “He’s able to look at those three types of information and make sense of it,” Tuveson said.

Krasnitz is grateful for the support of the Simons Foundation, the National Institutes of Health and the Breast Cancer Research Foundation for his work with Wigler. The most recent article with Wigler is an “invitation for the [research] community to join in the effort,” Krasnitz said. “We want collaborators and more competition in this area.”

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John Haley photo from SBU

By Daniel Dunaief

Once they reach their destination, they wreak havoc, destroying areas critical to life. All too often, when cancer spreads, or metastasizes, through the body, it becomes fatal.

John Haley, a Research Associate Professor in the Pathology Department at Stony Brook, is trying to figure out how cancer become metastatic and, even further, what they do to avoid recognition by the immune system.

Haley is “working on the mechanisms by which metastasis occurs,” he said. He is also studying the “immune recognition of tumor cells and, in the near future, wants to link the two.”

Understanding the way metastasis works can greatly reduce mortality in cancer, Haley said. Researchers are currently attempting to develop therapies that target metastatic cells, but these are often more difficult to kill than their primary counterparts, Haley explained.

The stakes are high, as 90 percent of cancer deaths are due to complications from the spread of cancer rather than the primary tumor itself, he said.

About 80 percent of human cancers are carcinomas, which are derived from epithelial cells. Those are the cells that make up the skin, and line the stomach and intestines.

“As cancers become metastatic, those cells have the ability to shape shift,” he said.

They become much more like fibroblasts, which are underneath the skin and glue the skin to bone and make up connective tissue layers. Haley said he has made some progress in understanding the molecular mechanism that allows cells to shift from epithelial to fibroblastic cells. They have “defined factors which promote” this transition, with differences in survival and growth pathways.

Haley works with a machine called a mass spectrometer, in which he identifies proteins in complex biological samples and measures how changes in composition alters function. He spends about half his time working on his own research and the other half assisting other researchers who are seeking to get a clearer view of key changes in proteins in their work.

In his own research, he wants to understand how cancers modify a cell’s proteins. He has helped define how cancers can change their protein signaling pathways to become drug resistant, which suggests targets for drug therapies.

Haley is tapping into an area of science that many other researchers are exploring, called bioinformatics. Using statistics and mathematical models, these scientists are cutting down on the number of genes and proteins they study, honing in on the ones that have the greatest chance to cause, or prevent, changes in a cell.

“We’re taking the data sets we’ve generated and trying to predict what we should look for in human patient samples,” Haley said. “We can find a tumor cell that have mutations or this expression profile and find drugs they are sensitive to.” Once scientists find those drugs, researchers can test them in cell cultures, then in mouse models and eventually in people, he said.

“We try to isolate someone’s cancer to understand what the molecular drivers are that occur in that cancer,” Haley said. The approach, as it is much of modern medicine, is to understand the patient’s genetics and biochemistry to select for a drug that would be effective against the particular mutations present in their tumor.

A resident of Sea Cliff, Haley is married to Lesley, whom he met while he was pursuing his PhD at Melbourne University. A native Australian, Lesley was completing her Masters in Opera when the couple met at a tennis match. They still play today. Lesley has sung at New York premieres for several living composers at concert venues including Avery Fischer Hall. She teaches music at her studio in Sea Cliff. Their children share their interests. John is a freshman studying biochemistry at Stony Brook University and Emma, who is a senior at North Shore High School, plans to study science and singing.

As for his work, Haley would like to see his efforts culminate in cancer therapies and diagnostics. Any novel therapy might also become a product for a start up company which could create jobs on Long Island. “There are some fabulous scientists” at the university, he said. “A major goal of the Center for Biotechnology and Diane Fabel, its director, is to create small businesses here in New York. I’m trying to help them in that goal.”