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Michael Wigler

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Alexander Krasnitz. Photo by Gina Motis?CSHL

By Daniel Dunaief

Seeing into the future is one of the most challenging, and potentially rewarding, elements of studying cancer. How, scientists and doctors want to know, can they take what evidence they have —through a collection of physical signs and molecular signatures — and determine what will be?

Researchers working on a range of cancers have come up with markers to divide specific types of cancers to suggest the likely course of a disease.

With prostate cancer, the medical community uses a combination of the prostate-specific antigen (PSA), magnetic resonance imagining (MRI) and biopsy results, which are summarized as the Gleason score, to diagnose the likely outcome of the disease. This analysis offers probable courses for developing symptoms.

Cold Spring Harbor Laboratory Professor Michael Wigler and Associate Professor Alexander Krasnitz recently published an article in the journal Cancer Research of a promising study of eight patients that suggests a way of using molecular signatures to determine whether a prostate is likely to contain cells that will threaten a patient’s health or whether the cells are in a quieter phase.

The third most common cancer among Americans, prostate cancer kills an average of 21,000 men each year. Doctors and their patients face difficult decisions after a prostate cancer diagnosis.

“A major challenge is to determine which prostate cancers have aggressive potential and therefore merit treatment,” Herbert Lepor, a professor and Maritin Spatz Chair of Urology at the NYU Langone Medical Center School of Medicine, explained in an email. A collaborator on the study, Lepor provided a clinical perspective and shared patient samples.

A conversation with a doctor after such a diagnosis may include a discussion about how the cancer is not likely to pose an immediate risk to a patient’s life, Krasnitz explained. In that case, doctors do not recommend surgery, which might cause other problems, such as incontinence.

Doctors typically recommend active surveillance to monitor the disease for signs of progression. Some patients, however, make their own decisions, electing to have surgery. The Gleason score, which is typically 3, 4 or 5, can’t provide “meaningful information regarding aggressiveness of the disease,” Lepor explained. “The unique genetic profile of a cancer cell should have infinite more prognostic capability.”

Wigler and Krasnitz, who have been collaborating since Krasnitz arrived at CSHL in 2005, use several hundred single cells from biopsy cores. The research group, which Krasnitz described as a large team including research investigator Joan Alexander and computational science manager Jude Kendall, look for cells with a profile that contains the same irregularities.

“If you take two cells and their irregularities are highly coincident, then perhaps these two cells are sisters or cousins,” Krasnitz explained in an email. “If they are less coincident, then the two cells are more like very distant relatives. We looked for, and sometimes found, multiple cells with many coincident irregularities. This was our evidence for a clonal population.”

By looking at how many biopsy cores contain clonal cells, and then determining how far these clonal cells have spread out through the prostate, the researchers gave these patient samples a score. In this group, these scores, determined before any intervention, closely tracked a detailed analysis after surgery.

“We get a high correlation” between their new score and a more definitive diagnosis that comes after surgery, Krasnitz said. “Our molecular score follows the final verdict from the pathology more closely than the pathological score at diagnosis from the biopsy.”

Wigler, Krasnitz, Lepor and other researchers plan to continue to expand their work at Langone to explore the connection between their score and the course of the disease. Lepor explained that he has been collaborating with Wigler and Krasnitz for five years and suggested this is “an exceptional opportunity since it bridges one of the strongest clinical programs with a strong interest in science (NYU Urology) and a world-class research program interested in clinical care (CSHL).

The research team has submitted a grant to the National Institutes of Health and hopes to expand their studies and provide “compelling evidence” that single-cell genomic mapping “will provide an unmet need defining aggressiveness of prostate cancers,” Lepor said.

While Krasnitz is encouraged by the results so far, he said the team has work ahead of them to turn this kind of analysis into a diagnostic tool physicians can use with their patients.

Realistically, it could take another five years before this score contributes to clinical decision-making, Krasnitz predicted. “You can’t do it overnight,” he cautioned. When this test offers specific signals about the likely outcome for a patient, a researcher would likely need to wait several years as the patient goes on active surveillance to see whether the score has predictive value for the disease in a larger population.

Krasnitz has a sense of urgency to produce such a test because there is “no point in delaying something that potentially looks promising and that one day might well be a part of a clinical practice.”

The work that led to their article took three or four years to complete. The study required technical improvements in the way the researchers processed DNA from single cells. They also had to develop algorithmic improvements that allowed them to use copy number variation to determine clonal structure. The scientists tapped into a wealth of information they gained by taking cells from several locations within the prostate.

Krasnitz was born in Kiev, now part of the Ukraine, and grew up in the former Soviet Union. A resident of Huntington, he lives with his wife Lea, who produces documentaries, including “Maria — The Russian Empress” on Dagmar of Denmark, who was also known as Maria, mother of Nicholas II, the last Romanov czar who was overthrown in 1917. As for his work with Wigler, Krasnitz is excited about the possibilities. “It’s very encouraging,” he said. “We look forward to a continuation of this.”

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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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