An inside look
3-D imaging of telomeres aids cancer diagnosis and treatment
Discovery, the goal of science, can frustrate medical scientists when their findings can’t be used to help people.
That was the case more than a decade ago for Hans Knecht, chief hematologist at McGill University in Montreal, when he realized that telomeres were key players in Hodgkin’s lymphoma, but he needed a way to advance his research.
Dr. Knecht said he was stuck: “I’m a translational researcher,” he said, referring to the idea of translating discoveries into diagnostic tools and treatments. “I couldn’t go any further.”
Soon enough, though, he learned about the work of Sabine Mai, director of The Genomic Centre for Cancer Research and Diagnosis at the Research Institute in Oncology and Hematology in Manitoba, Canada. She’d developed a method of using fluorescence to generate 3-D images of telomeres inside cell nuclei. That meant their size, shape and location among other characteristics indicating telomere instability could be readily imaged and analyzed by computer in one-two-three fashion,
or as Dr. Knech described it: “Bing-bing-bing.”
He had the idea. She had the method.
Their resulting collaboration for more than a decade produced a series of studies showing that aggressive Hodgkin’s lymphoma — a type of cancer that starts in the white blood cells — not only involved very small telomeres but also ones that were clumped together inside the cancer cell nucleus, among other unstable characteristics of the protective caps for chromosomes. They, in turn, are DNA structures containing most or all of a person’s genes.
At that point, their research breakthroughs served only to explain cancer progression. But Dr. Knecht said he hoped physicians could use the research to more easily determine the stage and aggressive proliferation of lymphoma in patients. That is key to preventing aggressive Hodkgin’s disease from being undertreated. Ultimately, they realized their research could be used to reduce the risk of Hodgkin’s relapse and death with a new diagnostic tool.
Early next year, technology based on that research is expected to be available to analyze Hodgkin’s lymphoma, resulting in more appropriate treatment regimens for patients. The same methodology to analyze telomere instability in 12 other cancers, including prostate and lung cancer and multiple myeloma, along with Alzheimer’s disease, is deep in development with their availability expected in coming years.
“I’m very excited,” Dr. Knecht said, noting current difficulties in diagnosing aggressive forms of various cancers. “We will be able to define prior to treatment whether it is aggressive or less aggressive. That’s a huge advantage in tailored therapy. I think this will be most important in prostate cancer.”
Diagnoses in three dimensions
The Toronto-based publicly funded company 3D Signatures Inc. now is preparing to market the imaging technology once late-round clinical trials fully confirm its reliability for Hodgkin’s disease, with clinical trials in the works to test accuracy in other cancers and Alzheimer’s disease.
“There is currently no biomarker available that can predict patient response to standard chemotherapy in Hodgkin’s lymphoma patients and thereby help guide treatment decisions on the individual basis,” said 3D Signatures CEO Jason Flowerday. “Generally we’re working on a cohort of people with cancer, and this personalizes medicine, showing the stage of cancer, what therapy is appropriate and who needs what course of action.”
The Hodgkin’s test, the company said, can “empower physicians to make treatment decisions on an individual basis” while cutting costs and expediting the use of alternative treatments.
Mr. Flowerday also said 3D Signatures has had discussions with the Mayo Clinic, the Dana-Farber Cancer Institute affiliated with Harvard University, UPMC and various centers in Canada to conduct clinical trials on the technology. UPMC spokeswoman Wendy Zellner, however, said UPMC isn’t involved with the project.
The website of Ms. Mai, who holds a Ph.D. in molecular biology, says that 3D Signature’s TeloView software and imaging technology can determine the 3-D organization of telomeres in normal and tumor cells, which “appear significantly different, which allows for analysis based on those differences.”
“It is our goal to introduce the 3-D telomeric signatures as a clinical tool for cancer prognosis, cancercell detection, treatment decisions and monitoring,” she said on her website.
Telomeres tell us more
For good reason, telomeres continue to draw scientific attention worldwide.
The National Institutes of Health’s research study archive currently lists upward to 20,000 telomere studies with a sizable proportion focused on how their length alone can reflect lifestyle and health levels, with shortened telomeres typically associated with health problems.
But telomere science is far more complicated than size alone, 3-D telomere imaging and analysis reveal.
The company’s technology uses fluorescence to make telomeres stand out to enhance imaging and analysis based on their size, the presence of damage features including stumps, and telomere clumping in what Dr. Knecht describes as telomere aggregation, which indicates health problems.
Its methodology requires 40 cancer cells for analysis. While telomere length has gotten most of the publicity as a means of predicting health and longevity, Mr. Flowerday said more robust information can be drawn from their organization inside the cell nucleus, including the distances between telomeres and how far they are from the cellular wall.
The database used for comparison now includes more than 2,000 results accumulated from various clinical trials. After the Hodgkin’s test reaches market, Mr. Flowerday said, the company hopes to continue doing validation testing on its program to analyze prostate cancer.
“This will not replace PSA [prostate specific antigen], but it may replace or augment information from needle biopsies to diagnose the level of aggressiveness of the cancer and better predict who needs a radical prostatectomy vs. another therapy,” he said.
The imaging process requires tissue samples or blood work for cancers. The test for Alzheimer’s disease involves swabs from inside the cheek to determine the stage of disease and other medical details. For now, a diagnosis of Alzheimer’s disease can be confirmed only after death, company officials said.
To date, clinical trials involving the testing procedures have shown nearly 100 percent accuracy, Mr. Flowerday said, noting that such levels most likely won’t continue as clinical trials proceed. But he said his company has expectations that 3D testing will achieve accuracy levels above the 90 percent range.
“Multiple myeloma and lung cancer will involve the same platform, the same technology,” he said. “Results are extremely encouraging and validation studies are currently being planned.”
“We will be able to define prior to treatment whether [the cancer] is aggressive or less aggressive. That’s a huge advantage in tailored therapy. I think this will be most important in prostate cancer.” — Hans Knecht, chief hematologist, McGill University, Montreal