Targeting tumours

Targeting tumours

Under the microscope, two bladder or prostate tumours may look identical but one may be deadly while the other is more easily managed. Researchers at the Murray Koffler Urologic Wellness Centre are using genetics to distinguish between the two — saving people with non-aggressive tumours from having to endure unnecessary surgery or therapies with major side effects, while aggressively targeting dangerous tumours.

Pussycats and tigers: Distinguishing between bladder tumours

Although bladder cancer is the fifth most commonly diagnosed cancer in Canada, patients still
have few options to manage the disease. Surgical removal of the tumour remains the standard
of care to assess its nature and aggressiveness. Because bladder cancer is often associated with genetic defects throughout the entire bladder mucosa, these tumours often recur, requiring
patients to undergo prolonged follow-up examinations, repeat surgeries and additional therapies, which can cause long-term side effects and diminish their quality of life.

Bladder cancers are generally categorized as low- or high-grade — determined by how aggressive the tumour cells look under a microscope — and non-muscle-invasive or muscle-invasive, which is determined by how deeply the tumour has penetrated the bladder wall. Dr. Alexandre Zlotta, director of Uro-Oncology and an associate member of the Lunenfeld-Tanenbaum Research Institute (LTRI), describes bladder tumours as “pussycats” or “tigers.” While one cancer may appear to be a pussycat, meaning it’s unlikely to become life-threatening, its biology may reveal it to be a tiger in waiting. Without knowing whether the low-grade tumours will become aggressive, patients undergo surgery as a precaution — and they are facing a 50/50 chance of their cancer coming back and sometimes even progressing.

But every tumour is unique, and rather than painting with broad brush strokes, Dr. Zlotta and his colleagues at Mount Sinai are using genetic sequencing to paint a more accurate picture and deliver the tools that will make individualized cancer treatment possible. They have now
designed a test using cutting-edge technology to provide enough genetic data for researchers
to know with greater certainty whether the cancer will become lethal, taking the guesswork out of the diagnosis.

For most bladder cancer patients in Canada, the cancer is non-muscle-invasive, which means it is confined to the superficial layers of the bladder. And among those patients, more than 60 per cent have low-grade tumours that are at very low risk of progressing to deadly disease. Yet some do progress. With this new test, doctors and their patients will get a more accurate view of whether the patient’s tumour is a pussycat or tiger, even when it looks low-grade under the microscope. For people with more aggressive tumours, this research could save their lives. For those with low-risk tumours, the test will allow them to bypass treatments and continue living a normal life while the physician monitors their tumours.

Dr. Jeff Wrana, CIBC Scientist in Breast Cancer Research, Mary Janigan Research Chair in Molecular Cancer Therapeutics and a senior LTRI investigator, collaborated with Dr. Zlotta to design the new test based on information contained in the transcriptome, the RNA transcript produced by the genome. Though every cell has the same genome and the same genes, not every gene is active in each cell. Transcriptomes provide a script scientists can “read” to understand when and where genes are turned on and off.

“When a cancer transitions from a benign disease to a malignant and metastatic disease, it’s the
changes in the transcriptome that will affect the behaviour of the tumour and drive metastatic
disease,” says Dr. Wrana. When researchers are able to read the transcriptome of a tumour, they know if the disease will spread or stay put.

Drs. Wrana and Zlotta are now also applying this new cutting-edge RNA sequencing technology
to distinguish between aggressive and less aggressive prostate cancers, one of many ways in which advances in bladder cancer research are directly benefiting prostate cancer research.

Reducing false-positives in prostate cancer

Prostate cancer is quite common — according to an international study published by Dr. Zlotta
and his collaborators, approximately 60 per cent of men over 60 have the disease — but only a
minority of men dies of the disease (approximately 3 per cent in Canada). As with bladder cancer, researchers are racing to find a test that can distinguish between the common, low-grade tumour and its deadly siblings.

A new, non-invasive test for prostate cancer being developed by Dr. Eleftherios Diamandis, Hold‘em for Life Chair in Prostate Cancer Research and section head of Clinical Biochemistry in the Department of Pathology and Laboratory Medicine, and Dr. Keith Jarvi, director of the Murray Koffler Urologic Wellness Centre, head of Urology and an associate LTRI scientist, promises to further improve the accuracy of prostate cancer diagnosis while dramatically reducing the physical and emotional toll on patients.

Currently, the standard test to screen men for prostate cancer is a blood test that measures the
level of prostate-specific antigen (PSA) in the blood. It is not a very accurate test; in fact, three
out of every four patients have false-positive results. When this test comes back positive, many
patients then undergo a biopsy, only to find they do not have prostate cancer. Drs. Diamandis
and Jarvi believe a more efficient, accurate and cost-effective test can be developed by analyzing seminal plasma, the liquid in ejaculate that can be separated from the sperm. Because it is partially produced by the prostate gland, seminal plasma is a concentrated source of prostate cancer biomarkers. Drs. Diamandis and Jarvi and their colleagues have been studying this fluid in search of DNA fragments that carry mutations to indicate cancerous cells. They are confident that if they can identify several biomarkers to work together like a panel, the test could prove to be more accurate and informative.

“Slowly but steadily we examine groups of proteins in seminal plasma, categorize them and find that many of them have value for diagnostics,” explains Dr. Diamandis. “We plan to combine several of those biomarkers to make a panel for prostate cancer.”

If a test can identify multiple biomarkers, its results would be more reliable than the current PSA test and would cut down on false-positive test results. Moreover, the panel would not only distinguish between a cancerous and benign tumour, it could also help researchers determine
whether the cancer is life-threatening.

“Right now, we’re over-treating men,” Dr. Jarvi explains. “The future of research is to tailor the
therapies to aggressively treat men who need it but don’t treat men who don’t need it.”

Cutting back on surgeries for both bladder and prostate cancer would significantly improve life after cancer, reducing the risk of long-term side effects including incontinence, erectile dysfunction and loss of sensation. Pinpointing those with aggressive forms of cancer and
treating their tumours aggressively will save their lives. Meanwhile, men with non-life-threatening
prostate cancer can continue living normal, healthy lives while their doctors closely monitor their tumours over time.

“I’m sick and tired of seeing people die with the same treatment and doing the same thing we’ve done for the last 20 years,” says Dr. Zlotta. “What we want is a change. A test that can detect the disease before it gets too deep so we can offer lifesaving treatment. We want people responding better to treatments. We want to discover new treatments based on the genetic makeup of tumours and personalize therapy accordingly. We want to help people.”

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Mount Sinai Hospital Foundation

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