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The physicians and researchers at Sunnybrook's Odette Cancer Centre are on a mission. From genetic research through to high-tech targeted radiation, they are working to provide the most advanced cancer therapies, individualized for each patient according to the progression of the disease at each stage of their journey.

MicroRNA: Tiny molecules, big risk factor
The Odette Cancer Centre’s latest groundbreaking research in identifying prostate cancer risk and, most importantly, prognosis, goes beyond genes to non-coding RNA (ribonucleic acid) molecules, known as microRNAs, that silence other genes. “Our aim,” says Dr. Arun Seth, director of Molecular Diagnostics at Sunnybrook and a senior scientist at Sunnybrook Research Institute, “has been to identify microRNA sequences which can distinguish more aggressive cancers from those that are indolent [slow-growing].” The big issue in prostate cancer, he explains, “is identifying which tumours will have recurrence or spread.” Dr. Seth is collaborating with Dr. Robert Nam, a urological oncologist at the Odette Cancer Centre and a Sunnybrook Research Institute associate scientist. MicroRNAs can’t be seen, even under a microscope, so the sequencing to determine the precise order of nucleotides (the building blocks of DNA/RNA) per molecule undertaken by Dr. Seth’s lab was no small feat. More than 2,000 microRNAs in the human genome were examined in tumour samples for associations with prostate cancer progression. The research discovered five microRNAs strongly associated with prostate cancer. These five can be used to determine a patient’s microRNA risk score. Patients with a high microRNA risk score have a significantly higher rate of metastasis and of recurrence compared to those with a low score. In other words, there’s hope that this microRNA research could lead to the establishment of another useful marker to detect a patient’s cancer risk and decide which course of treatment is best. Dr. Seth explains: “We think these microRNAs could be used for prognosis, to better distinguish which cancer patients require immediate treatment and which can be monitored with active surveillance.” (Active surveillance is the continued monitoring of men with low risk of developing prostate cancer, with the option of treatment if risk increases.)

Hunting down the most advanced tumours
About 75 per cent of prostate cancers that require treatment will be cured by surgery or radiation. The remaining 25 per cent will recur and spread to other places in the body, a process called metastasis. At this stage, prostate cancers are typically treated with androgen deprivation therapy (ADT), also known as hormone therapy. Androgens (male hormones, including testosterone) help prostate cancer grow. Blocking androgen production slows progression of the disease. But usually, sometime after two years or so, the cancer no longer responds to ADT alone. While Sunnybrook’s Odette Cancer Centre provides care for patients across the spectrum of the disease, medical oncologist Dr. Urban Emmenegger (pictured), specializes in much-needed research and treatments for prostate cancer at advanced stages when hormone therapy no longer works on its own. Conventional hormone therapy impairs the production of androgens in the testicles, the major, but not only, source of male hormones. One of the newest androgen-deprivation drugs used at Sunnybrook blocks production of male hormones everywhere in the body and even inhibits the prostate cancer cells from producing their own hormones. “When combining this drug with conventional hormone therapy, most patients will respond at first – only for the cancer to again become resistant after a while. How- ever, in some patients, not all of the metastases become resistant,” says Dr. Emmenegger. He looks for ways to strategically tailor novel treatments for men who have a combination of both resistant and treatable metastases. In collaboration with radiation oncologist Dr. Patrick Cheung, Dr. Emmenegger is conducting a clinical trial on the effectiveness of stereotactic body radiotherapy to stop the growth of such resistant, “rogue” metastases. The high-dose radiation finely targets up to five rogue tumours or progressing tumours, while the continued hormone therapy treats the stable tumours. This clinical trial was inspired by one man whose prostate cancer had spread to his spine after having been on an experimental treatment for a number of years. “He was treated with radiation while continuing the study medication, and his PSA came down again,” says Dr. Emmenegger. “Now, 18 months later, his PSA is increasing again, and the cancer has further spread. But, in essence, we have gained a year and a half.”

The hi-def biopsy
Just because you can’t see it, doesn’t mean it isn’t there. A new procedure currently in clinical trial at Sunnybrook is “smart biopsy” or “fusion biopsy” – so-called because it’s guided by an MRI (magnetic resonance imaging) scan fused with ultrasound imaging that puts a bull’s eye on prostate tumours. Dr. Masoom Haider (pictured), radiologist-in-chief at Sunnybrook, likens it to “a type of GPS navigation that gives a three-dimensional view.” A specialized MRI scan – superior to other imaging technologies for detecting and displaying tumours – is taken before the biopsy. The MRI is then fused with ultrasound imaging during the procedure. Lesions seen on the MRI scans are projected onto the ultrasound images to guide the biopsy needle to the best spot to ensure the cancer is not missed by the biopsy. “The biopsy with MRI is very good at finding the aggressive cancers,” explains Dr. Laurent Milot, clinical and co-lead research radiologist at Sunnybrook. As part of the clinical trial and in the case of some other patients, Sunnybrook is already doing fusion biopsies. Dr. Milot explains that they are performed on patients where the presence of an aggressive prostate cancer is strongly suspected. Perhaps the cancer is hidden, having not been detected on previous conventional biopsies; or perhaps the patient is on active surveillance and has a low-grade prostate cancer, but his PSA begins to increase inexplicably. The immediate benefit of the fusion biopsy is significant. “We can see exactly where the cancer is,” Dr. Haider explains. “You can see the prostate very well with ultrasound, but it gives a limited view of tumours.” The fused MRI scans will help pinpoint the tumours, making the procedure potentially quicker and more efficient, with much less needle sampling required. Longer term, there is strong potential for this fusion imaging technology to actually guide the delivery of therapies for a better cure with less side effects.

Risk calculator to add genetic data
Dr. Robert Nam, seen here in surgery, created the prostate cancer risk-calculator tool.
Every year, 24,000 Canadian men are diagnosed with prostate cancer. How can we better identify which men are at higher risk for the disease and which men will develop more aggressive forms. How can we be more proactive in our treatment? Is it necessary to treat all forms of prostate cancer? Or is it best to employ an active monitoring strategy? There are no easy answers. Enter Dr. Robert Nam, head of genitourinary cancer care at the Odette Cancer Centre. Predicting which men are at risk of prostate cancer, and whether that cancer is likely to be slow-growing or aggressive, is the focus of his research. The tool developed at Sunnybrook to calculate those risks has been shown to be remarkably effective. In fact, the Sunnybrook Prostate Risk Calculator, borne out of basic science and biomarker research, has greater accuracy than a similar tool used widely in the U.S., resulting in Dr. Nam’s team being recognized as a world leader in this area. Now, the latest research on genetics, biopsy and treatment outcomes is being integrated into the Prostate Risk Calculator: Next Generation. Last year, Prostate Cancer UK awarded Dr. Nam a large grant to research and build on the existing screening tool. He heads an international consortium to develop the new iteration. A risk calculator uses a statistical model called a nomogram. “This nomogram not only predicts an individual patient’s risk for prostate cancer, but it also gives his risk for the most aggressive forms of the disease,” he explains. “It’s going to say, ‘This patient needs a biopsy,” meaning his calculated risk warrants further tests. Or it tells us that he doesn’t need any intervention at the moment, and careful monitoring through our Active Surveillance with Select Delayed Intervention program would be the best course of action.” This program aims to reduce overtreatment of clinically insignificant prostate cancer while providing the option of treatment if, over time, the patient becomes higher risk. Among the data being used in the current version are the patient’s age, digital examination results, family history, ethnicity and PSA-based results. The next-generation version could include results of a test for microRNAs, a new genetic marker for prostate cancer now under investigation by Dr. Nam and Sunnybrook Research Institute colleague Dr. Arun Seth (read more about microRNAs on page 20).

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