Getting ahead of the curve

“Breast cancer isn’t one disease, it is many diseases,” says Dr. Pamela Goodwin, director of the Marvelle Koffler Breast Centre, the Marvelle Koffler Chair in Breast Research and a senior investigator at LTRI. “There’s an interaction between the tumour and the patient. One treatment doesn’t ‘fit’ all patients.”

Drs. Gorman and Woodgett

Dr. Goodwin’s research focuses on the relationship between the woman with breast cancer and her tumour to understand how a woman’s unique biological make-up influences her long-term outcome. She has been a pioneer in investigating whether and how obesity influences health outcomes in breast cancer, an area of study that Dr. Goodwin says was “considered fringe” when she started out 25 years ago. But as the epidemic of obesity has taken hold in Canada and other western countries, her work has moved increasingly centre-stage, in part because it looks at characteristics of a woman that can be changed to improve her long-term prognosis — putting some of the power back into patients’ hands.

Dr. Goodwin’s early research showed that obesity significantly increased a woman’s risk of breast cancer recurrence and that insulin is a potential factor in breast cancer growth. She has since demonstrated that the use of metformin, an inexpensive drug commonly used to treat type 2 diabetes by lowering insulin and promoting weight loss, can help sustain healthy insulin levels in overweight and obese patients with breast cancer, essentially making them more metabolically healthy.

Her latest study — an international clinical trial involving 3,650 patients at more than 300 centres in five countries — aims to take this research one step further to determine whether controlling insulin with metformin will lead to better survival rates for overweight and obese patients.
“If our hypothesis is correct,” says Dr. Goodwin, “this study has the potential to transform the way breast cancer is treated around the world, saving as many as 100,000 lives each year at a cost of less than 5 cents per day.”

Understanding metastasis: The new frontier in cancer research

When Dr. Goodwin first began treating breast cancer, it was the leading cause of cancer death among women in Canada. “Most of the patients I saw early in my career died of the disease,” she recalls.

Photo of Dr. Pamela Goodwin

The outlook for patients today is very different. Breast cancer mortality rates in Canada are the lowest they have been since statistics began in the early 1950s. Advances in early detection, more effective treatments, and improved surgical techniques for removing tumours have dramatically improved outcomes for breast cancer patients. Today, a woman diagnosed with breast cancer that is restricted to the breast has a five-year survival rate of 95 per cent.
The problem: Once her tumour has spread beyond the breast, a woman’s survival rate drops to 20 per cent over five years.

“That’s huge,” says Dr. Jennifer Gorman, a postdoctoral fellow in Dr. Jim Woodgett’s lab who is studying breast cancer metastasis. “That number shows everything we don’t yet understand. We’re getting better at detection and surgical techniques to remove tumours, but we’re obviously missing something very important.”

Metastasis has become the new frontier in cancer research because most patients who die of cancer — breast or otherwise — succumb to metastatic tumours that develop when tumour cells leave the site of the original, or “primary,” tumour and spread throughout the body. These metastatic tumours ultimately cause what Dr. Jeff Wrana calls “a cascade of events” that overwhelm and impair the body’s normal functions.

“For a long time we focused on the primary tumour,” says Dr. Jim Woodgett, the Koffler Director of the LTRI and a renowned cancer biologist. “But if we want to have an impact on cancer mortality, we need to prevent metastasis.”

Tracking metastasis

Metastasis remains a mysterious process, and scientists at LTRI are working urgently to better understand it. Among the most pressing questions is the most fundamental: How and when does metastasis begin? Discovering the answer will enable scientists to develop therapies that intervene in the metastatic process at the most impactful moment. 

Cancer progression is commonly perceived as an ordered process — a mutation occurs, causing a tumour to develop; the tumour grows larger; finally, as the tumour continues to grow, cancer cells leave the tumour and spread throughout the body. But that’s not necessarily the case, explains Dr. Gorman. Tumours could be shedding cells into the bloodstream all the time, almost as soon as the first tumour begins to develop. The earlier those cells shed, the less likely metastatic tumours are to share characteristics with the original tumour. Figuring out when this shedding occurs is critical to understanding how metastasis happens and why metastatic tumours are typically resistant to therapies that effectively treat primary tumours.

Dr. Woodgett’s lab is studying how much the metastatic tumour is similar to or different from the original tumour. Dr. Gorman’s approach combines a technique called bioluminescence,
which involves altering the genetic makeup of the tumour cells to enable them to produce luciferase (the enzyme that makes fireflies glow), with state-of-the-art, high-resolution imaging. She is then able to track tumour growth and spread over time. By “turning off” specific tumour-activating genes and observing changes in the light emitted by tumour cells, she hopes to see how these genes affect both tumours in order to identify the similarities and differences in the make-up of the two tumours. This information could help pinpoint why current therapies are ineffective against metastatic tumours and suggest new targets for more effective treatments.

Moreover, as part of the Hold’em for Life project, a major breast cancer research initiative supported by the real estate, asset management and mining industries of Canada, Dr. Goodwin and her team are collaborating with Drs. Woodgett, Gorman, and Wrana to investigate the role of circulating tumour cells (CTCs), which break off from the original tumour and enter a patient’s blood stream, in metastasis. CTCs are extremely difficult to detect and they are measured in minuscule quantities: the presence of just five or more CTCs in a test tube containing millions of blood cells has been linked with worse prognosis for patients. Through this project the team at LTRI is studying the relationship between CTCs and patient factors such as obesity and insulin, as well as the biology of CTCs in animal models to better understand these important cells and how they can potentially be leveraged to improve outcomes for patients.

Routing out metastatic “sleeper cells”

Metastasis is an invasive process that plays out slowly over time, often surfacing long after a patient’s original cancer has been eliminated. Tumour cells can hide in the body in as-yet-clinically- undetectable numbers, remaining dormant for five, 10, even 15 years before beginning to grow again. But what convinces these cells to re-awaken after years of dormancy?

A recent discovery by Dr. Wrana, CIBC Scientist in Breast Cancer Research and the Mary Janigan Research Chair in Molecular Cancer Therapeutics, could help answer this crucial question. While investigating cell polarity — how a cell knows its front from its back and top from bottom, a process that goes awry in cancer cells — Dr. Wrana and his team discovered a signal that is generated by a normal cell and entices a receiving cancer cell to become metastatic.

Dr. Wrana’s team is now using a wide range of state-of-the-art techniques to study the signal from every angle, looking for clues to help explain how the signal is generated and received, and how the cell translates this signal into metastatic behavior. High-resolution microscopic imaging allows his team to examine how the cancer cell is behaving when it receives the signal, while next-generation DNA sequencing technology enables the team to compare the genome of a normal cell to that of tumour cells. Mass spectrometry, a super-sensitive methodology that uses chemical mass analysis to identify each of the components of a cell, is helping to pinpoint the cell proteins that help produce the signal. Dr. Wrana’s team is also using an automated high-throughput screening platform to sift through all the genes in the normal cell and the tumour cell that are required to generate or receive the metastasis-triggering signal.

“Ultimately, we want to understand the nature of the signal,” says Dr. Wrana, “so we can find ways to block it and prevent the lethal effects of metastasis.”

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Mount Sinai Hospital Foundation

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