Campbell stewardship report 2011

THE CAMPBELL FAMILYCANCER RESEARCH INSTITUTE

at The Princess Margaret

January 2011

Progress and Impact Report

Linda, Gaye and Susan, We are extraordinarily grateful to you! The Campbell Family Cancer Research Institute is having a profound and important impact in Ontario, across Canada and around the world. This report outlines the impact, progress and future vision of The Campbell Family Cancer Research Institute. We hope you find this report informative and inspirational. With gratitude,

Dr. Robert BellPresident & CEO UHN

Dr. Tak MakDirectorThe Campbell Family Institute for Breast Cancer ResearchPrincess Margaret Hospital/UHN

Dr. Ben NeelResearch Director The Campbell Family Cancer Research Institiute and Ontario Cancer InstitutePrincess Margaret Hospital/UHN

Dr. Mary GospodarowiczMedical DirectorCancer ProgramPrincess Margaret Hospital/UHN

Dr. David JaffrayHead, Radiation Physics, Radiation Medicine ProgramPrincess Margaret Hospital/UHN

Paul AlofsPresident & CEOThe Princess Margaret Hospital Foundation

We are living in a time of unprecedented medical discovery. Every day, scientists are unraveling the mystery that is cancer. New genetic links are being found. New therapies are being designed to target those links. Lives are being saved. This is happening now. And it’s happening right here, each and every day, in Canada. At The Princess Margaret. At The Campbell Family Cancer Research Institute, a world leading facility in which every Canadian can take great pride. Honoured to be one of the Top 5 cancer research centres in the world, we strive every day to gain a deeper understanding and discover better methods of prevention and treatment for this terrible disease. And we could not be more grateful for your support in making this happen. Together, we are transforming cancer medicine. Changing thousands of lives. Nothing will stop our drive.

With your help, we will Conquer Cancer In Our Lifetime.

Few families can honestly claim to transform a hospital but through your remarkable generosity to The Princess Margaret (PMH), you are fundamentally changing how our scientists research cancer and how future patients will be treated for this disease.

The vision of the Campbell Family Institute for Cancer Research (CFICR) is to establish itself as the world’s leading comprehensive cancer research institute, dedicated to excellence and innovation in basic, clinical and translational research that improves the lives of individuals with cancer.

Our goals are to increase the Institute’s international impact and profile, expand infrastructure to capture new partnership opportunities, attract and retain scientific excellence while matching recruitment to resources, and increase and support medical research advances.

This report summarizes our view of the state of cancer research in 2010, our accomplishments over the past two years, and our strategy and plans for reaching our overarching goal of Conquering Cancer In Our Lifetime.

The Campbell Family Cancer Research Institute

Vision and Goals

You have helped transform The Princess Margaret as we strive to become the world’s leading comprehensive cancer research institute.

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Two years ago, key CFCRI researchers and clinicians embarked on a comprehensive review of our discovery, translational and clinical research efforts and capabilities, along with an analysis of the state of cancer biology and medicine worldwide. These efforts resulted in the development of a strategic plan for CFCRI/Ontario Cancer Institute (OCI).

This plan focuses on the people, platforms, and programs needed to maintain and enhance CFCRI/OCI’s status as one of the top 5 cancer research centres in the world. We have begun to implement the plan with several new faculty hires and the development of new initiatives, many of which would not have been possible without your support.

The plan identified four key programs: 1. Epigenetics, Stem Cells and Cancer Stem Cells OCI has a world leading position in this area.

2. Tumour Immunology and Immunotherapy This area of traditional strength at OCI is a source of great opportunity for future advances.

The Campbell Family Cancer Research Institute

Strategic Plan

3. Personalized Cancer Genomics and Medicine We need to develop the infrastructure and personnel to survey patient samples for cancer-associated mutations. This area also includes researching the best ways to combine targeted agents to improve anti-tumour efficacy. 4.Molecular Imaging/Imaged-Guided Therapies We will capitalize on our existing strengths and build capacity and expertise in molecular imaging.

In addition to the above programs and the people required to staff them our plan also includes key platforms such as the tumour bank and molecular pathology as well as substantial improvements in computational biology and informatics and a recognized need to enhance our clinical trials infrastructure.

Dr. Ben Neel is the Director of the Ontario Cancer Institute (OCI) and The Campbell Family Cancer Research Institute at Princess Margaret Hospital. He is also a Professor of Medical Biophysics at the University of Toronto.

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CFCRI: State of Cancer Research

Where We Are in 2010

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The past 30 years have produced an explosion of knowledge of the basic biology of cancer. We now know that cancer is a disease of the genome (our genes). Scientists around the world have identified hundreds of mutations in different types of cancers. These mutations can increase the activity of the products of certain genes (“oncogenes”), whereas the activity of other gene products (“tumour suppressor genes”) is decreased.

Recently, we learned that some oncogenes and tumour suppressor genes also can be dysregulated in cancer cells by “epigenetic” mechanisms, which involve changes in the proteins that regulate chromosome structure. At least some epigenetic changes are potentially reversible, making them particularly attractive targets for new therapies (particularly for tumour suppressor gene defects). The combination of mutations and epigenetic changes in oncogenes and tumour suppressor genes present in a given tumour determines its biological properties and behaviour: how fast the tumour will grow, whether it will invade local structures and if it will metastasize to other organs.

These features are more important than the appearance of the tumour under a microscope. We now know that two breast tumours can have dramatically different behaviour (including response to therapy), and we also know that tumours from different organs (e.g., some types of breast and ovarian tumours) can, as a consequence of similar mutations, be more similar to each other than to other types of same organ tumours.

We have also learned that all cells in a tumour are not equivalent. In many cancers, only a small fraction of tumour cells (tumour-initiating cells, sometimes called cancer stem cells) retain the capacity to infinitely self-renew. Although these cells have self-renewal capability, they often proliferate more slowly than the mass of cells within the tumour. Consequently, they may be less sensitive to conventional chemotherapeutic drugs, which tend to target rapidly dividing cells. Interestingly, epigenetic regulation seems to play a particularly important role in regulating the properties of tumour-initiating cells. In this way, these cells resemble normal stem cells, in which epigenetic regulation also plays a critical regulatory role. Durable cancer cures require the development of strategies to destroy tumour-initiating and bulk tumour cells. Owing to the central role of epigenetic regulation in both processes, we may learn much about normal stem cell biology by studying tumour-initiating cells and vice-versa. Such research may also help advance the field of regenerative medicine, in which scientists aim to use stem cells and their progeny to repair damaged tissue. These advances, in turn, could aid future cancer patients. As for the foreseeable future, our patients will continue to be treated with agents (chemotherapy, radiation, surgery—even some targeted therapies) whose side effects damage normal tissues.



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We also have learned that the immune system is constantly working to prevent tumour formation. Indeed, many emerging tumours probably never form because the immune system kills them before they grow to a significant size. Even in patients with a significant tumour burden, one can often isolate immune cells directed against, and trying to fight, the cancer cells.

Unfortunately, however, tumours use a variety of strategies to stymie the immune system and to disable anti-tumour immune cells. Tumours can even turn some immune cells into allies of the cancer. Luckily, we are beginning to learn how tumours subvert the immune system and to develop intelligent “immunotherapies”—drugs and cell-based therapies that re-activate and/or redirect anti-tumour immune response.

Finally, we know that many (although sadly not all) tumours develop through stages of increasing dangerousness. As a result, by detecting tumours when they are smaller we can often cure them. We have also seen dramatic advances in physics and computing power, which have enabled the development of extremely sensitive imaging devices. These techniques are now being supplemented by “molecular imaging,” in which novel agents that directly “see” features of the specific tumour can be used to detect remarkably small numbers of cancer cells.

These remarkable advances in cancer biology are just starting to reach the clinic—often to dramatic effect. Specific “targeted therapies”—drugs directed against the specific mutations that cause cancer—have been developed for several cancer-associated mutations.

The most dramatic example is Gleevec (Imatinib), which has substantially improved the survival of patients with chronic myelogenous leukemia, turning what had been a death sentence into a largely chronic disease. Other examples include Herceptin, which has dramatically improved the prognosis of (and in many cases, probably cured) patients with HER2 of breast cancer, and Erlotinib and Gefitinib, which target specific mutations found in certain lung tumours. Biotechnology and pharmaceutical companies worldwide are developing a host of new targeted agents against cancer-associated mutant proteins. Some of these new agents target the epigenetic abnormalities in cancer cells, whereas others are believed to kill tumour-initiating cells.

It is increasingly clear that in planning cancer therapy, the mutation is the message: consequently, the cancer medicine of the future will require us to rapidly define the precise mutational and epigenetic profile of each individual’s cancer cells and to select the appropriate combinations of targeted agents to kill—or at least control—them.



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Immune-based approaches (immunotherapy) that significantly impact selected tumours also have begun to reach the clinic. We need to learn how to further enhance these anti-tumour responses, and knowledge gained from these initial trials must be extended to other types of cancer. We also must determine how to appropriately combine targeted agents, conventional chemotherapy and immunotherapy to convert promising clinical responses to durable cures.

Improved imaging and the dawn of the molecular imaging era make it possible to detect tumours at ever smaller sizes. We are also witnessing the onset of image-guided radiation and surgery which enable tumour killing/removal with substantially less tissue damage. These remarkable—though highly expensive—advances will transform the operating room and the radiation suite of the future, but will require substantial new investments in both human and physical capital.

Finally, despite these advances and although the future looks far brighter than the past, we will continue to see cancer exact a terrible toll in human life and suffering for the foreseeable future. Even “successfully” treated patients continue to experience the psychological and physical scars of their disease. Consequently, there is a critical need to improve palliative care and to understand, and more effectively deal with, survivorship issues.

CFCRI: Progress and Accomplishments, 2008-2010

Pharma Partnerships

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Another major goal of the CFCRI leadership has been to promote increased interactions with, and funding by, major pharmaceutical and biotechnology companies. Although our investigators continue to obtain individual grants/funding from Pharma/Biotech to support pre-clinical and clinical studies, Institute-wide efforts have also led to three major successes in the past two years, including:

Merck:

Merck Pharmaceuticals launched a “preferred provider” network for Phase I/II clinical trials of its investigational agents. Selected participants in this process are also given preference in competitions for pre-clinical projects involving these agents. OCI/PMH was chosen as one of these “full service” cancer centres. Over the next five years, we will receive $17.5M—of which $2.6M is being invested by the Ontario government through its Biopharmaceutical Investment Program—in support of this program. Also, Dr. Malcolm Moore of PMH was chosen to serve as the academic lead.

POP-CURE:

Pfizer Global Research and Development joined forces with researchers at OCI/CFCRI and the Ontario Institute for Cancer Research (OICR) in a $6 Million program to discover and validate new targets for the diagnosis, prognosis and treatment of colorectal cancer. This program, entitled “POP-CURE” (PMH-OICR-Pfizer-CURE), is led by Dr. Bradly Wouters, Senior Scientist at CFCRI and OICR Senior Investigator, and includes CFCRI researchers John Dick, Ben Neel, Catherine O’Brien and Pat Shaw, along with a team of scientists at OICR.

MP Innovation Project:

Through a generous grant from Boehringer-Ingelheim, the PMH lung cancer group, under the direction of Drs. Frances Shepherd and Ming Tsao, will molecularly profile (by sequencing) all new lung cancer patients over the next three years, and use this information for informing therapeutic decisions. This grant will also provide funding for two fellows, one in molecular therapeutics of lung cancer and the other in molecular pathology.

Dr. Malcolm Moore holds theK. Y. Ho Chair in Prostate Cancer Research at PMH. He is also Chair of the National Cancer Institute of Canada GI cancer disease site and a Professor in the Department of Medicine and Pharmacology at the University of Toronto.


Grants, Contracts and Cancer Stem Cell Initiative

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The OCI, which includes the CFCRI and CFBCRI, comprises 228 researchers, 425 trainees and 622 research staff occupying over 373,000 square feet of space.

Since 2008, our investigators have obtained approximately $200 Million in external funding, produced over 1,000 peer-reviewed publications, given invited presentations at over 800 conferences worldwide, won numerous awards, and filed several patents based on their research.

CFCRI investigators continue to compete extremely well for the (declining) funds available at the CIHR (Canadian Institutes for Health Research), Canadian Cancer Society (CCS), the Terry Fox Research Institute (TFRI), and even the U.S. National Institutes of Health (NIH) and Department of Defense.

In addition, CFCRI/OCI investigators have obtained very substantial research support from several recent external competitions/sources.

The California Institute for Regenerative Medicine (CIRM) in concert with several Canadian funding agencies (CIHR, Genome Canada, CFI), launched a competition to award two large ($40 Million over four years, $20 Million to each country’s groups) grants to collaborative teams from California and Canada for developing new drugs against cancer stem cells. Teams from CFCRI co-led both successful grant applications.

One team, led by our scientist Dr. John Dick, along with Dr. Dennis Carson of University of California, San Diego, was awarded a CIRM grant for studying leukemia stem cell-targeted agents; the other, led by our own Dr. Tak Mak and Dr. Dennis Slamon of UCLA, received the award for solid tumour stem cells. In addition to the two leaders, multiple CFCRI researchers, including Drs. Minden, Schimmer, Wang, Neel and O’Brien, are involved in these projects.

Dr. John Dick is a Senior Scientist in the Division of Cellular at Molecular Biology at PMH/OCI and the Program Leader of the Cancer Stem Cells Program at OICR. He also holds a Canada Research Chair in Stem Cell Biology.


Global Leadership Round in Genomics and Life Sciences

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The Ontario Ministry of Research and Innovation awarded close to $30M in new funding to four OCI/CFCRI-led programs in genomics and gene-related areas of research. OCI awardees in the Ontario Research Fund-Global Leadership Round in Genomics and Life Sciences include:

• Drs. Benjamin Neel and Bradly Wouters ($10.1M) for their project using state-of-the-art genetic screens, next-generation genome sequencing and high-throughput synthetic antibody development to accelerate the discovery of novel cancer therapies and biomarkers.

• Drs. Igor Jurisica and Gary Bader ($10.02M) for their study which will provide an integrated database for systematic characterization of cancer proteins, their interactions and pathways; and will allow for the identification of new cancer targets in lung, prostate, breast, ovary and head and neck cancers.

•Drs. Peter Liu and Gordon Keller ($6.6M) towards their project which involves developing new screening and diagnostic tools to identify patients in the early stages of heart disease and determine the most effective treatment on an individual basis. Although this project is not directly related to cancer pathogenesis, knowledge gained from this work may help mitigate the cardiac damage caused by certain types of chemotherapy.

•Dr. Rama Khokha ($2.1M) towards her study which aims to understand how certain genes affect the development of osteosarcoma—a devastating form of bone cancer brought to the fore by Terry Fox thirty years ago on his Marathon of Hope campaign.

Dr. Igor Jurisica is a Senior Scientist at PMH, an IBM Life Sciences Discovery Centre and a Canada Research Chair in Integrative Computational Biology.


Ontario Research Fund: Research Excellence Program

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Ontario Consortium for Adaptive Interventions in Radiation Oncology (OCAIRO):

Radiation therapy is used to treat 50 per cent of all cancer patients. It is a proven cancer treatment that will soon become even more effective. Senior Scientist Dr. David Jaffray is leading a team of researchers and industry partners from across the province and around the world that are developing “adaptive radiation therapy”.

This new approach, which involves creating hardware, software, imaging and database systems, will enable oncologists to adapt radiation to each individual patient and their response during therapy. The goals are more effective outcomes and a better quality of life during and after treatment. This research builds on Ontario’s international reputation in the field of radiation therapy.

Integrated Molecular Pathology of Targeted Cancer Therapy in Lung Cancer:

A team led by OCI researcher Dr. Ming Tsao will establish the Integrated Molecular Pathology, Pharmacodynamic, Pharmacogenomic and Proteomics in Lung Cancer (IMP4-Lung Cancer) program in collaboration with several key industrial partners in Ontario and abroad. Instead of the more commonly used cancer “cell line” models, the UHN team will generate patient-derived tumour xenografts (from one species to another) models in immunodeficient mice. These models will be used to test novel therapeutic agents alone and in combination.

Dr. Ming Tsao holds the M. Qasim Choksi Chair in Lung Cancer Translational Research at PMH. He is a Professor of Laboratory Medicine and Pathobiology at the University of Toronto and a Director of the Lung Cancer Translational Research Laboratory at PMH.


Publications

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Publications: Analysis of publication metrics (see below) reveals that our research compares quite favourably in quantity (per capita) and impact (as measured by impact factor, citation index, etc.) with other top 5 cancer centres, including Dana Farber, Johns Hopkins, Mayo Clinic, MD Anderson and Memorial Sloan Kettering, which are considered by many to be the best in North America.

High-Impact Journals

Representing <2% of all journals, journals with a Citation-to-publications ratio of 10 or more are considered high-impact Journals

Citation Bibliographic acknowledgement of the contribution of one work to another. The number of times a work is referenced by others indicates its impact on a body of knowledge. Rates vary considerably by subject area.

Highly-cited paper

Papers with a citation count placing it amongst the top 10% of papers published in the year and subject -area (as per ESI). High-impact groups commonly have 25%-30% of papers achieving this standing

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Dana Farber JHM Mayo Clinic MDA MSK PMH

% Cited

% Highly Cited

% High Impact Journals


Research Advances

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Drs. Tsao, Jurisica and Frances Shepherd, in work published in the Journal of Clinical Oncology, identified a set of 15 genes (termed a gene “signature”) whose pattern of expression distinguishes non-small cell lung cancer patients at high and relatively low risk, respectively. They found that only patients with the “high risk” signature benefit from chemotherapy. Since these patients benefit substantially, it is critical that they be identified and treated. Conversely, patients with the low risk signature do not benefit at all from chemotherapy and should be spared its not inconsiderable side effects. These findings have been licensed to a biotechnology company that is attempting to commercialize this test.

Drs. Ming Tsao and Igor Jurisica helped develop a diagnostic tool to look at the genomic markers for malignant progression in pulmonary adenocarcinoma with bronchioloalveolar features. A patent was filed in June 2009 and their findings were published in Nature Medicine.

Lung adenocarcinoma (ADC) accounts for approximately 35% of all lung cancers and has an overall 5-year survival rate of 17%. Bronchioloalveolar carcinoma (BAC) has an excellent prognosis. Although BAC usually has a distinct appearance, some invasive ADCs can have components of a BAC-like pattern. Our researchers identified genomic regions that distinguish between subtypes of lung ADC. These differences can be used to classify patients with ADC into a BAC group with excellent outcome, or an invasive group with a higher risk of recurrence/metastasis and poorer survival. This will help physicians determine who most needs chemotherapy and who can be spared these treatments.

Dr. Frances Shepherd holds The Scott Taylor Chair in Lung Cancer Research at PMH. She is a Senior Staff Physician at the hospital and the Site Group Leader for the Lung Cancer site. She is also a Professor of Medicine in the Department of Medicine at the University of Toronto.


Research Advances

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Dr. Rama Khoka’s laboratory provided new insights into the relationship between reproductive history and breast cancer risk. Reproductive history is one of the strongest risk factors for breast cancer after age, family history and breast density. In a study published in the prestigious journal Nature, Dr. Khokha found that progesterone—an ovarian hormone that functions to prepare the uterus to receive a fertilized egg—plays a critical role in activating normal breast stem cells to proliferate. Breast stem cells give rise to the other cells within the breast and can also create multiple copies of themselves.

Until her work, they were believed to remain inactive, except during puberty and pregnancy. Dr. Khoka found that in the mouse breast, these cells are induced to proliferate during every estrous (equivalent of menstrual) cycle. During proliferation, breast stem cells may be particularly sensitive to mutation, which could explain why women who have longer periods of uninterrupted menstrual cycles (e.g., those who delay pregnancy or who do not ever become pregnant) have a higher risk of breast cancer.

Work by Dr. Norman Iscove, published in the high impact journal Cell Stem Cell shed new light on the complexities of blood cell development. Although blood stem cells (hematopoietic stem cells) have been studied extensively, the exact mechanisms by which these cells self-renew (make copies of themselves) while also giving rise to other blood cell types, has remained unclear. Dr. Iscove’s team identified a new population of ‘intermediate term’ stem cells that persist for a period of 6-8 months before losing their ability to self-renew. These findings may have important implications for stem cell transplantation and leukemogenesis.

Dr. Rama Khoka is a senior scientist at OCI and a Professor in the Department of Medical Biophysics at the University of Toronto.


Research Advances

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Drs. Laurie Ailles, Tom Waddell and Ben Neel, together with Dr. William Matsui and his colleagues at the Johns Hopkins Medical School, surveyed the frequency of tumour-initiating cells in a variety of different human tumours. Recent work by other groups on melanoma had suggested that tumour-initiating cells might be more frequent than previously thought. In a published work, the CFCRI/Hopkins group showed that melanoma appears to be the exception, and that in most solid tumours, tumour-initiating cells are, indeed, rare. Dr. Brad Wouters and colleagues from the OICR and in Europe, found that a specific pathway termed the unfolded protein response (UPR) protects human tumour cells under conditions of nutrient and oxygen deprivation by enabling them to carry out a form of self-eating termed “autophagy.”

Because this ultimately promotes tumour cell survival and contributes to treatment resistance, this work suggests that drugs that interfere with the UPR might have therapeutic utility. In their work published in Nature Medicine, Drs. Pam Ohashi and Tak

Mak and colleagues found that the protein interleukin-7 (IL-7) could dramatically enhance the response to an anti-tumour vaccine in a mouse model. These studies, if confirmed in humans, hold the promise of enhancing tumour-directed immunotherapies.

Dr. Brad Wouters is a Senior Scientist and Director of the Hypoxia and Microenvironment Program

at OCI and a Professor in the Department of Radiation Oncology at the University of Toronto. He is also a Senior Investigator in the Selective Therapies Program at OICR.


Awards

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• Canadian Medical Hall of Fame (Dr. Tak Mak)

• Premier’s Summit Award in Medical Research: Province of Ontario (Dr. Frances Shepherd; Dr. Benjamin Neel)

• MERIT Award: U.S. National Institute of Health (Dr. Benjamin Neel)

• Rx&D Clinical Chair in Oncology; CIHR/Wyeth Pharmaceuticals (Dr. Michael Jewett)

• Distinguished Scientists Award; Royal College of Physicians and Surgeons (Dr. Shereen Ezzatt)

• Royal College Medal in Medicine; Royal College of Physicians and Surgeons of Canada (Dr. Aaron Schimmer)

• Michael Fry Research Award; Radiation Research Society (Dr. Bradly Wouters)

• Innovators Hall of Fame; University of Saskatchewan (Dr. James Till)

Dr. James Till is an Officer of the Order of Canada and a member of the Canadian Medical Hall of Fame. He is currently a Senior Scientist at OCI and was recently inducted into the Innovators Hall of Fame at the University of Saskatchewan.

OCI/CFCRI scientists have been remarkably successful in obtaining prestigious awards from national and international organizations. Of particular note, they have won the highest award given for cancer research in Canada (The Noble Prize of the Canadian Cancer Society) and the most prestigious award for young cancer investigators in Canada (The Rawls Prize of the Canadian Cancer Society) for two of the last three years, and also have received multiple Premier’s Summit Awards (the most prestigious scientific award in Ontario). A selection of awards received by our faculty since 2008 includes:

•Robert L. Noble Prize: National Cancer Institute of Canada/CCSRI (Dr. Richard Hill; Dr. Brian Wilson; Dr. Mitsu Ikura)

•William Rawl Prize: National Cancer Institute of Canada/CCSRI (Dr. Geoffrey Liu, Dr. Camilla Zimmerman)

•E. Donnall Thomas Lecture and Prize; American Society of Hematology (Dr. John Dick )


Awards

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• Clifford Prize for Cancer Research; Centre for Cancer Biology (Dr. John Dick)

• The Failla Lectureship; Radiation Research Society (Dr. Richard Hill)

• Jeanne Manery Fisher Memorial Lectureship; Canadian Society for Biochemistry and Molecular & Cellular Biology (Dr. Cheryl Arrowsmith)

• Young Investigator Award; Canadian Society for Biochemistry and Molecular & Cellular Biology (Dr. Senthil Muthuswamy)

• CCO Chairs; Cancer Care Ontario (Dr. Lillian Siu, Dr. Geoff Liu, Dr. Ralph DaCosta)

Dr. Geoff Liu holds the Alan B. Brown Chair in Molecular Genomics at PMH. He was recently awarded a 2009 Research Chair from Cancer Care Ontario and is also an Assistant Professor at the University of Toronto.


Commercialization

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CFCRI faculty also have been very active in filing patents which is an important part of translating our research into products which can further research internationally and improve patient care. Examples of the technologies that have been licensed by our faculty include:

Avi Chakrabartty Pipeline - UHN has exclusively licensed out this technology to Amoxfix. This is a polyclonal antibody that selectively recognizes misfolded forms of the enzyme, superoxide dismutase (SOD1). This antibody may be useful for the diagnosis of amyotrophic lateral sclerosis (ALS), and provides a treatment target for immunotherapies or rationally designed small molecules.

Igor Jurisica Pipeline - Licensed to MedBiogene Inc: 15-gene prognostic mRNA expression-based signature to be used in the clinical management of lung cancers and messenger RNA expression-based methods for prognosing early-stage non-small-cell lung cancer survival.

Jeff Medin Pipeline – Licensed exclusively to Lentigen Corporation: Lentivirus expressing mutant forms of human thymidylate monophosphate kinase (tmpk), F105Y and R16G Large lid.

Gil Privé Commercially Available - Invention, “Lipopeptide Detergent LPD-12” licensed and sold non-exclusively by EMD Chemicals Inc.

Ming Tsao Pipeline – Licensed exclusively to Med BioGene Inc: 15-gene prognostic mRNA expression-based signature to be used in the clinical management of lung cancers and a 12-gene prognostic gene signature for squamous cell carcinoma of the lung.

Alex Vitkin and Brian Wilson Commercially Available - Endoscopic Coherent Optical Microscope – The EX1301 OCT Microscope reveals microscopic detail below the surface of a tissue samples instantly, without affecting or damaging them and with no special preparation. Designed for laboratory use on excised tissue (e.g. skin, oesophageal and cervical), complete organs and scientific materials, this bench-top scanner is a perfect solution for the researcher who needs to see inside a specimen but can't afford to alter or damage it in any way. Michelson Diagnostics has executed exclusive, worldwide license to this new biophotonic imaging technology.

CFCRI: Continuing to Implement Our Strategic Plan

Platforms

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Immunotherapy

Dr. Pam Ohashi led an international search for two scientists - one basic scientist and the other translational scientist - to buttress our immunotherapy program. Offers have been made to two external candidates, one from the US (Harvard Medical School) and another from Switzerland (Lausanne), and we are optimistic they will accept and allow us to attain our immediate-term goals in this area. CFCRI funds will be used to partially support these recruitments, but both candidates have also been offered OICR investigator positions. In addition, Dr. Ohashi has spearheaded efforts to organize a Toronto-area collaborative Immunotherapy Program, which involves investigators from Sunnybrook Cancer Centre, The Hospital for Sick Children, and the Department of Immunology at the University of Toronto as well as our scientists.

Molecular Imaging/Image-Guided Therapeutics

Dr. David Jaffray is leading an international search for investigators in these areas. Two candidates have been identified, one from Vancouver, the other from the US (Stanford Medical School), and offers are being negotiated. If successful, these recruitments should achieve our immediate term goals for this area.

Dr. David Jaffray is the Headof Radiation Physics in the Radiation Medicine Program and holds the Orey and Mary Fidani Family Chair in Radiation Physics at PMH. He is also Vice Chair and Professor in the Department of Radiation Oncology at the University of Toronto.

CFCRI: Progress towards Strategic Objectives

Platforms

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Dr. Pat Shaw is a ClinicalStudies Resource Centre Member at OCI, a member of the Department of Pathology and Gynecology-Oncology, at PMH and Associate Professor and Member of the Department of Pathobiology and Laboratory Medicine at the University of Toronto.

Biobanking

With major support from CFCRI funds, and under the leadership of Dr. Pat Shaw, we have substantially upgraded our tumour banking capabilities. Currently, four pathologist assistants, two technologists, one data manager, as well as a supervisory manager, comprise our biobanking efforts. This represents a doubling of resources since 2008. With this infrastructure, we currently bank about 3,000 new tumour, blood and normal tissue samples each year.

Proteomics/Biomarker Identification In addition to gene-based biomarkers for cancer detection and prognosis, modern proteomic analysis (the detection and analysis of cancer-associated protein markers) is an essential tool to delineate the basic biology of cancer and identify early detection and response markers. The CFCRI has several world class proteomics laboratories and we have recently purchased a state-of-the-art mass spectrometer to enable continued productivity by our proteomics group.

Computational Biology/Bioinformatics

The ability to analyze high content datasets is increasingly necessary in modern biology. This requirement is particularly fraught in the genomic era, where sequencing of individuals’ genomes is not only possible, but soon to be a relatively inexpensive reality, yet one that yields terabytes (1 trillion bytes) of information for each run! Dr. Igor Jurisica, a world leading expert in Bioinformatics and Senior Scientist at CFCRI/OCI, has been appointed to make recommendations for, and ultimately develop, a bioinformatics core at the Institute to enable the handling of the onslaught of data that will emerge in the next five years.


Platforms

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As indicated earlier, thanks to Boehringer-Ingelheim, we will also be able to molecularly profile all new lung cancer patients at PMH. These exciting studies represent the dawn of personalized genomic medicine in Ontario, and are critical to our keeping pace with similar efforts underway at major centres in the US and Europe.

Clinical Trials Infrastructure

Under the direction of Dr. Amit Oza and with CFCRI support, we have completely reorganized our Cancer Clinical Research Unit (CCRU). This allowed us to compete successfully for one of four $1 Million grants for translational research infrastructure from the OICR. We also received funding to purchase a state-of-the-art new clinical trials database (MediData Rave) which is currently being integrated with our tumour bank informatics effort and other hospital databases.

Molecular Diagnostics/Personalized Genomics

With CFCRI support, we have purchased a Sequenom which allows us to simultaneously assess the presence of common mutations in oncogenes and tumour suppressor genes in cancer specimens. CFCRI support has also been used to carry out pilot validation studies, wherein samples with known mutations were tested with the Sequenom machine. These studies revealed an extremely high concordance with some mutations detected by Sequenom that were missed by conventional approaches. We expect this facility to be certified soon.

In addition, led by Drs. Lillian Siu, Ben Neel and Suzanne Kamel-Reid from OCI/CFCRI, and Drs. John McPherson, Nicole Onetto and Janet Dancey at OICR, we are developing a pilot project that combines high content “next generation” sequencing using the newly developed Pacific Biosystems machine with Sequenom-based validation to prioritize patients with specific types of cancer-associated mutations for clinical trials.

Dr. Amit Oza is a Senior Staff Physician at PMH and Associate Professor of Medicine at the University of Toronto. He is a Scientist with the Ontario Cancer Institute and is cross appointed to the Department of Obstetrics and Gynecology at the University of Toronto.

CFCRI: Continuing to Implement Our Strategic Plan

Platforms

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Dr. Cheryl Arrowsmith is a Senior Scientist at OCI and a Professor at the University of Toronto. She is also the Chief Scientist for the Structural Genomics Consortium.

Epigenetics, Stem Cells and Cancer Stem Cells

With the recruitment of Drs. Ailles, Muthuswamy, and O’Brien and our earlier recruitment of Dr. Nadeem Moghal, who studies lung stem/progenitor cells, we have substantially increased our capacities in the area of normal and cancer stem cell biology. We still need to replenish our expertise in the area of hematopoietic stem/progenitor cells and we will certainly remain opportunistic for recruitment in this area. However, we would like to recruit a world-class leader in epigenetics with interests in stem cell biology and cancer.

This need extends to the entire Toronto scientific community, and we are working closely with the OICR to recruit a leader who will interact effectively with their genomics platform. An international search is underway, led by CFCRI scientists Drs. Cheryl Arrowsmith and Linda Penn. Candidates at both the junior and more senior level have been identified and invited to visit OCI.

We hope to secure at least one recruit in this area by Spring 2011. We also anticipate that additional investments in equipment and informatics infrastructure, and possibly the recruitment of new Bioinformatics faculty, will be required to support our epigenetics effort.

Personalized Cancer Genomics and Medicine

Although we do not expect to make additional faculty recruitments in this area at present, we anticipate continuing requirements for increased sequencing infrastructure. The Sequenom facility that we established within the last year is already besieged with requests for service by Institute investigators, and additional capacity will need to be added soon. In addition, sequencing technology is advancing extremely rapidly, with the $1,000 genome no longer a pipe dream, but an imminent reality. To maintain our standing as a top five cancer centre, the CFCRI/OCI will require new investments in this area in the near future, and we must retain sufficient financial flexibility to act quickly when opportunities present themselves.


Programs and People – New Recruits

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We have recruited the very best from around the world in these areas

Epigenetics

Dr. Laurie Ailles is a Canadian who was recruited from Stanford Medical School after researching stem cell and cancer stem cell there for nine years. Her group identified head and neck cancer stem cells, and she is continuing this research at the CFCRI. She is also collaborating with Dr. Neel’s laboratory on ovarian cancer stem cells and with Dr. Michael Jewett on kidney cancer stem cells, and has set up a high throughput flow cytometry platform that is dramatically accelerating the identification of markers for normal and cancer stem cells.

Stem Cells

Dr. Catherine O’Brien, discovered (while in Dr. Dick’s lab) colon cancer stem cells. Her work focuses on the further purification and characterization of these cells and developing approaches to their eradication. She is a major contributor to POP-CURE and the solid tumour CIRM program. She has also received support from the OICR.

Cancer Stem Cells

Dr. Senthil Muthuswamy is the Lee K. and Margaret Lau Chair in Breast Cancer Research at PMH. He is a world leader in mammary cell biology and the recipient of a prestigious Innovator award from the US. Department of Defence. Immunology

Dr. Naoto Hirano is a Japanese national who we recruited from the Dana Farber Cancer Institute. He is a budding star in the area of tumor immunology and immunotherapy who will join our growing program under Dr. Pamela Ohashi. In addition to support from the CFCRI, he will be an OICR Clinician-Investigator and member of the Biotherapies program.

Personalized Cancer Genomics

Dr. Rodger Tiedemann is a New Zealand native. His research focuses on the targeted therapy of multiple myeloma. He uses genome-wide functional genomic screening to identify new therapeutic targets for this disease.

Dr. Laurie Ailles is a Scientist at OCI. She is an Assistant Professor at the University of Toronto and an OICR New Investigator.

Tak Mak

Pam Ohashi

Linda, Gaye and Susan,

For many years now I’ve been the fortunate recipient of your support and trust, and I am both exceedingly grateful and humbled by your generosity.

My Co-Director, Pam Ohashi, and I - indeed our entire team of more than 120 researchers - work diligently day in and day out attempting to solve the mysteries of breast cancer and make a real impact on the thousands of Canadian families confronted by this disease. Your tremendous support has allowed us to take our research to new heights and I am confident that your continued investment in our collective work will give us the wind we need to continue to soar.

We are delighted to present to you this report on our progress during the past two years and look forward to sharing with you many new discoveries in the years to come.

Thank you,

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The Campbell Family Institute for Breast Cancer Research 23

Impact

Under the leadership of the world-renowned researcher Dr. Tak Mak, The Campbell Family Institute for Breast Cancer Research and its elite team of scientists and clinician-scientists have become an internationally known breast cancer research program.

Dr. Mak is one of the scientists ranked as having published the greatest number of highly cited papers. His lab has produced numerous important studies which have been cited more than 60,000 times by other scientists, both nationally and internationally. The number of citations is by far the highest rate in Canada to date with 3700-3800 citations a year.

Total Number of Total Number of Citations: 61,450Citations: 61,450

Total Number ofTotal Number ofPublished Papers: 735Published Papers: 735

The Campbell Family Institute for Breast Cancer Research24

Impact

Dr. Mak and his team’s research has been directed into the areas of prevention and discovery:

Prevention

Screening: Dr. Norman Boyd’s groundbreaking studies in imaging breast density have shown a correlation between breast density and the risk of developing breast cancer. Therefore, mammographic screening of breast density permits us to identify women at increased risk. His latest work has indicated that breast density is correlated with growth and development, as well as maternal breast density, in young women aged 15 to 30. These studies suggest that we may be able to assess the risk for breast cancer in women at a younger age. Young women with a high risk for breast cancer can then be monitored more closely to improve early detection and encouraged toward preventative behaviour modification.

Discovery

Our research team is strongly focused on scientific discovery to defeat cancer.

Drug Targets and Drug Development: Our basic research into the mechanisms of cancer onset and progression continues to find novel molecules in the cell which are critical in driving that cell to a cancerous state. As we discover and validate the activity of these molecules, they are assessed as candidates for new drug development.

•The Reedjik Laboratory has identified a set of genes that cooperate with a factor called Notch to promote cancerous growth, and are now confirming these observations in primary human breast tissue. They are currently looking for drug candidates in small molecule inhibitors of Notch.

•The Okada Lab has shown that estrogen receptor positive (ER+) breast cancer cells require a novel enzyme called JMJD2 in order to grow, whereas ER- breast cancer cells require a protein called BAT3.

The Campbell Family Institute for Breast Cancer Research25

Impact

Novel Biomarker Discovery: Novel biomarkers serve to aid early detection and timely treatment of cancer. Dr. Mak’s group has very recently discovered that a subtype of acute myeloid leukemias (AML) produce a novel small molecule which can be detected in patient serum. This molecule, called 2-HG, is also produced by most glioma and secondary glioblastoma brain cancers. These cancers are currently the subject of worldwide interest and research to learn the effect of this potential biomarker on the progression of cancer.

Immunotherapy: A powerful new approach to cancer therapy is to harness the potential of the patient’s immune system to attack and control cancer cells. This approach has been used successfully to treat cancers:

•Ipilimumab is now an approved immunotherapeutic for prostate and skin cancer; this drug targets the activity of a factor called CTLA-4 which was characterized in Dr. Mak’s laboratory. Dr. Pamela Ohashi’s lab has designed a clinical protocol to test this reagent in breast cancer and has received investigator-initiated funding for this project from Pfizer. This protocol has recently passed through the ethics committee and the trial has recently opened at PMH.

•Adoptive T cell Therapy: This is another approach to immunotherapy for cancer. T cells are white blood cells of the immune system that have the ability to specifically recognize and kill tumors.T cells that have been grown from patients’ tumours can be used as a therapeutic agent for the patient, to kill tumour cells. The investigators who developed a successful protocol using this therapy for melanoma are Steven Rosenberg and Mark Dudley at the National Cancer Institute. Dr. Ohashi has collaborated with this group to establish the technology here at the CFIBCR. Over the last four years, she has set up the required reagents and procedures and replicated their ability to grow tumor specific T cells from patients.

•Interleukin-7: The Mak and Ohashi labs have collaborated to show that a soluble protein called Interleukin 7 (IL-7) is a potent factor in enhancing the immune response to fight cancer cells.

The following pages highlight some the principal investigators at the Institute and shines a light on some of their exciting research.

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Dr. Tak Mak is Director of the Campbell Family Institute for Breast Cancer Research. He is a world renowned immunologist and a leader in the fight against cancer. In 2008, he was awarded the Order of Ontario, and in 2009 was inducted into the Canadian Medical Hall of Fame.

CFIBCR: Principal Investigators

DR. TAK MAK: Metabolism, Inflammation, Aneuploidy

Metabolism: Currently my research is centred on the role of changes in cellular metabolism which cancer cells rely on to survive and prosper in a hostile environment.

Some of the research projects my team and I are looking at include:

•How breast cancer cells become resistant to the drug Herceptin.

•Why a small change in one metabolic protein can lead to brain cancer or leukemia.

•The role of antioxidants in the developmentof cancer.

•A novel drug therapy target which cancercells use for survival when deprived of oxygen and nutrients. This work will elucidate new drug targets in pathways that cancer cells exploit for survival.

Inflammation: It has become clear that chronic inflammation accelerates the onset and progression of cancer. In collaboration with Dr. Pam Ohashi, I am currently studying the role of inflammation in the context of well established cancer models.

Aneuploidy: When cancer cells grow very quickly, the cell division process becomes faulty and cells often fail to divide their duplicated DNA accurately between the two daughter cells. This results in an abnormal number of chromosomes in the cancer cell. This effect, known as aneuploidy, causes tremendous abnormalities which accelerate the course of the cancer. I am interested in the mechanisms of cancer cell division which permit this to occur. I am also guiding the development of a novel drug which makes cancer cells with faulty cell division much more susceptible to death.

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DR. PAM OHASHI: Immune Therapy for Breast CancerOne way to promote the immune response to cancer is to block signals that shut down any ongoing natural immune responses to the tumour. The reagent that has been in clinical trials that is able to do this is called anti-CTLA4. My team and I have designed a clinical protocol to test this reagent in breast cancer and have received funding from Pfizer. The trial has recently opened at PMH.

Another method that has been used as an approach for immune therapy for cancer is called adoptive T cell therapy. T cells are white blood cells of the immune system that can specifically recognize and kill tumours. T cells that have been grown from patients tumours can be used as a therapeutic agent for the patient, to kill tumour cells. Over the last four years, I have collaborated with other investigators to set up the required reagents and procedures and replicate their ability to grow tumour specific T cells from patients.

The focus of my group is to develop immune therapy as a successful therapeutic alternative for women’s cancers. Our work is aimed at both understanding the biological mechanisms that will promote immune therapy in animal models, as well as exploring immune therapy for cancer at the clinical level.

Over the past two years, in collaboration with Tak Mak’s group, my team discovered that a factor, called interleukin 7, is extremely potent in enhancing immune responses to tumours.

One method for the immune system to attack breast cancer is to focus the attack on genes that are only expressed in breast

Dr. Pam Ohashi is Co-Director of the CFIBCR and a Professor at the University of Toronto in the Department of Medical Biophysics and Immunology.She holds the Canada Research Chair in Autoimmunity and Tumour Immunity.

development and in breast cancer. In this way, the immune response will not harm normal tissues of the breast. With this idea in mind, we also developed a model to explore ways to promote immune responses to breast tumours. We hope to gain insights into optimal ways to promote the immune response to breast cancer as well as understand critical parameters that are required for this process.

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DR. HAL BERMAN: Identification of Biomarkers To Improve Treatment

To identify biomarkers in ovarian cancer, my laboratory is part of an integrated team of scientists in the CFICR and UHN. Ovarian cancer is a leading cause of mortality in women’s cancers. Treatment of ovarian cancer is complicated by the fact that the majority of women are diagnosed at an advanced stage. The goal of identifying ovarian cancers at an early point in time awaits the discovery of biomarkers that reflect early events in the disease. To accomplish this goal, our team has initiated unique studies of ovary and fallopian tube tissues from patients at high risk for developing ovarian cancer. As in our studies in the breast, we have placed much of our focus on changes in the microenvironment in these tissues.

Over the past couple of years, this work has led to the identification of several ovarian cancer biomarkers that can be detected in "normal" tissue at high risk for future tumour formation. The next phase in this work is to determine whether these biomakers can provide risk stratification and whether they may be targets for therapy.

My laboratory has two major areas of focus, both involving the identification of “biomarkers” or key molecules that can tell us how to better manage breast and ovarian cancers. Our efforts to identify biomarkers in breast cancer focus on a portion of tumours termed the microenvironment.

Breast cancer occurs when invasive tumour cells invade the normal breast tissue. Therefore, breast tumours are composed of a microenvironment involving a mixture of cancer cells and normal cells. We are learning that normal cells within the breast tumour respond to the presence of cancer cells in unique ways and that this response can determine the aggressiveness of the breast tumour as a whole.

Over the past two years, we have identified biomarkers of this response in order to help differentiate patients with less aggressive disease from those with a worse prognosis. We are currently validating these biomarkers in a cohort of women who have been treated for breast cancer and subsequently followed to determine the outcome of their therapy.

Dr. Hal Berman was formerly a G.W. Hooper Fellow at the Department of Pathology, University of California, San Francisco. He was also the Director for the UCSF National Breast Tissue and Cell Bank. In 2004, he was a recipient of an NIH Clinical Research LRP Award.

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DR. NORMAN BOYD: Breast Cancer Prevention

To identify genes influencing breast density the team also performed a genome-wide linkage study. Epidemiological and genotype data were assembled on 1415 families. Suggestive scores for chromosomal regions associated with breast density were found in at least two sites and further investigations are needed to identify the genes that determine breast density with the long term goal of understanding breast biology and susceptibility to breast cancer.

Since all of the methods that currently assess breast density have limitations, there is a need for an improved method of characterizing breast tissue composition that uses no radiation. We collaborated with Detroit’s Karmanos Cancer Institute to evaluate ultrasound tomography as a way to characterize breast tissue composition. The Karmanos Institute developed a clinical prototype that typically completes a whole-breast exam takes about one minute without breast compression or exposure to radiation and, like mammography, it defines fat and tissue.

My research is focused on breast cancer prevention. I am concerned with developing improved methods of characterizing women at increased risk for the disease, and with the modification of risk.

Breast density, as assessed by mammography, reflects breast tissue composition. It is consistently associated with breast cancer risk, more strongly than most other risk factors for this disease, and extensive breast density may account for a substantial fraction of breast cancer.

Although mammographic density is an inherited trait that is a strong risk factor for breast cancer in middle aged and older women, little is known about the origins of this risk factor in early life. Our team recruited 400 young women aged 15-30 years and their mothers. Results suggest that mammographic density in mid-life may be, in part, due to genetic influences and growth and development in early life that determine breast tissue composition.

Dr. Norman Boyd is a Professor of Medicine at the University of Toronto. He has received a Distinguished Scientist Award from the Medical Research Council of Canada and is a recipient ofthe O. Harold Warwick Prize which recognizes research that has had a major impact on cancer control in Canada.

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DR. ROBERT BUCKMAN: Low Toxicity Chemotherapy

Currently a major collaborative oncology group in the U.S. is organizing a Phase III study comparing DalCM-P to another metronomic therapy. DalCM-P is being tested in other (‘non-breast’) cancer sites as well.

Another publication surveyed patients with cancer of the breast or of the prostate, and showed that three-quarters of them would opt for therapy with low toxicity even if it meant some loss of time or tumour control.The clinical and biological studies of DalCM-P continue, and may provide an important option for patients with widespread and incurable cancer of the breast and other sites.

For the last two years, I have continued my investigations into the clinical use and the biological mechanisms associated with metronomic (low dose-continuous) scheduling of chemotherapy, particularly a combination called DalCM-P, on which a full paper was published this year in the Journal of Clinical Oncology. Its benefits include the fact that this scheduling of chemotherapy agents has very little toxicity and is accepted by patients who have refused all previous chemotherapy. Seventeen patients are receiving (or have received) DalCM-P since April 2009, and several are in remission for prolonged periods (sixteen months is the current maximum).

In collaboration with Dr. Susan Done, we are looking at the Circulating Tumour Cells (CTCs) in these patients as a potential marker of tumour response (very preliminary results support that hypothesis). This may provide insight into mechanisms of action.

Dr. Robert Buckman is a medical oncologist at PMH, a full Professor in the Department of Medicine at the University of Toronto, and an Adjunct Professor at the M.D. Anderson Cancer Center.

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DR. MONA L. GAUTHIER: Early Events in Familial Breast and Ovarian Cancer

The answers to these questions require a better understanding of the earliest events that occur as a tumour develops.

In the laboratory, over the past two years we have developed new approaches to study normal breast and ovarian cells and to model the earliest alterations. We believe these insights will provide new biomarkers for the assessment of cancer risk and, ultimately, prevention of the disease in high risk individuals.

My team and I are using their knowledge of molecular biology to develop a ‘signature’ that will help determine an individual’s risk for developing breast cancer based on a combination of ‘markers’.

My laboratory focuses on understanding the early events that occur in breast and ovarian cancers that run in families. Individuals with mutations in the breast cancer gene BRCA have a 50-80% lifetime risk for developing breast cancer and approximately a 40% lifetime risk for developing ovarian cancer. Unfortunately, the tumours that develop in individuals who carry a mutation in the BRCA gene tend to be aggressive and tend to occur at a young age.

Important questions that remain to be answered include why mutations in BRCA cause cancer, why cancers that develop in mutation carriers tend to occur in the breast and ovary, and why the tumours that occur have a unique "molecular signature".

Dr. Mona Gauthier received the Theodore Puck Award for Scientific Excellence and the Young Investigators Award presented by BioMol Research Laboratories.

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DR. LISA MARTIN: Diet and Breast Cancer

to 20% after randomization, and remained 9-10% lower than the comparison group throughout. The trial is complete and the first paper describing the principal results is expected to be published soon. Then the details of the results will be disseminated. The trial has identified several potentially modifiable factors that influence breast cancer risk.

Using data from this study, my team and I also examined the association of glycemic index with breast cancer risk. Glycemic index ranks foods in terms of their effects on blood glucose and insulin. The study showed that glycemic index is not associated with the overall risk of developing breast cancer, but that it is strongly associated with the type of breast cancer that develops. Higher glycemic index is associated with a higher risk of developing hormone receptor negative compared to receptor positive cancer. Hormone receptor negative cancer is resistant to hormonal treatments, and has a poorer prognosis compared to hormone receptor positive cancer, and little is known about the factors affecting its development.

My long term research goal is to understand the cause of breast cancer and develop effective preventative strategies. My work examines the influence of lifestyle, biological, molecular and genetic factors on breast tissue composition, breast cancer risk and prognosis.

The wide variation in breast cancer rates between countries and the increase in rates seen in women who move from low to high risk countries suggest that environmental factors influence breast cancer risk. In collaboration with Dr. Boyd, my team and I conducted a long-term trial to determine if the incidence of breast cancer could be reduced by a low-fat high-carbohydrate diet.

We recruited 4,690 women with extensive mammographic density and randomized them to an intervention or comparison group. The intervention group received intensive dietary counseling to reduce fat intake and increase carbohydrates. Subjects were followed for an average of ten years. The main outcome was invasive breast cancer. Percent calories from fat in the intervention group fell from 30% at baseline

Dr. Lisa Martin was the 2004 AACR-GlaxoSmithKline Outstanding Clinical Scholar. She recently received a New Investigator Award from the Canadian Institute for Health Research (2010 to 2014).

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DR. HITOSHI OKADA: How Subtypes of Breast Cancer Develop

2. ER positive breast cancer: ER-positive breast cancer is the most common subtype of breast cancer. Hormonal therapy is an effective treatment; however, a critical problem is the eventual emergence of therapeutic resistance. Thus, understanding the ER signaling networks will be crucial for understanding the biology of breast cancer, overcoming the resistance and developing novel therapeutic targets.

Our current studies have also identified a novel enzyme (called JMJD2) which is required for the growth of ER positive breast cancer. JMJD2 inactivation severely impairs the growth of ER positive breast cancer. Our work will provide valuable insights into how dysregulation of the core signaling pathways enhances risk for cancer development. Since we have identified novel enzymes essential for the growth of breast cancer cells, further investigation of the molecule will lead to identification of novel therapeutic approaches for breast cancer.

My research focuses on understanding how different subtypes of breast cancer develop and how biological features of these subtypes reflect treatment response and patient prognosis. Through these studies, we aid identifying novel prognostic markers and therapeutic targets. My team and I identified two key molecules which are critical for the maintenance of estrogen receptor (ER)-positive and negative breast cancers, respectively.

1. ER negative breast cancer: My team and I found that a nuclear protein, Bat3, is a novel regulator of the protien p53. Bat3 has been shown to regulate BRCA1 expression. In support of our findings, Bat3 mutations were reported in multiple cancers. In addition, Bat3 expression levels correlate with patient prognosis in ER negative breast cancer.

Dr. Hitoshi Okadacompleted his medical training and doctoral studies at Tohoku University in Japan. He is an Assistant Professorat the University of Toronto.

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DR. MICHAEL REEDJIIK: Notch Signaling in Breast Cancer

how abnormal Notch expression changes the biology of breast cells to make them grow as cancers.

This work takes advantage of established breast cancer cell lines that can be cultured in the laboratory. From these cell lines the team identified genes that are necessary to cooperate with Notch to promote cancerous growth. The genes identified so far, promote cell division and cell migration/invasion, processes known to promote cancer progression.

The importance of novel Notch-interacting genes found in cell lines is being confirmed in primary breast cancer tissue. As such, our group, together with the PMH Phase I and II Consortium, is involved in the conduct of several clinical trials to study the effect of small molecule Notch inhibitors, in the treatment of solid malignancies, including advanced, triple negative breast cancer. Understanding the causes and consequences of corrupt Notch signaling in breast cells will provide insight into novel therapies that target Notch and associated pathways in TN breast cancer.

Breast cancer affects thousands of Canadian women every year, and ranks as the second most common cause of cancer death. There is emerging evidence that genes involved in controlling normal mammary growth and development are also involved in the pathological growth and development associated with breast cancer.

Genes of the “Notch” signaling family control growth and development in all complex animals. Notch signaling controls the normal development of the mouse mammary gland but when perturbed, Notch can contribute to the development of breast cancer in mice. Expanding this observation to humans, my group and I have shown that patients whose breast cancers abnormally express genes of the Notch family have poor survival rates. In addition, abnormalities in Notch are most common in the aggressive “triple negative” subtype of breast cancer for which there is currently no effective treatment.

To take full advantage of this discovery, the next phase of my work is focusing on determining how Notch becomesabnormally activated in breast cancer and

Dr. Michael Reedjiik is a surgical oncologist with both clinical and research interests in breast cancer. He has received several awards including the James Ewing Oncology Fellowship Award for Basic Research and the Society of University Surgeons Junior Faculty Grant Award.


DR. SENTHIL MUTHUSWAMY: Understanding the Architecture of a Cell

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Dr. Senthil Muthuswamyholds the Lee K. and Margaret Lau Chair in Breast Cancer Research at PMH. He is also an Affiliate Investigator at the Campbell Family Institute for Breast Cancer Research.

My research interest is in understanding the molecular mechanisms that regulate the development and progression of premalignant lesions. Pathologists use a number of criteria to diagnose and predict the prognosis of breast cancer including changes in cell number and in cell and tissue architecture. Although we are beginning to understand a lot about the mechanisms that regulate cell proliferation, very little, if any, is known about the mechanisms that regulate disruption of cell and tissue architecture.

My team and I discovered that proteins that regulate cell architecture, or “polarity proteins”, are direct targets of oncogenes (gene mutations that help turn normal cells cancerous). Our results suggest that pathways that regulate cell architecture are independent of those that regulate cell division and are a novel class of targets that can be exploited for therapeutic intervention. Since we made this discovery, research efforts in my lab have been aimed at understanding how cell polarity proteins regulate the transformation of epithelial cells (cells which help protect or enclose organs).

More recently, we demonstrated that polarity proteins function as modulators of cancer, and not just as effectors of oncogenic signaling. Disruption of Scribble (another protein in breast epithelial cells that disrupts cell polarity) blocks three-dimensional morphogenesis, inhibits cell death and induces cell changes that progress to tumours after long latency. Loss of Scribble protein expression also cooperates with oncogenes and induces tumours by blocking cell death. We found that Scribble is deregulated in primary human breast cancers. These results provide the first demonstration of a tumour suppressive role for polarity protein Scribble in mammals, and have opened a new area of cancer biology that can provide opportunities for diagnosis and treatment. We are continuing our investigations in developing a better understanding of the pathway used by HER2 (human epidermal growth factor receptor 2) to disrupt cell architecture. The HER2 gene is part of a family of genes that play roles in regulating cell growth. We anticipate that these investigations will identify new opportunities for novel prognostic markers and drug targets for HER2 positive breast cancer.

Summary and Perspective 36

Cancer continues to cause an immense amount of death and suffering. Because the major risk factor for cancer is age, we can, unfortunately, expect an ever-increasing number of cancer patients in the near term. Preventing cancer remains a major goal of cancer researchers worldwide. But even if every cause of cancer were identified and eliminated tomorrow, cancer would continue to be a, if not the, major cause of death in Western societies for the foreseeable future due to the 15-20 year lag between cancer initiation and its manifestation as clinically apparent disease. Yet because the remarkable achievements of cancer biologists worldwide —and especially at PMH—there is more hope than ever before. We know the enemy now—and though he is wily and resourceful, he is not invincible.

The cancer medicine of the future will look dramatically different than the cancer medicine of today—and it will be unrecognizable from the cancer medicine that preceded the dawn of molecular oncology in 1976. First, using molecular diagnostics and ever-improving imaging devices, we will detect tumours of ever smaller size. We will remove them—especially when they are located in sensitive areas—using robotic, image-guided therapies that exact far less tissue damage and side effects. Many times, these operations alone will be curative.

The pathologists’ “microscope” of the future will be a DNA sequencer. With that tool, tumours will not be diagnosed as only as a breast cancer or colon cancer. Instead, we will determine the complete spectrum of genetic and epigenetic abnormalities in each tumour. Research on basic cancer biology will allow us to pair that molecular diagnosis with specific targeted therapies that find the Achilles heel of each tumour. Not only will we target the bulk tumour cells, we will make sure we kill the tumour-initiating cells as well, destroying the roots as well as the leaves of the tumour. If targeted agents alone won’t do the job, we will know how to mobilize—or remobilize—the immune system, so that it more effectively eliminates the tumour and/or prevents tumour recurrence. Indeed, we will know how to intelligently combine targeted therapies and immunotherapy to yield maximum patient benefit.

To those outside the trenches of the fight against cancer, this vision may seem like science fiction. But it is no exaggeration to state that for most of the goals outlined above, the future is now. To finally defeat cancer will take hard work, and a lot of it, and it will require substantial additional investment by government, industry and private philanthropy. But the tipping point in the fight against cancer is at hand, and we at the CFCRI are committed to one goal: To Conquer Cancer In Our Lifetime.

Epic Fundraising Events37

Over the past eight years in Toronto, The Weekend has raised over $102 Million and remains the largest single event fundraiser for breast cancer in Canada.

Lifetime

Thanks to your extremely generous support, PMH has been able to leverage funds from other sources and inspire other donors through a variety of successful events:

In The Shopper’s Drug Mart® Weekend to End Women’s Cancers (formerly The Weekend to End Breast Cancer), thousands of women and men take to the streets of Toronto for this incredibly inspiring event benefiting the CFCRI. Last year alone, 4,623 walkers in Toronto raised over $10.8 Million for PMH and CFCRI. In the past eight years in Toronto, it has raised over $102 Million and remains the largest single event fundraiser for breast cancer in Canada.

Also benefiting the CFCRI, The Enbridge Ride to Conquer Cancer (formerly The Ride to Conquer Cancer) was established in 2008 as a unique, two-day cycling event where participants ride over 200k from Toronto to Niagara Falls. Since its inception, it has surpassed all other cycling events to become Canada’s most successful cycling fundraiser. The 2010 Toronto event saw 4,108 riders bring in $16.1 Million for a total amount raised since 2008 to over $45 Million.

We are excited to announce another bold new fundraising event which will benefit the CFCRI. Road Hockey to Conquer Cancer is the Foundation’s newest fundraising initiative which will take place on October 1, 2011. According to Dr. Ben Neel, “Today, researchers are embarking on a new era of discovery, and events like Road Hockey to Conquer Cancer have a major impact on the resources needed by these scientists to collaborate on research in order to conquer cancer in our lifetime.”

How to Contact UsIf you have any questions about this report, please feel free to contact

us.

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For more information, please go to: pmhf.ca

Paul AlofsPresident & CEOThe Princess Margaret Hospital Foundation(416) 946-6573

Dr. Robert BellDr. Robert BellPresident & CEOPresident & CEOUniversity Health University Health NetworkNetwork(416) 340-4800 (416) 340-4800 x3300x3300

Sherri FreedmanSherri FreedmanVice President, Vice President, Development Development The Princess The Princess Margaret Hospital Margaret Hospital Foundation Foundation (416) 946-4547(416) 946-4547

Greg LichtiGreg LichtiAssociate Vice Associate Vice President, Major President, Major GiftsGiftsThe Princess The Princess Margaret Hospital Margaret Hospital FoundationFoundation(416) 946-2168(416) 946-2168

Health & Medicine

Campbell stewardship report 2011