Cancer Drug Development at The Princess Margaret

The Princess Margaret is well-positioned to be a leader in new drug development, and is already recognized for its expertise and accomplishments both in developing new compounds and in testing new drugs in carefully controlled trials.

The Princess Margaret embraces a culture of innovation, sharing and collaboration at all levels. The size of the organization combined with the clear focus and passion for a cure enable the operation to move with agility and coordination.  This expertise in sharing information and identifying efficient approaches to problems can be seen in the:
  • translational research excellence where new discoveries and understanding of the disease move from the research bench to the patient clinic and back again with speed and discipline without compromising patient safety
  • ability to form complementary partnerships with external organizations, including other academic institutions, commercial laboratories, and pharmaceutical companies
  • number of young scientists we train and provide fellowships for (many of whom go on to do drug development work in other countries and institutions)

Building on tremendous basic science research strength where many cancer targets are identified, our growth and investment in drug development has been focused in two areas:
  • Closing the gap between target identification and the pre-clinical phase by recruiting world-class chemists, investing in complex computer-aided design technology for drug development, and taking an equity position in a research facility in Shanghai
  • Developing a world-leading cancer drug testing operation where the most promising cancer drugs can be evaluated and made available to our patients

Robert and Maggie Bras New Drug Development Program

In the early years of the new millennium, Dr. Malcolm Moore of The Princess Margaret was treating a patient with gall bladder cancer by the name of Robert Bras.  Robert eventually succumbed to his disease in 2002 but not before having many long discussions with Dr. Moore about the slow progress in bringing new cancer drugs to needy patients.  Robert, who was a very successful businessman, decided with his wife Maggie to leave his mark by making a major donation to the nascent drug development work of Dr. Moore and the hospital.
 
Today, several years later, the Robert and Maggie Bras New Drug Development Program at The Princess Margaret is a top-tier drug testing facility that is the only non-U.S. site to receive both a phase I grant and a phase II contract from the U.S. National Cancer Institute.  The program now has the credibility and the international reputation needed to be chosen by pharmaceutical companies and large government agencies for testing the most promising new cancer drugs.  This is obviously a wonderful opportunity for patients as well as an endorsement of the people who run the program.

What makes a drug testing facility world-class?

Princess Margaret Hospital has many innate advantages for drug testing in that it is located in a large, multicultural city that serves a patient population with many different types of cancer.  The facility also has a strong reputation for basic science research through the Ontario Cancer Institute and strong academic ties to the University of Toronto. 
 
However, like most knowledge-based activities, doing drug testing well requires very experienced, skilled, focused and dedicated people.  The work of testing a new drug must be led by specialists who are part clinical doctor, part scientist, part pharmacist and part compassionate care-giver.  There are not many people with such credentials. The work is highly specialized and fraught with disappointment.  Only one in approximately 10 drugs that come forward for testing at Princess Margaret Hospital are considered safe and successful enough to move on to larger clinical trials (10 years ago, that ratio was closer to 1 in 20).
 
Dr. Moore and his team are focused primarily on Phase I and II testing where new drugs are being tested for the first time on humans.  These drugs are administered to relatively small numbers of patients (usually in the range of 5 to 20).  The patients are observed very closely to monitor all their reactions to the drug, both positive and negative.  In Phase I, the focus is on determining a safe and tolerable dose and schedule, while Phase II measures how effective the drug is at the right dose.
 
How can you tell when a cancer drug is working?  Dr. Moore and his team would respond that the answer is not straightforward.  While there are blood tests that can give some indication of drug efficacy, they are simply indicators.  MRIs can provide a reading on tumor size, and often patients will be biopsied at certain points in their treatment.  Judging and determining the efficacy of a cancer drug is the expertise that Dr. Moore and his team have been honing for the past five years.
 
Often doctors will observe that some patients respond well to a drug, while others do not. The challenge then is to determine what it is about those patients and their disease that makes them respond in a positive way.
 
When they are evaluating a new drug, Dr. Moore’s team also needs to be intimate with the current ‘standard of treatment’ and the efficacy of other approved drugs for the patient’s type of cancer.  At the end of the day, the drug being tested needs to surpass the bar set by other cancer drugs.  That includes having as few negative side effects as possible.
 
The trial team carefully tracks and compiles large amounts of clinical and laboratory data over the course of the study, and, at the conclusion, prepares a comprehensive report including their expert observations and recommendations.  This is all provided back to the sponsoring company or agency so they can make a decision on the future use of the drug. 
 
And finally, to build and maintain a world-class reputation in any field, experts must publish their findings and share their knowledge. The Bras Family Drug Development team publishes quickly in highly-regarded academic publications, and makes it a priority to share their intelligence with colleagues at PMH and in other drug development programs around the world. 

The Bras Drug Development Team
 
Dr. Malcolm Moore

Dr. Malcolm MooreDr. Moore is the Director of the Robert and Maggie Bras New Drug Development Program at Princess Margaret Hospital. His major interest over the past 10 years has been innovative drug development for cancer therapy, and he has been a principal investigator for many phase I, II and III studies in gastrointestinal and genitourinary cancer. He has been instrumental in the development of several agents that have subsequently been approved for clinical usage, including both gemcitabine and erlotinib in pancreatic cancer.
 
Dr. Moore is a member of the American Society of Clinical Oncology Program Committee, an executive member of the North American Gastrointestinal (GI) Intergroup, and chair of the National Cancer Institute of Canada GI committee. He has authored over 130 peer-reviewed publications and has given over 150 invited lectures worldwide.

Dr. Lillian Siu
 
Dr. Siu is a staff physician in the Department of Medical Oncology and Hematology and Director of the Phase I Program and Co-Director of the Robert and Maggie Bras New Drug Development Program at Princess Margaret Hospital.  
 
Dr. Siu’s major research focus is in the area of new anti-cancer drug development, particularly with respect to phase I trials and head and neck malignancies.  She is principal investigator of many phase I, II and III trials supported by NCI, NCIC and the pharmaceutical industry. 
Nationally, Dr. Siu has been the co-chair of the NCIC CTG Data Safety Monitoring Committee.  Internationally, she has been a member of the AACR International Membership Committee, the ASCO Head and Neck Cancer Scientific Program Committee, and the EORTC Protocol Review Committee.  She is the current Neuroendocrine Tumor Task Force Chair in the Gastrointestinal Intergroup Scientific Steering Committee.
 
Dr. Siu has published 100 peer-reviewed manuscripts in journals including Journal of Clinical Oncology and Clinical Cancer Research.  She is on the Editorial Board of Investigational New Drugs and Journal of Clinical Oncology

Dr. Amit Oza
 
Dr. Amit Oza is Co-Director of the Robert and Maggie Bras New Drug Development Program. He has been the principal investigator and co-investigator in phase I, II, and III trials for gynecological cancer and advanced colorectal malignancies. His research interests are focused towards the development, assessment and validation of new therapeutic strategies for cancer including molecular targeted therapies. 
 
Dr. Oza is Co-Chair of the Gynecology Site Committee of the NCIC Clinical Trials Group and represents NCIC CTG at the Gynecologic Cancer Inter Group. He has also been principal and co-author of numerous publications in major peer-reviewed journals such as Cancer Research, Journal of Clinical Oncology, Annals of Oncology, Investigational New Drugs and Clinical Cancer Research
 
Dr. Oza is a Fellow of the Royal College of Physicians of London and Canada. 
 
If you would like to read more about the Robert and Maggie Bras and Family New Drug Development Program and their fundraising activities, click here.

Ontario Cancer Institute (OCI)  

OCI is a world-class institute focused 100 percent on basic science research that will help us Conquer Cancer In Our Lifetime.  The chemistry involved in identifying lead compounds to defeat cancer targets is not work that OCI has traditionally been involved with, but the leadership team is determined to close the gap made as the pharmaceutical companies prefer to wait until drugs have successfully passed phase I and II testing.
This means the addition to the research team of medicinal chemists who are working with the molecular and structural biologists to create and synthesize drugs that will bind to and defeat the different types of cancer.
 
Dr. Lakshmi Kotra is one of this ‘new breed’ of chemist that is helping to fill the gap and enable OCI to develop new drug compounds and put them into trial for cancer patients. Dr. Emil Pai is a structural biologist and together, he and Dr. Kotra are putting their knowledge together and coming up with some very promising drug treatments that will soon be ready for clinical trials.
 
Dr. Emil Pai 
 
Dr. Pai is a senior scientist with OCI, and leads the Division of Structural and Molecular Biology.  His lab specializes in the use of X-ray crystallography to understand the molecular architecture of proteins. One of the proteins for which he and his team recently solved the three-dimensional structure, ODCase, was being studied for its potential in treating cancer. The compound also shows great promise in the treatment of malaria.
 
Dr. Pai has received the Premier’s Research Excellence Award and has held the NSERC Chair in Protein Crystallography. He has authored more than 140 scientific papers in the area of protein structure and function.

Dr. Lakshmi Kotra
 
Dr. Kotra is the Co-Director at the Centre for Molecular Design and Preformulations (CMDP) at the University Health Network. Dr. Kotra’s research program is an interdisciplinary science spanning computer modeling, synthetic chemistry and biochemistry. His research group has interests in cancer, infectious diseases, diabetes and related complications.
 
Dr. Kotra is currently leading the preclinical development of new compounds for malaria and cancer. 
 
Dr. Kotra has served on various provincial, national and international initiatives in the areas of drug discovery and development. He is a recipient of several awards including the Premier’s Research Excellence Award (2004-2009), the Rx&D Health Research Foundation Research Career Award (2001-06) and the GlaxoSmithKline/Canadian Society for Pharmaceutical Sciences Young Investigator Award (2003). Dr. Kotra has authored/co-authored over 90 publications including peer-reviewed scientific papers, expert review articles and book chapters.  He has seven patents/patent applications and has delivered more than fifty invited talks.

One of the keys to bringing the biologists and the chemists together and getting them ‘on the same page’ is something called the Visualization Centre.  In this centre, scientists ‘visualize’ targets—usually proteins—in 3-dimensional form with the help of special 3D glasses (see the photo story below of the Lab). Then they use computer-aided design software to ‘design’ drugs that ‘lock on’ to the targets.

Shanghai-Toronto Institute for Health Research

The Shanghai-Toronto Institute for Health Research is a joint initiative formed in 2005 between University Health Network and two member institutes of the Chinese Academy of Sciences—the Institute of Health Sciences and Shanghai Institute of Organic Chemistry.
 
Dr. Chris Paige, Vice President of Research for University Health Network, who spearheaded this partnership, refers to it as a ‘brain gain’ in that it provides UHN with access to a large pool of medicinal chemists who are in short supply in Canada. With the help of this partnership, OCI/PMH is well-positioned to fast-track some of its promising lead compounds into clinical trials.

Commercial Partnerships and Drug Recycling

Dr. Aaron Schimmer is an example of what can be achieved when you combine an academic education that includes both a medical degree and a PhD in molecular biology with a knowledge-rich environment like OCI, plus a busy clinic where you can continue to see leukemia patients one day a week.  ‘Translational research’ is about fast-tracking findings from the laboratory to the clinic, and taking observations from the clinic and feeding them back to the basic scientists.  Dr. Schimmer’s lab and the academic medicine he is involved in epitomizes the term translational research.
 
He has several promising compounds in clinical trials being conducted at The Princess Margaret.  His lab identified XIAP as an important target for drug development.  XIAP antisense (an XIAP inhibitor) has the ability to kill cancer cells without damaging normal cells.  It is being used to treat both acute and chronic leukemia, and shows good potential with other types of cancers such as prostate.
 
What is especially encouraging to see in the work being done by Dr. Schimmer is the partnerships he has developed with industry.  In the case of XIAP antisense, he has teamed up with Aegera Therapeutics in Montreal.  They also have expertise in this area, and have the facilities to manufacture the compound efficiently. 
 
Dr. Schimmer is also a strong proponent of what he calls ‘drug recycling’ where off-patent drugs are screened and tested to see what effects they have on cancer targets.  One such drug, clioquinol, is being formulated into ‘pill form’ by PharmaScience in Montreal in preparation for a clinical trial planned within the next year.  This approach to drug development can be successful and highly efficient, as the toxicity and side effects related to the use of the drug in humans is already documented and well-understood.
 
Dr. Aaron Schimmer
 
Dr. Schimmer is a staff physician in the department of Hematology/Oncology at the Princess Margaret Hospital.  He is also a scientist at the Ontario Cancer Institute and the head of Experimental Hematology at the University of Toronto.
 
The Schimmer lab is interested in chemical biology and drug discovery with a focus on the cell death pathway. Using automated and robotic equipment, chemical compounds are screened to identify chemical probes and then used as tools to better understand biological pathways.  In addition, these molecules serve as leads and prototypes for new therapeutic agents for the treatment of malignancy.
 

Dr. Schimmer is the author of over 55 papers, holds three patents, and is the principal investigator on five clinical trials of new agents targeting the cell death pathway.  He has received over 30 awards and honours for academic achievement including an award from the Ontario Ministry of Research and Innovation for the best young scientists.  In 2007, he was named one of Canada’s Top 40 Under 40.

The Campbell Family Institute for Breast Cancer Research

The Campbell Family Institute for Breast Cancer Research (CFIBCR), under the leadership of the legendary Dr. Tak Mak, houses all of the breast cancer research taking place at The Princess Margaret/OCI.  
 
The team is focused primarily on breast cancer but has spent some time looking for lead compounds for ovarian cancer.
 
Dr. Mak believes strongly that the various scientists—biologists and chemists—working on drug development need to be engaged and collaborating closely in order to gain the understanding of the disease needed to implement effective therapies.
 
Thanks to critical funding raised by the Weekend to End Breast Cancer, Dr. Mak has built a multi-disciplinary team of chemists, molecular biologists, medical oncologists and immunologists that has been able to develop lead compounds for new breast cancer targets and take them right to the preclinical testing phase.