Many years ago, it was widely believed that cancers were similar across patients, and that all patients with cancers of the same type should be treated with similar treatments. After decades of scientific discovery and clinical observation, however, it became increasingly clear that this was indeed not the case. For example, patients with lung cancers that appear similar by standard microscopic tests can arise through entirely different sets of genetic mutations, and thus need to be treated differently. The same is true for breast cancer, colon cancer, and likely all different cancer types.

The difference amongst each individual cancer lies within the DNA. Every patient has a unique combination of genetic mutations, causing their tumours to localize, grow, metastasize and respond to therapy differently. Yet understanding the role that each gene plays in driving cancer behaviour remains an arduous and complicated task for researchers worldwide.

At The Princess Margaret, however, we are getting closer. Every day, our researchers are decoding new genetic mysteries that offer new insights into cancer biology and behaviour. This is taking us the extra mile in Personalized Cancer Medicine – by understanding the role of genes in driving the development of tumours, our clinicians will be better equipped to predict tumour behaviour, and optimally select individualized therapies that will be best suited to each patient’s genetic makeup.

Molecular profiling is a complex regimen of testing, whereby cancer cells are examined for genetic mutations. The Princess Margaret has the expertise required to interpret molecularly profiled tumours, and is making increasing use of this personalized approach in patient diagnosis and treatment planning.

In March 2012, under the leadership of Dr. Lillian Siu, Dr. Philippe Bedard, and Dr. Suzanne Kamel-Reid, The Princess Margaret launched the Integrated Molecular Profiling in Advanced Cancers Trial (IMPACT) – the first comprehensive molecular profiling program in Canada.

Through the clinical trial, tumour tissues from consenting patients are obtained (from prior biopsies or surgical samples) and tested for hundreds of cancer-associated gene mutations simultaneously. The genetic profile for each patient’s tumour is then uploaded to the patient’s electronic health record, and is discussed at monthly multidisciplinary IMPACT Tumour Board Meetings. The primary objective of IMPACT is to provide the treating clinician with molecular profiling information, which can be used to match patients with drugs in approved usage or clinical trials.

Given the tremendous success of IMPACT, the Community Oncology Molecular Profiling in Advanced Cancers Trial (COMPACT) was opened later that year. The purpose of this trial is to expand our molecular profiling expertise and services beyond the walls of The Princess Margaret into Ontario. Patients receiving cancer care at select hospitals can be referred to the COMPACT Clinic at The Princess Margaret by their community medical oncologists, where they can have their tumours profiled free of charge.

Since March 2012, 2,500 patients with advanced cancers have had their tumours successfully profiled in both IMPACT and COMPACT. Many of these patients received new therapies based on the findings. These trials are offering new hope to patients in Ontario, and are contributing to an expansion of global knowledge in cancer genomics.

The Princess Margaret plans to use the knowledge gained from IMPACT and COMPACT to begin implementing this technology for routine patient care at the time of diagnosis, rather than just in the clinical trial setting, and to enable use of these technologies in patients earlier in their cancer treatments. Our goal is to develop effective approaches to genetically profile all cancers that can benefit from new targeted agents.

Molecular profiling allows clinicians to target therapies to patients’ particular genetic make-up – which has already generated life-saving outcomes. However, the most frustrating part for our clinicians and researchers is that we cannot reverse or fix the cancer-causing mutations in our DNA – they are there to stay.

While this may be true, it has been shown in the laboratory that many cancer genes are turned on or turned off through epigenetic changes, rather than mutations. Epigenetics refers to changes in gene expression that do not involve alterations to the underlying DNA sequence (hence the term “epigenetics”, which literally means “above genetics”). Every cell in your body contains the exact same copy of DNA. Cells differentiate into their specialized forms (i.e. skin cell, muscle cell, brain cell, mammary cell) depending on which genes are epigenetically turned “on” or “off.” We now understand that this machinery can go awry in cancer, causing faulty gene regulation that leads to unrestricted cell growth and tumour formation. These epigenetic changes are regulated by many factors, but offer a significant therapeutic advantage because they have the potential to be reversed.

Our researchers have recently discovered that by altering cellular biochemistry, we can ultimately “reset” the epigenome to re-establish normal gene regulation. In doing so, influential leaders in the field, such as Senior Scientist Dr. Cheryl Arrowsmith, believe that we will be able to reprogram a cancerous cell into a benign one. She is leading screening efforts where libraries of drugs that target epigenetic players are tested against several different cancer types in pre-clinical systems to identify novel compounds capable of reprogramming a cancerous cell.

The Princess Margaret has actively recruited a world-leading group of new epigenetics experts who are researching how epigenetic changes cause cancer, and how they can be targeted. For example, since joining The Princess Margaret in 2012, Dr. Daniel De Carvalho has discovered a new mechanism of action for Decitabine. He has discovered that this epigenetic drug mimics a viral infection, inducing an antiviral response against the cancer stem cells, the root cause of cancer. In this manner, the drug can activate the immune system to fight cancer as an infectious disease, potentially improving the efficiency of cancer immunotherapy. Based on Dr. De Carvalho’s discovery, clinical trials are now being planned at The Princess Margaret to combine epigenetic therapy with immunotherapy in order to improve both treatments.

Dr. Mathieu Lupien, another recent recruit at The Princess Margaret, has also made major strides by combining his expertise in epigenetics and bioinformatics to bring new understanding to the genetic and epigenetic drivers that cause breast cancer.
The integration of our knowledge of the cancer genome and epigenome are providing new and more tangible links that are revealing new insights into the development of tumours and patient treatment. However, these tests alone are not sufficient to yield improvements in therapy – they require robust computing power to analyze, manage and make the genomic information comprehensible for patient outcome prediction and treatment selection.

At The Princess Margaret, we have a strong team of individuals who are committed to big data management. These scientists, such as Dr. Igor Jurisica, Dr. Daniel De Carvalho, Dr. Mathieu Lupien, Dr. Cheryl Arrowsmith are focused on the development of algorithms and innovative computational approaches to best characterize tumours using high throughput genomic and epigenetic data. They are working tirelessly to build a catalog of genomic datasets generated from the aforementioned clinical trials, and to develop an efficient informatics system to annotate genomic features (mutations, gene fusions, etc.) with clinically relevant information.

By matching the genetic mutations particular to each patient’s cancer to treatments that have shown promising results for those mutations, The Princess Margaret plans to improve survival rates and quality of life for our patients.

We envision a day when all cancer patients across Canada will receive comprehensive genetic sequencing as a routine part of their cancer care. We need your support to achieve new knowledge standards that will further our capacity to explore genomic data through Personalized Cancer Medicine, and maximize the benefits from molecular profiling initiatives.