The molecular dissection of aggressive B-cell lymphoma

Aggressive B-cell lymphomas are the most common form of lymphoma and ~50% of patients are cured with modern treatments. However, the outcomes for patients whose disease is not cured are dismal with ~10% of those patients alive at 5 years. This shows that these lymphomas, although grouped together on the basis of what they look like down the microscope, represent clusters of different lymphoma groups. A better understanding of the 'molecular wiring'of these lymphomas is critical to identify patients at high risk of resistant lymphoma and providing better treatments.

This project will provide a rational new way to group lymphomas based on differences in the molecular wiring. This will be acheived by performing and analysing genomic sequencing on a large number of aggressive B-cell lymphomas brought together through an international lymphoma consortium. Further, tumour samples will be analysed from the time of diagnosis and when the lymphoma relapses to see whether this molecular wiring remains stable or changes with treatment. It is anticipated that this major step forward in our knowledge will be translated into new tools for matching a patient's lymphoma to the correct treatment and improving patient outcomes. 

Predictors of immunotherapy benefit in patients with microsatellite stable metastatic colorectal cancer

Introduction: Colorectal cancer (CRC) is the second most common cancer. Once metastatic, patients are generally incurable and receive treatment to prolong survival. Immunotherapies use a patient's immune system to attack their cancer. These treatments are effective in CRC patients with microsatellite instability (MSI). Unfortunately, 95% of patients lack MSI and are called microsatellite stable (MSS). This group usually doesn't respond to immunotherapy and we need to explore why.

Specific Aims:  

We aim to identify:

  1. why some MSS patients benefit from immunotherapy, and  
  2. what can we target to activate immune cells in patients who don't respond to immunotherapy.  

Methods: We will investigate how the immune system and tumors interact in patients from two clinical trials. These trials evaluated immunotherapy in MSS CRC. Blood and tumor samples from these trials will be tested to identify features that predict response. These results will then guide the creation of new clinical trials with immunotherapy for CRC using our findings.  

Significance: Immunotherapy does not work for the 95% of CRC patients who are MSS. We will identify how to activate the immune system in CRC patients with MSS so they too can benefit from immunotherapy.   

Genomic Organization At Large (GOALS) predicts aggressive biological behaviour in prostate and breast cancers

Prostate cancer is the most commonly diagnosed form of cancer for men in North America. Prostate cancer deaths have been in decline since the mid-1990s after the discovery of Prostate-Specific Antigen (PSA), which, when used for screening, results in a steep increase in the number of early diagnoses. A large percent of these PSA-detected cases do not express clinically, are slow growing, and do not require treatment, and therefore do not contribute significantly to overall mortality. Conversely, some slow growing cancers are very aggressive and result in death. 

Treatment for prostate cancer can have significant negative impact on quality of life and healthcare costs, and should only be utilized when the cancer itself is likely to be fatal. Treatment recommendations are based on PSA levels , clinical staging, and Gleason scoring. Active surveillance is a preferred approach when the disease is low-risk and small. Significantly, 5-10% of individuals with low-risk disease treated up-front experience poor outcomes. Additionally, >40% of active surveillance patients may progress and require treatment – and half of those will ultimately fail treatment. The effectiveness of active surveillance is limited without a clinical tool to accurately assess risk of progression.

In small pilot studies, Dr. MacAulay’s lab has demonstrated the ability to predict aggressive behaviour in prostate cancers with >80% accuracy using a specific imaging technology that uses the measurement of GOALS in individual cells along with the cell’s position within the patient’s tissue.

DNA-PK inhibitors for use in combination with radiation therapy

Half of all cancer patients receive radiation therapy, impacting about seven million people worldwide each year. Enhancing tumour sensitivity to radiotherapy would have a far reaching and significant impact on patients with many kinds of cancer. 

Funded by a $5M grant from the Wellcome Trust, Dr. Minchinton’s lab has developed novel inhibitors of DNA-repair that can dramatically enhance the elimination of cancer cells with radiotherapy. He will improve his previously developed small molecule inhibitors of a DNA repair protein by developing therapeutic regimens to optimize their use for maximum anti-cancer benefit and minimize their effect on normal tissue. The overall aim of the project is to identify optimized inhibitors suitable for clinical candidate evaluation.

After the preclinical work, Dr. Minchinton will seek corporate partners to take the candidate into full clinical evaluation involving Phase I through III clinical trials. DNA damage repair mechanisms as a route to improved therapy could have a significant impact on the effectiveness of radiotherapy for cancer treatment.

Canada-wide comparison of patient reported outcomes by complexity of radiotherapy technique for bone metastases

Radiotherapy (RT) is a common and cost effective treatment for patients with painful bone metastases (BoM). Complex and lengthy RT courses are increasingly used for BoM, despite substantial evidence and Choosing Wisely Canada guidelines recommending the use of single fraction RT (SFRT) over lengthy courses. Reluctance to adopt SFRT is based on lack of evidence of its effectiveness in patients ineligible for trials, such as those with poor performance status and BoM complicated by fracture or neurological compromise. Unfortunately, guidelines recommending SFRT use in Ontario did not lead to a durable change in practice. Therefore, evidence of SFRT’s effectiveness in a broad population is necessary, including patients ineligible for trials. Comparison of SFRT to lengthier and complex techniques, such as intensity modulated RT (IMRT) and Stereotactic Ablative Body RT (SABR), will build a population-level evidence base to support increased prescription of SFRT in BC and across Canada.

My research team has demonstrated it is feasible to collect and use Patient Reported Outcomes (PRO) on a population scale in BC. We used these PRO to demonstrate that pain improvement is similar between SFRT and weeklong RT courses, the results of which have led to increased prescription of SFRT across all six BC cancer centres. This gained international attention and the Canadian Partnership for Quality Radiotherapy (CPQR) has since invited me to lead PRO collection across the Canadian RT community. Under the current proposal, we will apply a similar integrated knowledge translation (iKT) approach used in our BC-based research to demonstrate evidence for SFRT on a population-level.

Our primary KT goal is to use our research results to increase evidence-based prescription of SFRT. As we did in BC, we will integrate nursing, radiation therapy, and oncology into all stages of PRO collection and comparison between treatments, with subsequent educational outreach and centre-specific interactive small group discussions of research results. We will engage with various levels of health government, leverage our existing relationship with CPQR and the Canadian Partnership Against Cancer, and create an advisory committee of key stakeholders including policy makers, oncologists, and allied health professionals from each province. Impact evaluation of end-of-grant KT activities will focus on reach, collaboration, practice change indicators, and behaviour changes to increased use of SFRT.

 

Towards individualized treatment for pancreatic ductal adenocarcinoma (PDAC)

Pancreatic cancer kills almost 5,000 Canadians each year and if progress is not made to improve outcomes, the annual number of deaths will double by 2030. In 80% of patients, the cancer has spread at the time of diagnosis, and is not operable. Most of these patients die within one year due to the lack of effective therapies and the fact that clinicians have no clear guidance on which existing treatment option would work best for individual patients.

Precision medicine in cancer has gained a lot of attention in the last decade, as it may provide the best approach to treating tumours on an individual basis. Cancer treatment does not benefit from the one-size-fits-all approach because individual tumours, even if affecting the same organ, are biologically different, which can impact their response to treatment. Tumour subtyping, a method by which scientists identify the unique characteristics of individual tumours, is critical for precision medicine enabling personalized treatment based on the tumour's specific biological traits. Advances in the understanding of cancer subtypes have revolutionized treatment in multiple cancers, but we have yet to uncover pancreatic cancer subtypes that can help with treatment decisions.

Our goal is to define clinically meaningful pancreatic tumour subtypes, and study their impact on tumour aggressiveness and response to treatment. These findings will be rapidly translated to the clinic to have immediate impact on treatment selection for patients. We will perform detailed genetic and molecular analysis of patient tumour samples to investigate the distinct molecular characteristics. The patients will be enrolled in a clinical trial at the BC Cancer Agency and will be provided with detailed and cutting edge analyses of their tumours to help the clinical team guide further therapy decisions. 

Currently, over 90% of diagnosed pancreatic cancer patients are not expected to survive five years. Our program has the potential to dramatically change the trajectory of pancreatic cancer and improve outcomes for thousands of Canadians diagnosed with the disease.

Determining the virulence determinants of Fusobacterium nucleatum to define diagnostic and therapeutic targets for colorectal cancer

A substantial portion of the cancer burden worldwide is attributable to infectious agents (viruses or bacteria). Some of these can directly cause cancers, others can facilitate cancer development, and the rest may have no causative role but their existence can indicate the presence of a cancer or risk of developing one.

Recently, Fusobacterium nucleatum, a bacterium present on mucosal surfaces, has been found to be highly elevated in a subset of colorectal cancers. F. nucleatum is an invasive bacterium that can cause acute oral and gastrointestinal infections and can act as a pro-inflammatory agent, thus it is a reasonable candidate for having a facilitating role in tumorigenesis. However, F. nucleatum is also well recognized as a benign resident of mucosal surfaces in the absence of pathology. The reason why F. nucleatum may in some cases be pathogenic and at other times an apparently benign, commensal organism is not yet completely understood.

The overall goal of this study is to identify gene(s) associated with F. nucleatum virulence, and to determine how expression levels of these genes are modulated during infection using RNA-Seq. The Canadian Cancer Society estimates that currently 12 percent of all cancer deaths in Canada are attributed to colorectal cancers; a tendency toward late diagnosis indicates a dire need for simple strategies to help detect colorectal cancers early. The finding that F. nucleatum is strongly associated with a significant number of colorectal cancers cases raises the possibility of developing a simple diagnostic pre-screen for the disease, enhancing early detection rates. The proposed work will identify the F. nucleatum genes that are associated with the disease, creating a signature that will markedly increase specificity of new screening tests. Moreover, this study will indicate how pathogenic F. nucleatum strains cause disease, dramatically increasing our knowledge of this enigmatic bacterium and its interactions with host cells that lead to oncogenesis.

Armed with this new knowledge, it will be possible to develop novel diagnostics, and create new tools such as vaccines to combat, and even prevent, infection. Knowledge translation activities for this study will include presenting results at conferences, writing papers and building on the network between the BC Cancer Agency and our anaerobic bacteriology collaborators at the University of Guelph.

Toward personalized immunotherapy: defining mechanisms of immune suppression across the molecular subtypes of ovarian cancer

Ovarian cancer affects approximately 1,700 women per year in Canada. Current treatment involves surgery and chemotherapy, which is initially effective in most cases. However, most patients relapse with chemotherapy-resistant tumors within a few years of treatment; this highlights the urgency for new, effective treatment strategies. Encouragingly, the immune system has a strong influence on survival in ovarian cancer. Tumors that are densely infiltrated by T cells (a type of immune cell) are linked to improved prognosis. However, a large proportion of patients lack dense T cell infiltrates. Instead, T cells are trapped in the surrounding stromal regions of the tumor and fail to make direct contact with tumor cells.

I hypothesize that the infiltration of T cells is inhibited by suppressive mechanisms in these stromal regions and with better understanding, these mechanisms can be reversed by immunotherapy. One objective of this project is to determine whether T cells that are trapped in stromal regions are capable of recognizing tumor cells. If so, then these T cells have the potential to recognize and eradicate tumors. Another objective is to identify and then block the signals by which stromal cells carry out suppressive functions. I will assess the effects on T cell infiltration and tumor regression following this blockade. This project will facilitate the development of new treatments that release T cells from the suppressive effects of stroma to launch more powerful attacks against ovarian cancer and related malignancies. The possibilities of using off-patent fibrosis drugs for cancer treatment will be investigated; this might result in an inexpensive, effective new form of immunotherapy, thus reducing costs and increasing the number of patients benefitting from these approaches. Since the BC Cancer Agency’s Deeley Research Centre (BCCA-DRC) is able to perform clinical trials, the work can be directly implicated into clinical research.

This research will be presented at both national and international conferences and published in international peer-reviewed journals. The BCCA-DRC’s clinical trials program will also provide me with ongoing opportunities to speak to patient support groups, clinicians, and lay audiences at forums focused on education, awareness and philanthropy.

Understanding and exploiting genome instability in cancer

Cancer is caused by specific DNA mutations that can arise spontaneously over time. Conditions that increase DNA damage or inhibit DNA repair can promote cancer. Genetic factors that affect a cells’ ability to protect and repair DNA promote cancer formation by causing so-called genome instability, defined as an increase in the frequency with which mutations are passed to daughter cells. Genome instability is a double-edged sword: it can contribute to cancer formation, but it can also help with treatment by sensitizing cancer cells to anti-cancer chemotherapy or radiation treatments.

This program studies how defective RNA molecules may lead to genome instability by binding to DNA. If these hybrid DNA:RNA structures accumulate they can lead to DNA damage, increasing the chance of mutations in the DNA. Focus areas include cancer-associated mutations that lead to an increase in DNA:RNA hybrids, determining how and where those hybrids form, and how they might form the basis of new anti-cancer drugs.

The program also investigates how proteins respond to DNA damage. When a protein is made, it must fold into a three-dimensional structure and assemble with other biological molecules to perform its function. In response to DNA-damaging stress, cells can promote survival by halting this process and sequestering newly-made or damaged proteins in a regulated way. Characterizing the network of protein changes that occurs after DNA damage could help with understanding how cells cope with ongoing genome instability or treatment with chemotherapies that damage DNA.

Mutant cell-free DNA as a non-invasive blood test to monitor pancreatic cancer

Close to 5,000 Canadians are diagnosed with pancreatic cancer every year and it is the fourth most common cause of cancer-related deaths in Canada. Unfortunately, a majority of these patients die within a year of their diagnosis, due in part to late diagnosis and tumour resistance to chemotherapy. In addition, most patients who are successfully treated eventually recur and succumb to the disease.

There is a need for reliable blood tests for more routine diagnosis, monitoring treatment response, and detecting tumour recurrence in pancreatic cancer patients. We seek to develop such tests using cell-free DNA in the blood. Mutant forms of cell-free DNA that originate from tumours can be detected in the blood of patients with pancreatic cancer, and this project will explore how we can use it to:

  1. Diagnose pancreatic cancer earlier
  2. Detect cancer recurrence earlier
  3. Identify patients whose tumours do not respond to chemotherapy in order to help guide treatment decisions

We will collect blood from patients who have undergone surgical removal of pancreatic cancers and follow their progress over two years to examine whether we can detect cancer recurrence by monitoring the presence of mutant cell-free DNA after surgery. We will also collect blood from patients with advanced stage pancreatic cancer who are undergoing treatment to explore whether changes in mutant cell-free DNA levels predict whether their tumours respond to chemotherapy.

In these ways, a non-invasive blood test will help to improve quality of life and optimize treatment for thousands of Canadians diagnosed with pancreatic cancer.