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.
Staphylococcus aureus infections are a leading cause of healthcare and community associated infections worldwide. Some strains of the pathogen have developed the ability to resist most of the classic antibiotics including penicillins and cephalosporins. There is an urgent need to develop new drugs that work against these resistant strains including methicillin-resistant Staphylococcus aureus, or MRSA.
A promising new set of antibiotic targets has recently been proposed involving the wall teichoic acid biosynthetic pathway of Gram positive pathogens. These long, acidic polymers are synthesized in the cell, transported out and ultimately attached to the growing outer cell-wall protective layer, a process essential to virulence and survival of MRSA in the infected host and in the environment. Small molecule inhibitor screens have identified compounds that block the action of one of these components, TarG/H, an intimately associated pair of membrane localized proteins that transport teichoic acids from the cytosol to the outer cell-wall layer. Learning more about the structure and function of the TarG/H transporter and its partner proteins in the pathway could allow scientists to design drugs that work much more effectively and specifically against Gram positive pathogens such as MRSA.
The goals of my research are therefore to solve the three-dimensional structure of the purified TarG/H transporter in native, mutant and inhibited forms at atomic resolution using X-ray crystallography and secondly, to characterize the molecular details, using single particle cryo-electron microscopy, of how TarG/H binds with other proteins involved in making and transporting the teichoic acid chains to the outer regions of the cell. The ultimate goal of this work is to enable the structure-guided design of potent new antibiotics that block TarG/H action and MRSA virulence.
Asthma is a complex disease caused by a combination of genetic, epigenetic and environmental factors.
Although several studies have attempted to identify the specific genes associated with asthma, the underlying genetic mechanisms are still unclear. Genomic imprinting, an epigenetic phenomenon that occurs early in life whereby only one gene copy is active and the other parental copy is fully methylated and hence inactive (“parent-of-origin effects”), may be involved.
I performed the analysis of the first large-scale genome-wide association study (GWAS) of parent-of-origin effects in asthma on data collected from three Canadian family-based studies/cohorts. Preliminary results strongly suggest the involvement of long non-coding (lnc) RNA.
lncRNAs are known to be involved in genomic imprinting. I hypothesize that lncRNAs identified from the parent-of-origin effects in asthma are involved in imprinting.
Due to their length and low information density, lncRNA regions are very time- and cost intensive to confirm and study. I will develop a hierarchical algorithm that will automate the selection of lncRNA regions and specific sites to investigate for DNA methylation.
The ability to select important lncRNA regions in an efficient and automated manner will result in increased efficiency for researchers, and will save time, materials and personnel costs. The selection algorithm will be added to our collection of web-based tools on the Genapha website and will be widely used by researchers interested in genomic regulation.
Streptomyces bacteria are the source of nearly half of our clinically used natural antibiotics. Production of bioactive compounds is usually linked to complex networks of signal-sensing proteins that regulate genes. How do these complex systems come together? Recent advances in molecular biology provide the tools to uncover the detailed mechanisms that underlie the evolution of vast regulatory networks that create complex biological systems.
This project will examine the molecular mechanisms that allow two regulatory proteins that arose from a single duplicated gene in Streptomyces coelicolor to regulate distinct and critical components of sporulation, quorum-sensing, and antibiotic synthesis.
By using a combination of ancestral sequence reconstruction and experimental protein evolution, this project will explore how these proteins took up new regulatory roles, resulting in the current system. Furthermore, we will recreate the intermediate steps along this evolutionary trajectory, in order to discover how the functions of these essential genes were rapidly separated by evolution. Finally, using a system of experimental laboratory evolution, we will alter these proteins to more effectively regulate their targets in an attempt to accelerate antibiotic production.
Ultimately, we will map out some of the ways in which new regulatory proteins can evolve through duplication and modification of genes for existing regulatory proteins. We will also aim to provide new mechanisms that can accelerate the production of antibiotics for clinical use.
Michael Smith Foundation for Health Research/Pacific Alzheimer Research Foundation Scholar Award
Frontotemporal dementia is a progressive neurodegenerative syndrome, and the second most common cause of young-onset dementia after Alzheimer’s disease. Members of our team recently reported that loss-of-function mutations in the gene for a protein called progranulin cause 25 percent of frontotemporal dementia cases. Of these mutations, 30-40 percent are “nonsense mutations” that act as stop signs to prematurely end a process required to produce normal progranulin. When progranulin production ends too early, it leads to a shortened protein that cannot carry out the normal brain functions, eventually leading to dementia in the sixth decade.
The goal of this project is to investigate small molecule combinations that can bypass the abnormal “stop sign” in the progranulin gene, increasing the normal production of this important protein. The small molecule combinations will be refined and optimized to find the most effective combination. This approach, also referred to as “suppression of nonsense mutations”, offers the possibility of developing a new drug for patients with frontotemporal dementia cause by a progranulin mutation. The team also plans to develop a mouse model of frontotemporal dementia to test the small molecule combinations in a living organism.
The long-term goal of the project is to bring new drugs for frontotemporal dementia into clinical trials. An effective therapy would alleviate the devastating impact of dementia in many patients and their families, in BC and beyond.
End of Award Update
Source: CLEAR Foundation
We studied frontotemporal dementia (FTD) with the aim of developing novel drugs for this devastating condition. A subset of FTD patients have a genetic mutation that leads to reduced levels of an important protein called progranulin. Our project aimed to develop a drug that could counteract this genetic mutation. We used brain cells cultured in a dish to test new drugs and found a known antibiotic to have properties that could increase progranulin in this model.
This work laid the foundation for ongoing research to develop drugs to increase progranulin in patients with certain forms of FTD.
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.
In Canada, cancer is the leading cause of disease-related death in children beyond the newborn period. Each year, more than 3,000 Canadian children, adolescents, and young adults are diagnosed with cancer. Childhood cancer survivors with secondary cancers in adulthood are the sixth most common form of adult cancer, and late effects of cancer treatment are estimated to cost $1 million per child over their lifetime.
An improved understanding of disease and treatment mechanisms at the systems level could improve our ability to treat cancer. This project addresses two fundamental questions in pediatric cancer biology by integrating advanced protein analysis of patient tumor biopsies with cell and computational models:
- Can we identify new drug and diagnostic targets for difficult-to-treat and relapsed cancers?
- How can we improve treatment specificity for late effects?
This project focuses on changes in proteins produced by cells with DNA mutations associated with cancer. A single gene can give rise to a whole spectrum of variant and modified proteins, or "proteoforms", through a process called post-translational modification. This process can happen differently for genes that bear mutations associated with cancer, giving rise to a noticeably different panel of proteoforms.
This altered pool of proteoforms is a potential source of cancer diagnostic markers and cancer drug targets. The protein experts in this project team aims to work with the genomics experts at the Child & Family Research Institute, Genome Sciences Centre, and BC Cancer Agency to synergistically study next-generation signature-based biomarkers, drug targets, and innovative drugs.
The ultimate goal of the project is to contribute to improved quality of life for childhood cancer survivors, reduce the socio-economic burden, and add to treatment options for children with cancer.
Uncontrolled bleeding is a leading cause of death worldwide. Specifically, postpartum hemorrhage leads to maternal death in 1-2 percent of all births in low-resource settings, while hemorrhage due to trauma is the largest killer of young people worldwide. Conversely, undesired clotting, or thrombosis, is a leading killer of Canadians because it causes strokes and heart attacks.
New drugs have led to advanced treatments for thrombosis and hemorrhage. Attaching the drugs to carrier materials that target sites of damaged blood vessels would further improve the treatments. Biological materials that target damaged blood vessels already exists in nature, providing a guideline for developing improved targeting materials: platelets and blood clots adhere selectively to injured vessels to stop bleeding.
This project will investigate the components and mechanisms that cause blood clots to selectively adhere to injured blood vessels. It will also use these findings to explore ways to engineer new materials that mimic these properties to target drugs to damaged blood vessels.
One material we recently developed self-propels through blood flow and deep into wounds to deliver drugs that help stop bleeding. It was highly effective in large animal models of fatal hemorrhage by locally delivering pro-coagulants. Our next step is to conduct preclinical tests toward developing a clinical trial for postpartum hemorrhage.
The project aims to produce a treatment for postpartum hemorrhage in order to save the lives of new mothers, and to contribute to broader prevention and treatment of hemorrhage and thrombosis.
Epidermal Growth Factor Receptor (EGFR) is a key regulator of cell proliferation and a driver oncogene in several tumors. Many cancers have constitutively activated EGFR which leads to excessive signalling. Inhibition of EGFR using erlotinib or gefitinib significantly improves survival in patients with Non Small Cell Lung Cancer (NSCLC) while panitumumab and cetuximab are currently used in colorectal and head and neck cancer. Despite good initial responses to these drugs, the patients develop resistance and eventually die of recurrent disease. EGFR inhibitors induce stress responses that promote emergence of acquired resistance.
We identified Heat Shock protein 27 (Hsp27), a stress induced chaperone protein correlated to treatment resistance in several tumors, as a mediator of resistance to erlotinib in NSCLC. Hsp27 becomes phospho-activated after erlotinib and helps stabilize EGFR. We developed the Hsp27 antisense inhibitor OGX427 which can block the adaptive survival response and enhance the activity of erlotinib and other anti-cancer drugs and now in phase II clinical trials in lung, pancreas, bladder and prostate cancers. While the activity of OGX427 is promising, a more potent and orally active inhibitor may improve cancer control; however small molecule inhibitors are difficult to develop because of the complex structure of Hsp27.
Using a series of drug screening assays, we identified a new drug, VPC27, that functionally inhibits Hsp27 with a good tolerability profile in mice studies. The aims of this project are: a) to compare the activity of VPC27 and OGX427 on tumor proliferation/survival in different EGFR dependent solid cancers alone or in combination with EGFR inhibitors; b) to define the molecular mechanisms that link Hsp27 with resistance to EGFR inhibitors, focusing on kinases and phosphatases proteins that regulate the phosphorylation and dephosphorylation of Hsp27 and EGFR.
These studies aim to build upon two strategies that are revolutionizing the treatment landscape in cancer: the use of molecular-targeted agents inhibiting driver oncogenes and the inhibition of adaptive responses that support development of resistance. Co-targeting treatment-induced adaptive responses mediated by Hsp27 can sensitize cancer cells to EGFR inhibitors and improve the efficacy of these drugs. Moreover, understanding mechanisms by which Hsp27 regulates EGFR activity is important to identify new molecules that could be used as new targets in cancer therapy.
Acute myeloid leukemia (AML) is a cancer in which blood cells grow out of control. Blood cells have to suffer at least two mutations to become cancerous: one to make them grow faster, and another to stop them developing normally. However, even with whole genome sequencing, in some patients we have been unable to find both mutations using existing methods, and we need to look deeper.
MicroRNAs are one place we can look. These are small pieces of RNA which reduce the production of proteins by targeting specific messenger RNAs. We know that cancers tend to have more or less of some microRNAs, and that many of these play important roles in cancer biology. However, whole-genome studies have mainly looked at the amounts of well-known microRNAs, without looking deeply at mutations of the microRNAs themselves, which can completely change their targets. Smaller studies have shown that microRNA mutations (as well as normal variations between people) can be important drivers of cancers, but nobody has investigated these at the genome-wide scale.
I will examine mutations of microRNAs in the genomes of around 200 AML and myelodysplastic syndrome patients. I will measure the effects of each mutation on messenger RNA levels. I will then look especially in patients in which two driver mutations could not be found to see whether any microRNA mutations could be oncogenic. The results will increase our understanding of the biology of AML, thereby leading to new research into improved therapies. They will also improve our ability to diagnose AML, which will give more information to doctors and patients making difficult decisions on treatments. After analysing our local dataset, I intend to similarly analyse all cancers in the Cancer Genome Atlas (TCGA) data set. Since the microRNA sequencing for the TCGA was performed at the Michael Smith Genome Science Centre in Vancouver, this is an excellent opportunity to extract further value from a locally-produced resource.
For knowledge translation activities, I intend to present this work at the annual meetings of the American Society for Hematology and the International Society for Computational Biology. Further, I will write up the AML analysis for submission to Genome Research or Leukaemia, and the later work applying the method to the TCGA data to a similar (or higher-impact) venue. Lastly, I will release the source code to perform the analysis as an open source software package.
