Each year in Canada, around 3,000 women will be diagnosed with high grade serous ovarian cancer (HGSOC) — the most common type of ovarian cancer. Despite good responses to first line treatments for many women, it comes back as a resistant disease. Targeted treatments such as PARP inhibitors (PARPi) have made a big difference to HGSOC that is deficient in a DNA repair pathway (Homologous recombination repair), but this only benefits around 50 percent of women with HGSOC. PARPi combinations with drugs that target angiogenesis and the immune response remain under investigation. This project will investigate how chemotherapy vs. targeted therapies differentially affects the DNA damage and immune response in cancer and how effective non-chemotherapy combination treatments work, including different doses and schedules. Also, which patient might benefit from which treatment and when for example should the targeted therapies be given before or after the chemotherapy? Creating models similar to humans, we will transplant patient tumors (removed at surgery) on the skin and inside the abdomen of mice and analyze the molecular nature (at single cell level) of these tumors before/after treatment. Results of these studies will inform future clinical trials.
Research Location: BC Cancer
Integrating clinical, functional and chemical genomics to understand lung cancer biology
Lung cancer is the leading cause of cancer mortality worldwide, suffering from a late stage of disease at the time of diagnosis and a paucity of effective therapeutic strategies to treat advanced tumors. However, with our increasing understanding of lung cancer biology has come the advent of targeted therapies to combat this devastating disease. These therapies target mutated components of key cellular pathways on which tumors have become dependent on for survival, yielding drastic initial response rates without the major side effects of traditional chemotherapies. Despite these successes two major problems remain: first, the majority of lung cancer patients have tumors without mutations in targetable genes and; second, all patients eventually develop resistance to treatment with these targeted agents. In addition, since lung tumors commonly have hundreds of mutated genes, it is difficult to pinpoint those that are responsible for tumor growth and resistance to therapy, creating a clear bottleneck in the translation of laboratory findings to a clinical setting.
I propose an integrative strategy to address these issues. Through analysis of the genomic profiles of human lung tumors, I aim to identify novel genes and pathways that are altered during lung cancer development. Furthermore, by combining this information with the characterization of mice genetically engineered to develop lung tumors, I attempt to elucidate the key genes driving lung cancer initiation, progression and response to therapy. Lastly, by screening libraries of chemical compounds across lung cancer cells, I aim to characterize novel inhibitors of these identified genes and their corresponding pathways that show promise for use as targeted therapies. Together, this work will further our understanding of lung cancer biology and create insight toward the development of new approaches to diagnose and treat patients suffering from this disease.
Transforming adolescent and young adult cancer care in BC in partnership with patients and cancer care allies
In Canada, approximately 7,600 adolescents and young adults (AYAs) aged 15 to 39 are diagnosed with cancer each year, representing 4 percent of annual cancer diagnoses. Currently, cancer care systems have limited capacity to meet the complex needs of AYAs and survival outcomes for AYAs are often worse when compared to children and adults over 40.
This research program will use the principles of participatory action research (PAR) and patient-oriented research (POR) to meaningfully engage AYAs and cancer care allies (healthcare professionals, decision makers, researchers, and community organizations) to better understand AYA cancer care and explore how cancer care systems can respond to the unique, complex needs of AYAs with cancer. Led by a researcher with lived experience of cancer as an AYA and 15 years of experience conducting PAR, the work seeks to inform AYA cancer care research, policy, and practice in BC and beyond. Initial research funding from the Vancouver Foundation, MSFHR, and British Academy is in place, as are collaborators from Royal Roads University, BC Cancer, BC Ministry of Health, Young Adult Cancer Canada, the BC SUPPORT Unit, Callanish Society, InspireHealth, Innovation Support Unit, and AYAs with cancer.
Novel carbon fibre breast positioning device (CARA) for reducing toxicity in breast radiotherapy
Radiation therapy is used to reduce the chance of breast cancer recurrence after surgical removal of the primary cancer in approximately 2,000 British Columbian patients and approximately 2 million women around the world annually. Because the breast is a mobile organ sitting over the lungs and heart, these organs and other normal tissues may receive unwanted radiotherapy dose leading to serious side effects. Our group has designed a carbon-fibre device suitable for breast positioning in radiotherapy to optimize the position of the breast during treatment to reduce these side effects. Initial tests in our clinic are very promising. To bring this device into widespread use for patients, further work is required to improve the quality of the device to meet the highest standards for patient care and those set by Health Canada. Carbon fibre devices are very challenging to make when complex shapes are required, as is the case for this breast support. We will work with a research group specializing in carbon fibre to find the best materials and manufacturing process for the device, and then get the improved device into the hands of leading experts in breast cancer treatment for further evaluation in the clinic.
Moving towards a biology-based care model in germ cell tumors
Testicular germ cell tumors (GCTs) are the most frequent solid tumors in young men. Chemotherapy can cure most patients even when the tumor is advanced. However, there are still two main issues of concern.
- Survivors have an increased risk of developing other diseases (e.g. heart disease, new tumors, strokes, etc.) as results of the late side effects of chemo- and radiation- therapies.
- Current methods to detect GCTs rely on a CT scan and blood work for tumor markers which are not specific enough for GCTs. This means there are patients who are falsely considered as having the tumor and more importantly, being treated unnecessarily with chemotherapy, radiation or surgery.
Our research program aims to reduce this uncertainty by analyzing some small RNA fragments (micro-RNAs) in the blood of GCTs patients that are produced only by the GCTs cells. Although several small studies have demonstrated those micro-RNAs are better than the CT scan and serum tumor markers to detect GCTs, we still need to validate this test in a larger number of patients before it can routinely be used in clinical practice. We have therefore designed two clinical trials to validate the clinical utility of micro-RNAs in the management of GCTs.
Interpreting and addressing barriers impeding effective care transitions for women diagnosed with breast cancer in British Columbia
The number of Canadians diagnosed with cancer is rising with a growing and aging population and we need to ensure our healthcare system is equipped to meet this growing demand. As the most common female cancer worldwide, breast cancer is the second leading cause of cancer deaths in Canadian women. In recent decades, advancements in breast cancer screening and treatments have resulted in approximately 87% of Canadian women diagnosed with breast cancer surviving 5 years after diagnosis. Increased survival rates are due in part to adjuvant endocrine therapy (AET) (e.g., tamoxifen), which is used to treat early-stage, hormone receptor-positive breast cancer, representing the large majority of breast cancer diagnoses. Women prescribed AET are recommended to take this medication everyday for 5-10 years depending on their diagnosis, which results in the need for increased follow-up care over a long period of time. Previous research, however, has shown there are many issues associated with transitions in care, particularly as breast cancer survivors move from receiving care from their oncologist back to seeing their family physician or nurse practitioner in the community. The objective of this project is to improve transitions in care to better support women diagnosed with breast cancer and also the healthcare providers that deliver care to these women. The goal is to meet the supportive care needs of breast cancer survivors as they transition through the healthcare system to support them in living well beyond their breast cancer diagnosis.
Improving the methods of economic evaluation to support decision-making: CAR-T, uncertainty, and real-world evidence
The emergence of novel technologies in health care is associated with promising opportunities to improve patient health outcomes. Advances in health technologies also come at a substantial cost. New gene therapies have been estimated to cost between $300,000-$4,000,000 per patient. These new therapies offer promise, but do not offer certainty; decision-makers have to choose whether to reimburse the therapy with little evidence for how it might work in the real-world.
Health economics can be used to assess the value of a new therapy compared to current therapies. While the use of health economics seems to be supported, the extent to which it impacts decisions seems to be limited. The proposed research will improve health economics analyses to support decision-makers at BC Cancer. The approach will incorporate real-world evidence, expert and patient opinion, and effective communication with decision-makers. Chimeric antigen receptor T-cell (CAR-T) therapy will serve as a case study as it is promising, but is associated with high costs and uncertainty about long-term effectiveness.
This project will bridge the gap between the type of evidence that is provided by standard health economics analyses and that required by decision-makers.
Biologically informed ovarian cancer prevention: Promoting education and awareness
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Over 11 percent of cancers and 9 percent of cancer deaths in women are from reproductive cancers. This represents a substantial disease burden; however, public dialogue levels and research funding doesn’t reflect this. Breast cancer, which has more public awareness, received 60 percent higher investment between 2005 and 2014 in research compared to reproductive cancers on a per case basis; this gap is even greater when comparison is based on cancer-related deaths. This team will create knowledge dissemination tools focusing on reproductive cancer prevention, to raise public awareness, and start a discussion about reproductive cancers. Public education could improve outcomes and lead to a national focus and investment in clinical care and research on reproductive cancers.
Prevention initiatives could reduce 1/4 of the 12,000 reproductive cancers that occur in Canada each year. Videos will be created and aimed at the target audience (women who can benefit from prevention), focused on three areas:
- Opportunistic salpingectomy (removal of fallopian tubes during hysterectomy or other pelvic surgery) to prevent ovarian cancer.
- Cervical cancer screening and prevention.
- Genetic testing for inherited risk factors.
These will be short, animated videos, less than three minutes, and succinctly describe the preventive strategy and current state of research. They will be posted on the OVCARE (BC’s multidisciplinary research group focusing on reproductive cancers) website (www.ovcare.ca) and linked through other outlets (other websites and online news sites, social media). A parallel set of videos will be created to convey the same information but designed for selected patient waiting areas and silenced to minimize disruption. Once created, these videos can be used at speaking events, fundraising events, and other venues. Along with inadequate funding for prevention research, participation in prevention activities has been identified as a barrier to uptake of prevention strategies. Education is one strategy to increase uptake.
This team has a strong track record of successful educational campaigns, informing clinicians and the public about opportunistic salpingectomy in 2010, and more recently to inform health care providers about new molecular stratification of endometrial cancers. It is hoped that this initiative will increase uptake of prevention activities and lead to greater public awareness of reproductive cancers.
Molecular classification for stratification and improved clinical management of endometrial cancers
In the current landscape of endometrial cancers (ECs), there is a shortfall in the management, treatment and evaluation of EC patients. Treatment tends to not be standardized, patients are commonly over- or under-treated, and diverse ECs are grouped together in clinical trials. Because of this inconsistency in diagnosis, it is difficult, if not impossible, to properly assess and compare how different treatments work.
In response to this gap, Dr. McAlpine has developed a molecular-based classifier called "ProMiSE” – Proactive Molecular Risk Classifier for Endometrial Cancer, which assigns EC patients to one of four prognostic groups. This classification would greatly improve the reproducibility and reliability of pathological diagnoses of endometrial tumours. The tool can be used to help categorize ECs into different risk classes to help guide surgery, treatment and surveillance based on the molecular features of the individual cancer. It can also identify women who may have inherited conditions placing them at increased risk of other cancers.
The next step for ProMisE is making the tool available across Canada. Although it is low cost and uses methods familiar to pathology laboratories, one of the testing components is currently unobtainable outside of a research lab setting. Dr. McAlpine is currently working with a Vancouver-based company to acquire, add and test this component in order to make ProMisE widely available.
Then, collaborating with eight other cancer centres across Canada, Dr. McAlpine will collect EC data, classify the data with ProMisE, and compare the treatment given with how molecular classification would have directed care.
This study is the last step in bringing this new molecular test to clinical use. With access to ProMisE, not only will there be immediate changes to how women with EC are managed, but it will allow the design of new studies to define the best, most personalized therapies for every woman with EC.
Assessment of breast cancer and response to systemic therapy before surgery using diffuse optical imaging technology
Breast cancer is the most common cancer in women. Patients with large breast tumour or palpable lymph nodes often receive chemotherapy first, followed by surgery. During chemotherapy, a doctor performs serial breast exams and occasional imaging to monitor tumour shrinkage, but this is not good enough to capture shrinkage accurately. It is important to develop a better way to measure breast cancer response on chemotherapy before surgery, as it can predict outcomes and change treatment plans.
Diffuse Optical Imaging (DOI) takes advantage of different light scatter properties in different biological tissues (for example, normal tissue, cavities, cancer and blood have different scatter properties in infrared spectrum). Our team has developed a hand-held DOI-Scan probe (optical probe) which has shown promising preliminary findings in patients without prior diagnosis of breast cancer.
We will use this real-time, easy-to-use, point-of-care imaging tool to examine normal breast and breast tumour characteristics in patients with locally advanced early breast cancer prior to and after each cycle of systemic therapy, alongside serial breast examinations and ultrasound imaging, to see how breast cancer appears and responds to chemotherapy given before curative surgery. The results will be compared with the final surgical specimen and patient outcomes.