Treating advanced disease and early detection are two main challenges in lung cancer. More than half (~55 percent) of people with advanced disease are unlikely to respond to a simple standard treatment. We’ll use advanced computer-assisted analysis technology to assess a special form of x-ray — computer tomography (CT) imaging to identify people less likely to respond to usual care. This, in turn, will allow care teams to provide more appropriate care decisions. Lung cancer screening uses CT to monitor abnormalities in the lungs. Some people with “normal looking” lungs on CT may rapidly develop aggressive cancer before the next CT appointment. We will use advanced technology to assess the “normal looking” lung CT images to identify early cancer-related changes in the lung tissue that can not be seen by the human eye. This research will guide personalized care decisions and improve the survival of people with lung cancer in BC. Our multidisciplinary research team at BC Cancer Vancouver includes cancer care clinicians, scientists, and patients and families with lived or living experiences with lung cancer. We will ensure the needs and priorities of those most likely to be impacted by our research will be integrated throughout the research.
Research Location: BC Cancer Research Centre
Lung cancer detection using the lung microbiome and exhaled breath
Lung cancer is the leading cause of cancer death worldwide. The number and proportion of lung cancers in people who have never smoked is projected to outpace active smokers in the next 25 years. Evidence indicates that outdoor air pollution, specifically one of its major components, particulate matter (PM 2.5), consisting of small particles measuring less than 2.5 microns in the air, is a major cause of lung cancer in never smokers. Chronic exposure to PM 2.5 can affect the layer of bacteria lining the lung (lung microbiome), changes in the lung microbiome referred to as dysbiosis have been shown to occur 10 years prior to a lung cancer diagnosis, signaling an increased risk for cancer. A promising, non-invasive tool to detect dysbiosis in the lung microbiome is studying the components of exhaled breath.
Objectives:
- Define the lung microbiome composition and function in people who never smoked, with and without lung cancer, including the effect of high levels of air pollution by direct bronchoscopic sampling.
- Use exhaled breath to detect early lung cancer in people who have never smoked based on the differences in the lung microbiome between cancer and non-cancer individuals.
Tumour tissue biomarkers to guide personalized lung cancer treatment in British Columbia
Non-small cell lung cancer (NSCLC) is the most common cause of cancer death in BC and worldwide. In 2020, 29,300 Canadians were diagnosed with lung cancer and 21,000 died from it — more than colon, breast, and prostate cancers combined. Patients amenable to surgery have the best prospect of cure, but often cancer returns and is lethal. Only 5 percent of patients benefit from chemotherapy after surgery. Return of cancer is caused by changes in the tumour genes and immune system. It is possible to predict these changes to identify patients who would benefit from targeted gene and immune therapies, but testing for tumour genes and immune biomarkers is not done in Stage I-III NSCLC in BC. We will use novel tests to understand how the immune system and tumour genes predict cancer recurrence after surgery. This will be led by thoracic surgeon Dr. Anna McGuire. Tumour gene analysis will be done at the BC Cancer Genomic Lab and immune system analysis will be led by Drs. MacAulay and Guillaud at the BCCRC. Our results will reveal which features predict cancer recurrence so patients who can benefit from targeted gene or immune therapies can be identified. This is first step to implementing this testing for NSCLC patient in BC to improve survival.
Developing a collaborative research agenda to improve the care of patients living with metastatic breast cancer in British Columbia
Metastatic breast cancer (MBC) affects up to 30 percent of women with early breast cancer and represents up to 10 percent of new breast cancer diagnoses. It is one of the most common causes of death from cancer amongst females. The availability of new treatments has improved survival; however, the treatments are very toxic. There is a trade-off between managing treatment toxicity for these patients, in terms of extending survival and maintaining a decent quality of life. Constant treatment and monitoring are required; this results in a burden at the patient and at the health systems levels. Through a series of virtual meetings, we will bring together front-line cancer care providers, academic researchers, and patients and families to reflect and share their experiences about the MBC care in BC. The meetings will aim to discuss the facilitators and barriers to accessing specialized MBC care. Our goal is to establish partnerships, encourage knowledge exchange, and develop a collaborative research agenda to ensure quality care for individuals living with MBC in BC.
Team members: Stephen Chia (BC Cancer); Leah Lambert (BC Cancer); A. Fuchsia Howard (UBC – School of Nursing); Robert Olson (BC Cancer); Fiona Mitchell (BC Cancer); Scott Beck (BC Cancer); Jagbir Kaur (BC Cancer); Sara Izadi-Najabadi (BC Cancer); Nathalie LeVasseur (BC Cancer).
Roles of the Lysine Methyl Transferase (KMT) 2d in hepatocyte identity and hepatocellular carcinoma progression
Liver cancer is the third most common cause of cancer-related deaths globally, and patients with liver cancer currently have limited treatment options, including tumor ablation and liver transplant. More than half of the liver cancer cases have mutations in regulators of genome structure, which play a crucial role in cellular differentiation and development by controlling gene expression patterns. Lysine Methyl Transferases 2d (KMT2d) is one of the most frequently mutated regulators. However, we do not fully understand how changes in the KMT2d can drive liver cancer. In this project, I will investigate the mechanism in which KMT2d influences liver development as well as induces liver cancer from normal liver cells using organs that mimic human livers. Moreover, discovering its interaction partners, such as transcription factors that function in turning on and off genes, will provide more comprehensive mechanistic insight into the roles of KMT2d in liver formation and health. This study will advance fundamental knowledge for future research on the liver’s developmental biology and provide promising alternative therapeutic avenues for liver cancer.
Medulloblastoma plasma membrane proteomics to inform optimal immunotherapy design
Brain cancer is the most common pediatric solid cancer, devastating the lives of more than 5,000 children and their families every year in North America. Current chemoradiotherapy approaches are often ineffective and cause serious side effects on the developing brain, such as permanent seizures and learning disabilities. Thus, more effective and less damaging therapies are urgently needed. Immunotherapy has been recently credentialed as a breakthrough in cancer therapy, with novel immunotherapy agents approved by the FDA for the treatment of childhood cancer. There is every indication that this progress presents the tip of the iceberg and that with continued efforts, effective immunotherapies can be developed for many currently incurable pediatric cancers. The ability for cancers to grow rapidly is in part due to the activation of specific proteins exposed on the membrane of cancer cells. The goal of immunotherapy is to target cells exposing these proteins while sparing normal, healthy cells; however, a major barrier is that most proteins on the surface of medulloblastoma cells are currently unknown. In this proposal we will identify optimal targets to ultimately develop immunotherapies against medulloblastoma.
Evaluation of SMPD3 as a quarterback for extracellular vesicle-mediated metastasis in oral carcinoma
Mouth cancer remains an under-studied and significant global cancer killer; dismal survival rates (~50% over 5 years) have not changed in decades. Potential spread to neck lymph nodes (metastasis) is the single most important prognostic factor but clinical assessment has not been very accurate. This results in insufficient surgery or over-treatment for many patients. A better understanding of mouth cancer and its way to spread is needed to improve treatment for the patients.
The SMPD3 gene is frequently dysregulated in mouth cancer it has been linked to metastasis. SMPD3 expression can impact microRNA (miRNA: small non-coding RNA molecules that regulates gene expression) cargo within extracellular vesicles (EVs). Many of these miRNAs have been linked to tumor invasion and metastasis. I hypothesize that mouth cancer cells that exhibit decreased SMPD3 expression plays a role in lymph node metastasis via specific miRNA EV content and that SMPD3 expression can be used as a biological marker for lymph node spread in mouth cancer.
We hope this project will lead to novel tools to identify the patients at highest risk for lymph node involvement, ultimately increasing survival rate and quality of life for mouth cancer patients.
Role of SASH1 in generation of hematopoietic stem cells
For many patients with a serious blood disorder or malignancy the primary treatment option is a stem cell transplant (SCT), which involves destroying the unhealthy blood cells of the patient and replacing them with healthy donor stem cells. Unfortunately, a large number of patients are unable to find a suitable donor, and die as a result. Thus, there is an urgent need to identify new sources of healthy blood stem cells for these patients.
One promising solution is to harvest other types of cells from the patient and reprogram them to become blood stem cells, which can then be reintroduced later. Key to the success of this approach is placing the cells in an environment which mimics how the first blood cells are generated during embryonic development (called endothelial to hematopoietic transition [EHT]). To date little research has focused on the external cues needed for EHT, and this presents a bottleneck to producing stem cells for SCT. Therefore, our project will use models of EHT to identify external drivers of EHT, and the mechanisms by which they program cells to transition into blood cells. The knowledge from this project will help to create protocols to reproducibly reprogram patient-derived cells into blood cells for SCT.
Cost-effective biomarker driven treatment for chronic lymphocytic leukemia in the era of precision medicine
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Ibrutinib, a new drug that works differently from chemotherapy, is a major breakthrough for CLL treatment and allows patients to live longer; however, it comes at a high cost to the BC health system.
Objective
- Our goal is to determine which patients benefit most from ibrutinib at what point in their disease, so that ibrutinib, and other drugs like it, are given to the right patients at the right time and avoided in those who will only suffer side effects.
Methods
- We will analyze the impact of ibrutinib on the BC CLL population including patterns of use, side effects and survival. We will perform genomic testing on samples from CLL patients on ibrutinib to find gene mutations that develop over time that may help predict who will respond well. Finally, we will combine this information to determine the overall cost of ibrutinib to the BC population, particularly when treatment is targeted to those who will benefit most.
Impact
- This approach is crucial to ensure ibrutinib is affordable for healthcare systems and accessible for all those who need it, ultimately leading to improved quality of life and survival of CLL patients.
Cytology-based DNA measurement for oral cancer screening
Oral cancer (OC) presents a global burden on society and the healthcare system with remarkably high incidence rates and poor prognosis. Despite the oral cavity being easily accessible for visual assessment and diagnostic procedures, it remains to be detected at an advanced stage when the prognosis is poor and radical interventions are necessary. An invasive biopsy of a clinically suspicious lesion is the current standard of care for OC diagnosis and lesion monitoring; however, repeated biopsies may not be feasible.
This study aims to provide a non-invasive, objective, and accurate OC diagnostic test using high throughput DNA-based cytometry. This test incorporates the OralGetafics platform, which combines artificial intelligence software with a commercially available and affordable scanner, which has been widely used in China and India for OC screening. We recently showed that the system could detect cancer or normal cells with sensitivity of 100 percent and specificity of 86.7 percent with minimal input from the cytotechnician. Potentially, this new technique can be used in remote communities with limited access to care and provides a significant benefit in early detection of at-risk oral lesions and reduction in OC burdens.