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).
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.
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.
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.
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.
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.
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.
Diagnosing cancer early is critical to achieve positive patient outcomes. The COVID-19 pandemic has had an unprecedented impact on cancer diagnosis in BC, suspending screening programs and drastically reducing diagnostic services. The patient and population health impact of a prolonged reduction in these services is unknown. Further, as COVID-19 restrictions ease, the expected demand for these services will exceed the system’s capacity, significantly increasing wait times. It is now critical for BC Cancer to establish priorities for the re-introduction of services to reduce negative impacts of delays. Our research will quantify the impacts of reductions in cancer diagnostic services on patient outcomes and develop effective strategies for re-introduction.
The genetic material of cells is DNA. The popular notion in biology for a long time was that DNA makes RNA which in turn makes proteins. But over the past two decades, research has shown that not all types of RNA are converted to protein. These RNAs which do not make (or do not code for) proteins are called noncoding RNAs. Long noncoding RNAs (lncRNAs) belong to one of the classes of noncoding RNAs. Based on various studies, we know that lncRNAs are crucial during different biological contexts including embryonic development as well as disease. The importance of lncRNAs in blood stem cells and blood cancer is not yet studied in detail. We will study how lncRNAs can help blood stem cells to either remain as stem cells (maintain stemness) or convert into different blood cell types (differentiate) and how they control the blood stem cells from forming cancer.
One of the very recently studied modes of action for lncRNAs is the binding of long noncoding RNAs to other class of noncoding RNAs called microRNAs and blocking the action of microRNAs. By using several techniques, we will systematically decipher lncRNAs acting by the microRNA mechanism to the blood stem cells in maintaining stemness or differentiation. The knowledge from this project will improve our understanding of the biology of blood stem cells and can be helpful in future for treatment of disorders of the blood system, bone marrow failure and cancer.
Metastatic disease remains the single most powerful predictor of adverse outcomes in Ewing sarcoma (ES) and other childhood sarcomas (malignant connective tissue tumours). High risk ES appears to be characterized by uninhibited outgrowth of neoplastic clones that have acquired additional genomic or epigenomic alterations, which facilitate the spread of the cancer cells.
Considerable research has focused on understanding the genetic and biomolecular alterations that underlie ES, including drug resistance. The challenge is to identify targetable events that can be used to characterize metastatic disease, which is widely held as an inefficient process, with only a tiny fraction of primary tumour cells surviving.
Emerging evidence suggests that a largely overlooked component of the spread of tumour cells is the impact of stress adaptation, occurring through acute changes in mRNA translation and protein synthesis. It is likely that specific ribonucleoprotein complexes known as stress granules (SG) are intimately connected to cancer biology, and even resistance to chemotherapy. However, targeting these structures in cancer cells has not been widely pursued. Dr. El-Naggar’s research will focus on understanding the link between stress granules and conditions that promote the spread of cancer cells.
