Comprehensive dissection of tumor evolution in pediatric acute myeloid leukemia using single cell methylation sequencing

Pediatric acute myeloid leukemia (pAML) is a common type of cancer in children and is diagnosed in roughly 40 Canadian children each year. Although 90% of all children respond well to the initial treatment the cancer comes back for 20% of the children while being resistant to treatment, leading to a poor outcome. Current studies of treatment resistant cancers are not able to detect rare but important cells that form the cancer, which may be especially important in how treatment resistance occurs. Fortunately, new technologies allow for measurements from each of the thousands of individual cancer cells that form the tumor allowing us to detect rare cancer cells, including those that may result in treatment resistant disease. For the first time, we aim to use these technologies to focus on chemical properties of the DNA that influence how the DNA is interpreted, or read, by the cell. By studying patterns of these chemical properties in rare cancer cells and also normal cells we aim to learn if, and how, these patterns contribute to the phenomenon of treatment resistance in pediatric AML. With this knowledge, our ultimate goal is to prevent the formation of treatment resistant disease in this vulnerable population of patients.

Defining the landscape of genetic variation underlying rare human disease using nanopore long-read sequencing

Collectively, rare diseases affect millions of people worldwide. Understanding the molecular cause of rare disease has important implications for clinical management. However, although most rare diseases are suspected to be genetic in origin, the causal genes are not known in a majority of affected families. This study will use emerging technologies to better understand the molecular basis of rare genetic diseases. Long-read genome sequencing, a recent genetic testing technology, will help us to identify rare and complex genetic changes in individuals suspected to have harmful genetic variation. These findings will allow us to study how specific genes lead to congenital disorders and adult-onset cancer predisposition syndromes, genetic syndromes that increase the risk of developing specific types of cancers. This research will improve our understanding of normal and disease-causing genetic variation and help establish a foundation for the broader application of new technologies in the clinic.

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.

Creative knowledge translation to support BCC’s Personalized OncoGenomics Program

Co-lead:

  • Marco Marra
    BC Cancer

Team members: 

  • Jessica Nelson
    Canada's Michael Smith Genome Sciences Centre
  • Lindsay Zibrik
    BC Cancer – Vancouver
  • Kirstin Brown
    Canada's Michael Smith Genome Sciences Centre
  • Kevin Sauve
    Canada's Michael Smith Genome Sciences Centre

The Personalized Oncogenomics (POG) program at BCC is a patient-driven clinical research project which uses genome sequencing to inform cancer treatment and care. Delivery of the POG program involves a diverse group of stakeholders, all with varying health literacy levels. To close the literacy gap, POG must explore new knowledge translation channels to improve health literacy and education.

Knowledge translation is becoming increasingly common in clinical practice. Best practices recommend the use of lay language and to present material in popular, engaging and creative formats such as video and online content to reach and engage a large audience. Research suggests one of the most effective methods is through animated videos (Meppelink et al., 2015; George et al., 2013).

The goal for this project is to develop a short, patient- and public-focused animated video about the POG program and to showcase the video to our knowledge users  in a web-based format. Outcomes include improved awareness about the POG program, improved health literacy for patients considering POG or healthcare professionals new to POG, and improved understanding of how POG supports and enhances patient care in BC.
 

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.

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.

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.

Development and application of comprehensive T-cell receptor reactivity profiling technologies to aid in the discovery of novel immune cell therapies

The success of chimeric antigen receptor (CAR)-T cell therapy in the treatment of leukemia has spurred significant effort into developing similar "living medicines" for other cancer types. A large component of this effort is to discover new immune cell receptors that can be engineered into T cells, a specialized subset of immune cells, to function as the guidance system needed to attack and kill specific tumors. However, the difficulty associated with this lies in finding immune receptors that effectively target cancer cells but do not damage healthy tissues. Indeed, multiple clinical trials to-date have resulted in patient deaths due to catastrophic and unanticipated autoimmune reactions. We have developed an innovative laboratory screening method that profiles the reactivity, up front, of candidate T cell therapies against very large sets of possible targets. With this capability, our technology can comprehensively screen candidate cell therapies and predict which ones represent an unacceptable safety risk early in the discovery phase of development. As a result, our platform will increase the likelihood of T cell-based therapies achieving success in clinical trials and becoming approved treatments.

Modulating microRNA-193a expression levels as a treatment for acute myeloid leukemia (AML)

Acute myeloid leukemia (AML) has a dismal prognosis in Canada with only every 5th patient surviving 5 years. To find novel treatment options, we explore the therapeutic potential of the tumor suppressor microRNA (miR)-193a in AML patients together with InteRNA, a company that developed a novel drug based on the liposomal encapsulation of miR-193a (1B3), which showed very promising preclinical results in solid tumors and provided the rational for a phase I trial starting in spring 2020. We and others have previously shown that miRNAs are small RNAs that impact leukemia cells and are an emerging class of drugs. Recent data from our group showed a strong leukemia inhibition via miR-193a in animal AML models, highlighting the tumor suppressive effect of this miRNA. In addition, we are studying the regulation of miR-193a in AML cells to develop strategies to reinstate miR-193a expression and thus enhance its tumor suppressor function. This innovative study pioneers a novel class of RNA-based drugs in the treatment of AML and the groundwork for future clinical trials.

B cells: New players in the immune response to cancer

High-grade serous ovarian cancer is an aggressive disease with a low survival rate (~30%). Patients who survive longer mount strong antitumor immune responses as evidenced by the recruitment of immune cells to their tumors. Among those tumor-infiltrating immune cells, B cells that produce antibodies are particularly prognostic, yet poorly studied. We still do not know how B cells help to control tumor growth.

Using a technique that captures gene expression with single-cell resolution, I will profile immune cells isolated from 50 ovarian tumor specimens. I will then leverage these single-cell gene expression profiles (i) to identity prognostic B-cell subpopulations and (ii) to determine how B cells interact with other immune cells to ultimately eliminate tumor cells. Next, I will isolate the antibodies produced by tumor-infiltrating B cells and use these antibodies to define what B cells recognize on tumor cells.

My findings will provide unprecedented insights into the inner workings of the immune system in patients, informing the design of new immunotherapies that boost antitumor immunity and promote long-term survival of patients.