One-third of patients with aggressive non-Hodgkin lymphoma relapse after conventional chemotherapy and die of their disease. We need new methods to identify, at diagnosis, which patients have a high risk of relapse to improve their treatment. Genetic profiling is a powerful tool that can identify these high-risk patients. ‘Double-hit lymphoma’ (DHL) is one type of lymphoma that responds poorly to standard treatment. Current testing strategies cannot accurately identify all patients with DHL. We aim to improve the identification and treatment of DHL with a new test that uses a unique ‘genetic blueprint’. We will apply this test on lymphoma samples from 900 aggressive lymphoma patients in British Columbia to find out its ability to identify DHL patients compared to current methods. Patients who carry this genetic blueprint may benefit from different treatment approaches that overcome the high risk of relapse. We will also conduct an in-depth genetic analysis of DHL to understand how these lymphomas develop in the body. This new knowledge will help design smarter therapies that target the tumour while sparing normal body cells. These ‘targeted therapies’ can avoid the significant side effects caused by intensive chemotherapy.
Research Location: BC Cancer - Vancouver
Self reactivity as a driver of extranodal diffuse large B-cell lymphoma transformation and survival
Lymphoma is a form of cancer that affects immune cells called lymphocytes, a type of white blood cell. There are many subtypes of lymphocytes and lymphomas. Diffuse large B-cell lymphomas (DLBCL) develop from B lymphocytes (B-cells) and are the most common subtype of non-Hodgkin lymphoma. About one third of DLBCL extend beyond the lymph nodes (“extranodal DLBCL”), and invade vital organs such as the kidneys, lungs, and brain, with an often-fatal outcome. Our ability to predict which patients will develop extranodal DLBCL is limited, and we also lack disease-specific treatments, partly due to an incomplete understanding of how and when these tumors originate. Interestingly, recent evidence suggests extranodal DLBCL share features with autoimmune disorders — conditions in which lymphocytes abnormally react against organs in our bodies, instead of external foes. In this study, we will investigate the relationship between the origin and progression of these diseases, in an effort to better understand how B-cells transform into cancerous cells, disseminate, and expand. Our work could help identify patients at high risk of developing extranodal DLBCL, and unveil key tumor dependencies to be leveraged as specific therapeutic targets.
Post-transcriptional regulation of hematopoietic stem cell function during normal and malignant hematopoiesis
In 2016, there were approximately 22,510 Canadians living with leukemia and an estimated 2,900 Canadians died from leukemia. Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults. About 30 percent of AML patients eventually relapse after treatment and suffer from very poor overall survival at this stage. It is postulated that leukemia stem cells (LSCs), a small population of leukemia cells characterized with regenerative ability, mediate resistance and relapse after therapy. My work sought to uncover the largely unknown role of the processes that control protein generation in maintaining blood stem cells and how it contributes to transformation of leukemia stem cells in cancer. This research program aims to identify new factors, which can serve as targetable molecules and pathways to specifically eliminate leukemia cells while sparing normal cells. The work will provide the scientific foundation for future developments of therapy targeting these pathways as a novel strategy in eradicating leukemia stem cells to improve outcomes in AML patients.
Exploring oxidative phosphorylation as therapeutic vulnerability in high risk acute myeloid leukemia
The standard of care for AML patients was introduced in the 1970s and has not significantly changed since then. Patients suffering from acute myeloid leukemia (AML) with unfavourable genetics are characterized by dismal overall survival due to poor treatment response to standard chemotherapy. In this research proposal, I aim to better understand the energy metabolism of high-risk AML cells and explore this as a novel treatment avenue. My research will create a rational for future clinical trials to improve patient care and develop novel treatment perspectives for a patient collective with a bleak prognosis.
Leveraging TCR reactivity using viruses and vaccines to improve CAR T therapy
T cells patrol the body using their T cell receptors (TCR) to look for cells which display evidence of intracellular pathogens or cancers. In order to focus their attention on specific cancer antigens, T cells can be engineered to express an artificial recognition receptor (termed a Chimeric Antigen Receptor or CAR). CAR technology has been shown to be extremely powerful clinically in leukaemia and lymphoma patients who have not responded to other lines of therapy, leading to recent FDA and Health Canada approvals.
However, only one third of lymphoma patients treated with CD19 specific CAR T cells exhibit long lasting curative responses, thus leaving significant room for improvement. CAR T failure can usually be attributed to either loss of the tumour antigen (ie CD19) or to dysfunction of the T cells, and we are developing a strategy to address the latter. Once T cells express a CAR, they can still receive signals through their TCR, and we have shown in preliminary experiments that this type of stimulation can help CAR T cells to proliferate and kill tumour cells. Our research will use oncolytic cancer killing viruses, and other vaccines, to help mobilize CAR T cells which recognize viral antigens using their TCR.
Creative knowledge translation to support BCC’s Personalized OncoGenomics Program
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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.
Award Update: March 2022
The POG Knowledge Translation working group produced an animated video that explains cancer, genomics, and precision medicine using vocabulary and engaging graphics (in six languages) suitable for many audiences, from experts to those with no knowledge of the science.
Learn more on Genome Sciences Centre’s website.
The molecular dissection of aggressive B-cell lymphoma
Aggressive B-cell lymphomas are the most common form of lymphoma and ~50% of patients are cured with modern treatments. However, the outcomes for patients whose disease is not cured are dismal with ~10% of those patients alive at 5 years. This shows that these lymphomas, although grouped together on the basis of what they look like down the microscope, represent clusters of different lymphoma groups. A better understanding of the 'molecular wiring'of these lymphomas is critical to identify patients at high risk of resistant lymphoma and providing better treatments.
This project will provide a rational new way to group lymphomas based on differences in the molecular wiring. This will be acheived by performing and analysing genomic sequencing on a large number of aggressive B-cell lymphomas brought together through an international lymphoma consortium. Further, tumour samples will be analysed from the time of diagnosis and when the lymphoma relapses to see whether this molecular wiring remains stable or changes with treatment. It is anticipated that this major step forward in our knowledge will be translated into new tools for matching a patient's lymphoma to the correct treatment and improving patient outcomes.
Predictors of immunotherapy benefit in patients with microsatellite stable metastatic colorectal cancer
Introduction: Colorectal cancer (CRC) is the second most common cancer. Once metastatic, patients are generally incurable and receive treatment to prolong survival. Immunotherapies use a patient's immune system to attack their cancer. These treatments are effective in CRC patients with microsatellite instability (MSI). Unfortunately, 95% of patients lack MSI and are called microsatellite stable (MSS). This group usually doesn't respond to immunotherapy and we need to explore why.
Specific Aims:
We aim to identify:
- why some MSS patients benefit from immunotherapy, and
- what can we target to activate immune cells in patients who don't respond to immunotherapy.
Methods: We will investigate how the immune system and tumors interact in patients from two clinical trials. These trials evaluated immunotherapy in MSS CRC. Blood and tumor samples from these trials will be tested to identify features that predict response. These results will then guide the creation of new clinical trials with immunotherapy for CRC using our findings.
Significance: Immunotherapy does not work for the 95% of CRC patients who are MSS. We will identify how to activate the immune system in CRC patients with MSS so they too can benefit from immunotherapy.
Identification of IL1RAP as a novel oncoprotein and therapeutic target in Ewing sarcoma
Ewing Sarcoma (EWS) is an aggressive form of childhood cancer that occurs on bone and soft tissue. Although conventional cancer therapeutic strategies, such as chemotherapy, radiation and surgery, have improved survival in patients with localized EWS tumours, they are ineffective for patients with metastatic disease. In addition, conventional chemotherapy is often toxic and carcinogenic, which carries short- and long-term toxicities. In the past few years, immunotherapy has been promoted as an effective means to prolong survival or eliminate tumor cells in patients with specific cancers.
However, effective immunotherapeutic strategies for EWS have not yet been described. Identification of highly specific cell surface markers of tumor cells is critical for developing targeted immunotherapy strategies. We have identified IL1RAP (Interleukin 1 receptor accessory protein) as a cell surface protein that is highly expressed in EWS in comparison to normal tissues/organs, and that is important for tumorigenesis in this disease. In this project, we aim to develop immunotherapeutic strategies by targeting IL1RAP in human EWS, while also delineating the key mechanisms mediating the tumor-promoting function of this protein.
End of Award Update – March 2022
Most exciting outputs
During the Health Research BC / Lotte & John Hecht Memorial Foundation award period, my work in Dr. Poul Sorensen’s lab identified IL1RAP (Interleukin 1 receptor accessory protein) as a cell surface protein that is highly expressed in Ewing sarcoma, but minimally expressed in pediatric and adult normal tissues, nominating it as a promising immunotherapy target. Our mechanistic studies show that IL1RAP maintains cyst(e)ine and glutathione pools in Ewing sarcoma, which are vital for redox homeostasis and metastasis.
To therapeutically target IL1RAP, we have collaborated with Dr. Dimiter Dimitrov of the University of Pittsburgh to develop IL1RAP binders via phage-display biopanning. We identified highly specific IL1RAP binders, one of which has been engineered into a humanized IgG1 antibody. This antibody can induce antibody-dependent cellular cytotoxicity (ADCC) in Ewing sarcoma cells. Moreover, in collaboration with Dr. Rimas Orentas of the Seattle Children’s Hospital, we have developed IL1RAP CAR (chimeric antigen receptor) T cells, which can mediate potent tumor cell killing in vitro, and we are currently optimizing the IL1RAP CAR for higher in vivo efficacy in mouse models. Some of these findings have been published in Cancer Discovery.
With regard to the mechanistic studies of the pathobiological function of IL1RAP, i.e. IL1RAP maintains cyst(e)ine and glutathione pools that promote Ewing sarcoma metastasis, we recently published a review article on this topic in Trends in Cell Biology, a Cell Press journal.
Impacts so far
Based on our findings, we have filed a patent for IL1RAP CAR-T cell therapy in human cancers.
Potential future influence
Based on our findings, we may initiate clinical trials in the near future to target IL1RAP with immunotherapeutic strategies, including highly specific chimeric antigen receptor (CAR) T cells and antibody-drug conjugates.
Next steps
We aim to develop various immunotherapeutic strategies to target IL1RAP in human cancers, including highly specific chimeric antigen receptor (CAR) T cells and antibody-drug conjugates.
Useful links
- Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma (Cancer Discovery, November 2021)
- Transsulfuration, minor player or crucial for cysteine homeostasis in cancer (Trends in Cell Biology, March 2022)
- Childhood cancer discovery may stop tumour spread before it starts (UBC News, June 2021)
Defining mechanisms of lineage transformation in lung cancer to combat resistance to targeted therapies
Lung cancer is the leading cause of cancer-related death in Canada. A major reason for the poor prognosis is the lack of effective drugs for treating advanced tumours.
New understanding of the mutations driving lung cancer has led to the development of targeted therapies that selectively inhibit mutated genes, leading to rapid cancer regression in specific subsets of patients. However, while these therapies improve patient survival and quality of life, they are not curative as all patients develop drug resistance.
While some causes behind this resistance have been defined, others remain elusive, and are becoming more prominent with newer generations of drugs. A major example is tumours changing how they look—shifting from one type of lung cancer to another—but what causes this is still not clear.
Dr. Inoue’s research will test whether treatment with targeted therapies creates the environment that allows tumours to “change their skin” and continue to grow in the presence of drugs. The goal is to determine the genes involved in this shift and prove they are responsible for drug resistance. This will lead to new therapeutic strategies that will provide longer-term survival benefits for lung cancer patients.