Seven CIHR Project Grants awarded to Cancer Researchers
Cancer research featured prominently among the grants awarded to the University of Calgary from the CIHR Spring 2020 Project Grant competition. In fact, 7 of the University’s 26 new Project Grants are led by cancer researchers and members of the Arnie Charbonneau Cancer Institute. The Institute’s overall success rate in this competition was 33% and the grants listed below represent a commitment of over $4.5 million dollars in federal revenue for cancer research at the University of Calgary. Congratulations to all recipients!
Oncofertility among adolescent and young adult cancer survivors in Alberta: a mixed methods study
Each year, approximately 7,600 adolescents and young adults (AYAs; aged 15-39 years) are diagnosed with cancer in Canada. Since people are having children later in life now, more AYA cancer patients have not started a family at the time of diagnosis. As a result, fertility is the second biggest concern among AYA cancer patients because previous research has found that radiotherapy and chemotherapy treatments can cause infertility. Although fertility counseling before cancer treatment is recommended as a part of standard AYA cancer care, it is unclear how often it is being used. Also, no one has explored how many AYA cancer patients have cancer-related fertility appointments or use fertility services before or after cancer treatment. Thus, this proposal's aim is to understand the impact of cancer and its treatment during adolescence and young adulthood on fertility by using a mixed methods study to explore cancer-related fertility care in Alberta. Specifically, among AYA cancer patients from Alberta that were diagnosed from 2010-2019, our first objective is to assess: -referrals to fertility services; -appointment attendance at a fertility clinic; -fertility procedures (and what kind); and -fertility-related financial costs. For Objective 2, we will use a mail-out to invite AYA cancer survivors to complete an electronic questionnaire that will collect information on fertility and sexual health factors, as well as demographics. This questionnaire will then be used to identify participants for focus groups (Objective 3) that will explore psychological and social factors that influence reproductive experiences and choices, as well as the impact of cancer on family building among survivors and their partners. The results of this study will help us understand how AYA cancer patients' fertility is impacted by cancer, and may lead to clinical or policy recommendations in Alberta and beyond.
Mechanisms of epigenetic evolution in pediatric high-grade gliomas
Pediatric high-grade gliomas are rare and always lethal brain cancers. Unlike other malignancies, they harbor few mutations in genes. Only some tumors have mutations in established cancer driver genes. These results led us to hypothesize that the biology of pediatric high-grade gliomas may be driven in large part by epigenetic events. Specifically, we hypothesize that DNA regions that that act as switches for genes could be aberrantly turned on or off to maximize the ability of the tumor to grow. These switches are controlled by proteins called transcription factors. In this application, we propose to investigate the role of control regions (the switches) in determining gene expression and functional properties of malignant cells. Our preliminary data indicate that different switches are turned on when the tumor recurs after treatment, and that this phenomenon may contribute to the emergence of properties that are typical of the tumor at relapse. Because tumors at diagnosis and relapse are so different, our data highlight the importance of specifically studying relapse samples, which are the entities that ultimately kill patients. Our studies will focus on rare pairs of diagnostic and relapse samples from the same patients, as well as on patient-derived models for functional validation. In the proposed studies, we will identify the transcription factors that are turning these switches on or off. The ultimate goal of our proposal is to understand how pediatric high-grade gliomas originate and evolve, and to identify strategies to prevent relapses through new and targeted therapeutic interventions.
Proteogenomic profiling of heterogeneity in glioblastoma
Sequencing the DNA of tumors has revealed important insights into how they arise and evolve, and in some cancer types has led to design of better treatments that significantly improve patient outcomes. In glioblastoma, the most common and fatal adult brain cancer, prognosis and treatments have remained essentially static over the last few decades. DNA sequencing has revealed significant genetic diversity within individual tumors and established this as a significant and unmet challenge to development of new therapies. In this project we aim to advance our understanding of glioblastoma tumor biology by utilizing state-of-the-art technologies to profile the DNA, RNA and proteins from the same cells, enabling us for the first time to link the state of the genome (DNA) to effects on the RNA and subsequent effects on proteins. This approach will reveal which of the diverse genetic changes within individual tumors lead to functional consequences that alter cell biology, and which are unimportant. By performing these measurements in multiple locations within individual tumors, both before and after therapy, we will be able to determine if there are key changes important to disease progression, with specific attention at the protein level, where most drugs and immune therapies act.
High-Throughput Analysis of Low Dose, Repetitive Alpha Particle Irradiation as a source of Radon-Induced Lung Cancer
Lung cancer is the highest lethality Canadian cancer. It is overwhelmingly caused by tobacco smoke and/or inhalation of radioactive radon gas. Radon emits ionizing radiation that can cause serious health effects depending on dose and type. Relative to photon radiation (such as x-rays), the alpha particles emitted by radon produces much more disease-causing, complex DNA damage. Radon is very prevalent in our environment and is the main cause of lung cancer in the ~20% of patients who are never-smokers, encompassing >25,000 North Americans per year. Despite this, technological limitations to conveniently deliver alpha particles repetitively, in low doses and in an affordable, high throughput manner have constrained research on this topic. Consequently, our knowledge of why some people, tissues and cell types are susceptible to radiation is mainly derived from high dose, acute exposure photon research. This is problematic, as health protection risk models are being built on data derived from photon studies that have an ambiguous relevance to what we are most exposed to in life, which are alpha particles via radon inhalation. To resolve this, our lab has developed a next-generation, high throughput alpha particle irradiator able to deliver adjustable, low doses that reflects what is happening to Canadians in our environment. We will use this to define - in exquisite molecular detail - alpha particle effects on the stability of our DNA and changes that can lead to cancer. This project will be the first to employ a high-throughput approach to systematically solve key alpha particle biology questions. This is important as, while radon causes thousands of lung cancer diagnoses annually, knowledge to meaningfully intervene before clinical manifestation is unacceptably low. We will be impactful by building the essential knowledge to identify those at risk of radon-induced cancer based on novel, next-generation methods fuelled by expert knowledge of DNA damage repair biology.
Social adjustment in survivors of pediatric acute lymphoblastic leukemia (ALL)
Acute lymphoblastic leukemia (ALL) is a cancer that affects the white blood cells and is the most common cancer affecting children. Thanks to many advances in treatment, most children diagnosed with ALL will survive. The treatments needed to cure ALL, however, are toxic because they are directed at the brain and therefore negatively impact survivor's health and psychological well-being. Survivors of ALL experience social difficulties. As children, these survivors do not have as many friends because they are more withdrawn. As adults, these survivors are less likely to go as far in school, have a job or be married compared to others who have not had ALL. In recent years there have been efforts to reduce the toxicity of treatment for ALL. We do not yet understand how less toxic treatments might effect the social difficulties of survivors. We need to understand this in order to find the best way to treat these problems. Social difficulties are a serious health risk that may be comparable to the health risks associated with drinking and smoking. The goal of the current study is to better understand the social difficulties in survivors of pediatric ALL treated with less toxic treatments. Methods: One hundred and twenty survivors of pediatric ALL and 120 survivors of solid tumours who have not received brain-directed therapy will be invited to participate and complete tests that will assess aspects of their social function. Their parents, teachers and classroom peers will also complete measures designed to assess social function. We will assess other factors that might be related to social function such as mental health. Expected Results: This study will increase our knowledge about the social functioning of survivors of pediatric ALL as well as to identify factors that might be related to their social function. This will help us identify which survivors may be at greatest risk of social difficulties and design better treatments to help these survivors.
The role of TOR kinase signaling and lipid metabolism in hypoxia tolerance
Our cells and organs need oxygen from the air we breathe in order to survive. However, although air contains twenty percent oxygen, our cells are exposed to much lower levels. In addition, our cells are often deprived of oxygen in diseases such as stroke, heart disease and cancer. This lack of oxygen, known as hypoxia, leads to the tissue damage seen in these diseases. In important challenge in biomedical research is to understand how cells and organs can respond to, and cope, with low oxygen. We use the fruit fly as a model to address this question. Fruit flies naturally live in rotting fruit which is an environment characterized by low oxygen. Hence, they have evolved mechanisms to tolerate this hypoxia. Our work in the fly has identified the regulation of one enzyme - TOR kinase - as a mechanism by which cells adapt to low oxygen. The goal of this project grant is to use the ease and speed of fruit fly genetics to understand exactly how TOR controls the ability of tissues and organs to survive low oxygen. The fruit fly is proven as a 'lead' model system to discover new biological mechanisms that can guide work in other systems including human cells. For example, the TOR pathway is controlled the same way in human cells as in flies. In addition, TOR becomes deregulated in disorders such as cancer and heart disease. Hence our work will help identify how cells and organs can cope with hypoxia, and in doing so, will provide clues about the defects caused by disorders such as cancer and heart disease.
Aynharan Sinnarajah and Jessica Simon
Automatic Palliative Care Referrals: Acceptability and Uptake by Patients with Advanced Lung Cancer
People living with advanced (incurable) cancer are not routinely provided with timely access to a therapy that is proven to help them feel better, reduce depression and anxiety, and support their quality of life. That therapy is palliative care. Patients, and those close to them, experience high levels of distress when faced with a life-limiting diagnosis, and often don't know that palliative care can be received at the same time as cancer treatments as an added layer of support. Other barriers to timely access to palliative care include cancer clinic time constraints, healthcare provider concerns that referring patients to palliative care might increase their distress, and cost of having a palliative care provider in every clinic. To overcome these barriers, our study asks "Can we develop a process so that everyone recently diagnosed with advanced cancer is automatically phoned by a palliative care provider and offered a consultation? Would patients find this phone call acceptable and how many would take up the offer of a comprehensive palliative care consultation?" What will the study do? We will work with patients and healthcare providers to design the process and appropriate language for these automatic referrals. We will then test the process, starting with people recently diagnosed with advanced (stage IV) lung cancer. We will interview patients about the acceptability of being called directly by a palliative care provider shortly after their advanced cancer diagnosis, and will measure how many patients attend a palliative care consultation. Why do this? If acceptable, automatic referral will overcome existing barriers to palliative care referral and guarantee EVERY patient is offered early access to palliative care. If we find that direct phone contact is acceptable and leads to more people receiving timely palliative care, this will provide a routine, effective way to enhance the lives of all Canadians living with advanced cancers.