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:

  1. 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.
  2. 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.

Knowledge translation and mobilization to support exercise recommendations for people with bone metastases

The objective is to develop a knowledge translation and mobilization plan for exercise recommendations for people with bone metastases. In advanced cancer, cancer can spread to bone, called ‘bone metastases’. This makes bones weaker and more likely to break, leading to pain and disability. Physical activity can help people living with bone metastases to maintain their independence and engage in more activities they enjoy. However, health care professionals, exercise professionals and people living with bone metastases (user groups) are uncertain about how to safely engage in physical activity. In 2022, expert recommendations were published on physical activity specifically for people with bone metastases. Without specific tools for user groups and communication plans, it could take years for these recommendations to be taken up into practice. We will bring together people who are part of the intended user groups across British Columbia to “co-design” the best way to get information about the recommendations to people who need it, in the most useful way possible. This project aims to raise awareness about the recommendations and start the process to increase use of the recommendations for people living in British Columbia.


Team members: Christine Simmons (BC Cancer Agency); Alan Bates (BC Cancer); Cathy Clelland (BC Cancer); Sian Shuel (BC Cancer); Leah Lambert (BC Cancer); Sarah Budding Smith (BC Cancer); Chiara Singh (Fraser Health & Physiotherapy Association of British Columbia); Hardip Jhaj (British Columbia Association of Kinesiologists); Rebecca Tunnacliffe (BC Recreation and Parks Association); Tracy Torchetti (Canadian Cancer Society); Sarah Weller (BC Cancer); Stephanie Skourtes (Women’s Health Research Institute); Kirstin Lane (Exercise Science, Physical & Health Education University of Victoria); Sarah Neil-Sztramko (National Collaborating Centre for Methods and Tools); David Langelier (University of Toronto and Princess Margaret Cancer Centre); Michelle Nadler (Princess Margaret Cancer Centre); Samantha Myers (UBC – Rehabilitation Sciences).

Risk and protective factors for cognitive health across the adult age span: Impacts of physical and mental health and illness on cognitive outcomes

The virus causing COVID-19 can invade the brain, raising concern over long-term impacts on thinking abilities. We aim to identify long-term impacts on these cognitive abilities in those who have had COVID-19, and pinpoint factors that predict long-term outcomes. Adults positive for COVID-19 and those with no evidence of infection, are completing a series of cognitive and psychological tests in a current study. The proposed project will follow these individuals over time, with one and three-year follow-ups to examine changes in cognition across time. We will examine group differences in cognition, mental health, and other factors at each time point, determine if one or more cognitive profiles (clusters) characterize COVID-19 positive individuals, examine changes in these profiles across time, and test a screening measure to detect these cognitive difficulties. Findings will inform clinicians (e.g. neurologists, rehabilitation specialists) on trajectory of recovery of function and inform healthcare service provision in BC. Results will help ensure long-term impacts of infection are appropriately addressed, so those affected can efficiently resume complex activities requiring cognitive effort (e.g. employment, academic pursuits).

Does timing matter? A trial of intermittent fasting in haematological malignancies

Does when we eat make a difference to our health? We know that food choices can impact cancer risk but what if the timing plays a role as well? Evidence shows that fasting may slow cancer growth through a process called autophagy. Through an interdisciplinary research team, I am currently running a small trial testing the effects of intermittent fasting (IF) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) at BCC-Victoria who not on anti-cancer treatment. Specifically, I am asking whether IF regimens, differing in fasting timing and duration, stimulates autophagy, improves quality of life, impacts gut microbiome, and/or results in clinical benefit (i.e. reduced lymphocyte count). I am also following participants’ safety, ability to follow the fast, and fasting preferences. While early results look promising, I propose growing this study into a larger trial with three phases to clarify the effects of IF on cancer and the microbiome. Understanding these effects may help discover simple diet recommendations for patients with cancer that cause a response in cancer cells or slow cancer progression, are safe and reduce treatment side effects when used alongside current, standard treatments.

A patient-oriented mental health recovery effort: Working across sectors to alleviate suffering related to burnout, post-traumatic stress disorder, or treatment resistant depression

The mental health of healthcare providers is understudied and inadequately supported, especially given the current pandemic. Workplace stress can lead to burnout, Post-Traumatic Stress Disorder (PTSD), and Treatment Resistant Depression (TRD), which affects morale, absenteeism, retention, and patient care. The focus of this application is to address PTSD and TRD with a combination therapy involving Roots to Thrive (RTT) Communities of Practice (CoP) with Ketamine-Assisted Psychotherapy (KAP). The RTT CoP have documented enhanced efficacy for resilience, mental wellness and cognition. Ketamine is described as the single most important advancement in the treatment of depression in over 50 years.

My program of research innovatively examines the synergy of these two interventions, an evidence-based treatment known as RTT CoP-KAP. My research aims to lead the development and implementation of a more inclusive mental health model that continues to prescribe connection to self, spirit, and community as the primary healing modality, and further supporting with medicine-assisted healing modalities (beginning with ketamine and then expanding to include MDMA).

Vitamin C-induced epigenomic remodeling as a preventive therapy for leukemic transformation

Despite the overall improved diagnostics, standard of care and therapeutic options, most acute myeloid leukemia (AML) patients suffer from severe therapy-related side effects and still only 28% of them reach 5-year overall survival. The hypothesis that drives my project is that mutations which affect DNA-modifying enzymes disrupt a methylation-based control mechanism that regulates gene expression in a way that halts the normal cellular differentiation process. The discovery that vitamin C acts as an enzymatic co-factor that is able to revert this methylation defect in affected cells, provides a unique opportunity to transfer this knowledge to the development of novel, less toxic treatment strategies for patients that harbour these mutations. Within the scope of this project, I plan to explore whether and to which extent I can restore the normal DNA methylation signature in patient-derived leukemic cells in mice, either through vitamin C treatment alone or in addition to Health-Canada approved AML drugs. Further, I will explore the potential of vitamin C treatment to delay or prevent the transformation of not yet leukemic cellular states towards myeloid malignancy.

 


 

End of Award Update – August 2023

Most significant outputs

The most exciting results are yet to come: two manuscripts are currently in preparation to be submitted to Genome Biology and Leukemia within the year.

 

Impact

Despite the overall improved diagnostics, standard of care, and therapeutic options, most acute myeloid leukemia (AML) patients suffer from severe therapy-related side effects and only every third patient reaches 5-year overall survival. An observation that formed the foundation for this project is the frequent occurrence of mutations in AML cells which affect enzymes that contribute to a special control mechanism that regulates if and how much of a gene is read from our DNA to produce functional proteins. This control mechanism involves the precise placement and removal of “methylation marks” – either directly on top of the DNA strands or at proteins that help to organize the DNA into the three-dimensional structure we call chromosomes. If the placement or removal of these methylation marks is altered, protein production and cell survival mechanisms are disturbed as a consequence – a characteristic which we often observe in cancer cells. In the past, our lab contributed to the discovery that vitamin C acts as a co-factor that helps to re-activate the enzymes that deposit and remove methylation marks, even despite their mutations. Thus, treating affected AML cells with vitamin C can help to revert their methylation defect, which directs their gene expression to a healthier state and causes cancer cells to die under controlled laboratory conditions. As vitamin C is a non-toxic, well-tolerated, widely available, and cost-effective substance, its potential anti-cancer effect provided us with a unique opportunity to test whether this knowledge could be translated into effective but less toxic alternative treatment strategies for AML patients who harbour these mutations.

 

Within the scope of this Health Research BC and Lotte and John Hecht Foundation co-funded project, we have created murine leukemia model systems that allowed us to confirm the vitamin C anti-leukemic effect in living organisms. Interestingly, while studying these models more deeply, we observed that not all cells within a pool of leukemia cells responded equally to vitamin C – whereas most cells matured and died, there seemed to be some cells that were able to survive the treatment despite carrying the same disease-initiating mutations. This observation directly impacts the potential to utilize vitamin C in a therapeutic setting, arguing that even among AML cases that display the same disease-driving genetic abnormalities, not all patients will respond to vitamin C. Also, these findings are consistent with clinical observations, where historically, vitamin C was reported to be both highly effective and not effective at all in a series of trials in the 1970’s and 80’s that assessed the activity of vitamin C against terminal stage solid cancers.

 

Potential Influence

In the remaining months of finalizing this project, we are focusing on identifying what makes some cells sensitive and others tolerant to vitamin C, despite the presence of the same disease-driving mutations. Therefore, we have selected individual cells from a pool of mutation-positive AML cells which display the ability to produce a leukemia-like myeloid cell hierarchy in a culture dish. Through repeated treatment and testing, we could identify both model hierarchies that repeatedly tolerated or succumbed to the presence of vitamin C. As each cell within a model hierarchy stem from a single ancestor cell, we hypothesize that it is the maturation state of the ancestor cell – in combination with the present mutations – that mediates the observed differential vitamin C responsiveness. Further, we argue that we will be able to observe this difference in maturation state in a cell or a hierarchy’s DNA methylation patterns. We are working to confirm this hypothesis to define a diagnostic molecular signature (a so-called biomarker) that might help decide which AML patients can benefit from vitamin C in a clinical setting.

 

Next Steps

This research will be continued in the Hirst lab; however, I will move on to a new position soon as the time I am allowed to work as a postdoctoral fellow in Canada is coming to an end

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

 

Using host defense peptides and their synthetic analogs as alternative therapy for chronic infection caused by multi-drug resistant organisms

The discovery of antibiotics was one of the greatest advances in modern medicine, enabling control of infections. However, bacteria can develop antibiotic resistance over time, and become less sensitive to antibiotics. Without effective treatments, infections by these organisms can lead to prolonged illness, and routine surgeries can become life threatening. The lack of new antibiotics to combat the rapidly growing number of multi-drug resistant (MDR) organisms has become one of the most serious global health concerns. There is an urgent need to develop new therapeutic strategies against MDR organisms.

Dr. Choi’s research will investigate the potential use of a group of natural molecules known as host defence peptides as an alternative therapy to treat chronic infection caused by MDR organisms. The advantage of these peptides is that they do not directly target microorganisms; instead, these molecules promote the body’s immune system to fight against infections. This unique ability prevents microorganisms from developing resistance towards the peptides.

Results from this research will be an exciting example of alternative therapy to treat antibiotic resistant infections.


End of Award Update: October 2022

Most exciting outputs

One of the most exciting outcomes is to have the opportunity to present my results at an international conference—the Gordon Research Conference—and establish networks with scientists across the world.

Impacts so far

The Michael Smith Health Research BC/ Lotte & John Hecht Memorial Foundation Research Trainee award allowed me to focus on my project to develop alternative therapeutic strategies against multi-drug resistant organisms, especially during the COVID pandemic.

Potential future influence

The award gave me opportunities to attend various conferences where I presented my work, met with researchers whom I can learn from to advance my knowledge and skills, and built supporting networks, all of which are invaluable for my career goal as a researcher.

Next steps

We are in the process of writing a manuscript on utilizing lung organoid model for screening antimicrobial and immunomodulatory therapies against Pseudomonas aeruginosa infection.

Useful links

Behavioural and neural correlates of placebo responses in healthy and clinical populations

Michael Smith Foundation for Health Research/Lotte and John Hecht Memorial Foundation Post-Doctoral Fellowship Award

Placebo effects pose challenges to the conduct of clinical research. Double-blind randomized placebo-controlled trials can demonstrate superiority of an active intervention to a placebo. However, in some cases placebo control / complete blinding is difficult or impossible. For instance, in invasive or surgical interventions, placebo use raises ethical questions.

Susceptibility to placebo effects varies substantially across individuals: some experience pronounced placebo effects, while others show little or no response. Sources of this variation are poorly understood. Recent evidence from basic research has pointed to the role of reward expectancy and neural reactivity to rewards as key mechanisms of placebo response.

We seek to identify predictors of individual placebo responses in a sample of healthy volunteers, focusing on reward expectancy and reactivity. We will also examine individual variation in placebo response in an ongoing randomized controlled trial of an endovascular procedure in multiple sclerosis at UBC.

Understanding individual variation in placebo response could ultimately be used in clinical research:

  1. To model placebo-related variance of patients in clinical trials where placebo control is impossible or problematic
  2. To guide selection of patients for clinical trials

Co-registered optical coherence tomography and autofluorescence imaging

Lung cancer is the most common cause of cancer death with more than 1.3 million mortalities annually. Autofluorescence (AF) bronchoscopy is an established clinical technique that has proven to be extremely effective for early detection and staging of cancer by identifying high-risk areas where biopsies should be collected.

Currently, AF imaging is the most sensitive means of lung cancer detection. However, the improved sensitivity of AF broncoscopy comes at the cost of a decrease in specificity due to false-positive fluorescence in areas of inflammation or an increase in epithelial thickness. Moreover, performing biopsies and conducting histology on the removed tissue are costly and time-consuming.

The efficacy of the treatment would be significantly enhanced by differentiating carcinoma from other non-dangerous anomalies. OCT, the optical equivalent of ultrasound, enables high resolution in vivo imaging of airway morphology to study the high-risk tissue sites without performing biopsy and removing tissue. Therefore, when used in combination, AF-OCT imaging can provide rich biochemical information. The aim of Dr. Pahlevaninezhad’s research is to combine AF imaging and optical coherence tomography (OCT) to manage this disease through earlier detection. Dr. Pahlevaninezhad’s research method begins with combining the two modalities in free space to test ex vivo samples and to calibrate the system. The next step will be to build a fibre-based system for in vivo imaging of lung and to test the system on a small number of consenting patients.

Through the combination of these imaging techniques, Pahlevaninezhad’s research will provide both architectural and biochemical information which will aid in avoiding unnecessary biopsies. Significantly, the applications of the proposed device are not just limited to lung cancer; it also could target other applications like the oral cavity, considerably enhancing the ability to detect cancers effectively and efficiently.