PhD Researcher (UQ)
Repurposing an existing medication (prochlorperazine) to improve patient response to immunotherapy in breast cancer
I’m a doctor training to be a surgeon with aspirations of subspecialising in Breast Surgical Oncology. Concurrently, I am conducting my PhD research in the UQ Simpson Lab. My aim is to find a treatment that can traverse the gap from my laboratory benchtop to the bedside of my breast cancer patients.
Unfortunately, a significant proportion of breast cancer patients cannot be treated with surgery alone and require additional treatment. Strategies such as immunotherapy are based on amplifying the immune system response to fight cancer. Although there have been incredible breakthroughs –many patients do not respond.
The crux of my research is how prochlorperazine, a medication already used in the hospital, can be repurposed as a cell uptake inhibitor to improve the way receptors are presented to the cell surface. The goal of this technology is to improve immune cells’ ability to kill breast cancer; ultimately improving patient response to immunotherapies.
Breast cancer is the most commonly diagnosed cancer in women in Australia and approximately 1 in 7 Queensland women will be diagnosed with breast cancer in their lifetime. Although we have fantastic screening programs in Queensland, which assist in the earlier detection of the disease – a significant portion of patients will already have advanced or aggressive disease that requires additional therapy to surgery such as chemotherapy or immunotherapy.
Trastuzumab (commonly known as Herceptin) is a drug currently used to treat ‘HER2-positive breast cancer’ which is typically associated with a poorer prognosis and shorter overall survival. In a healthy individual, the HER2 protein is responsible for normal cell division and growth; however, in a cancer context, HER2 significantly worsens the condition via tumour growth. Trastuzumab is a monoclonal antibody; it functions as a cancer targeting drug by attaching itself to the HER2 protein and preventing its cell division and growth functions – hence, preventing cancer growth. Despite the ground-breaking nature of this therapy, response rates are less than 35%. Clinicians and patients often share heart-sinking disappointment with the absence of a response. In addition, the current literature estimates an excess of $355 million is spent on monoclonal antibody therapy for non-responders.
The poor response rate of these targeted therapies has become the focus of the Simpson Lab at The University of Queensland. Our lab observed significantly improved response rates to the monoclonal antibody therapy in patients that expressed a larger number of cell surface receptors in a particular pattern. The juxtaposition to this is patients whose cells have internalised their receptors (the target of the drug) into the cell – hence, their cells do not respond as effectively to this targeted therapy. This observation formed the basis of our hypothesis that we could repurpose prochlorperazine, an anti-nausea medication already stocked in hospitals, as a tool to maintain high level of cell surface receptors in the afore pattern. Through rigorous experimenting, we have demonstrated this hypothesis correct; furthermore, published in Cell 2020 (Chew et al) we’ve proven the increased clustered receptor levels directly influence and improve the binding of trastuzumab and immune cell killing of breast cancer cells.
Antibodies like trastuzumab have a drawback. The average cost of treating one patient for a year is approximated at $300,000. Making these drugs work better for each patient and for more patients who are given these drugs makes economic as well as health sense. Prochlorperazine is offered at $20 per vial on the Australian PBS. So, why would we not add a $20 drug to the very expensive antibodies to improve outcomes?
In summary, the benefit of our work to Queensland is to potentially improve current response rates to trastuzumab in breast cancer patients. Hopefully this means better outcomes and longer lives for our lovely Queensland ladies.
Role modelling is complex and evolves as you experience life and all the bizarre, wonderful and sometimes painful ups and downs that it has. In my early years, my role models consisted of pinnacles of perfection – prestigious individuals who had excelled in their fields and portrayed constant excellence. Through maturity, my view of who I value as a role model has adapted. I am in awe and admiration of those who can break barriers, and persevere through hardship to become successful. My role models today are the mature aged students returning to university to study their true passions: or those who somehow manage to balance an incredible career in science with taking the kids to afterschool activities.
My pathway to STEM has not been linear. I failed my first high school biology exam and was encouraged to pursue a career in humanities. Whether it was through stubbornness or eagerness, I persisted, worked hard and was fortunate to be offered a position to study medicine. Very early on, I had deemed surgery as an incompatible pathway for me, owing to the multiple stigmas and false rhetoric clouding this specialty.
In my surgery rotation in my intern year, this narrative took on an entirely different perspective. My registrar was a blonde, funny, wonderful woman. She wore the same brightly coloured dresses that I did and people would frequently comment that we looked like high school art teachers rather than surgeons. Watching someone I could easily align myself with allowed me to defy the stigma and rhetoric’s surrounding surgery, opening the door that I never would have walked through alone.
My path was curbed after a numb patch on my leg evolved to a diagnosis of Multiple Sclerosis and a year off clinical work to receive monoclonal antibody therapy. Devastated to be away from clinical practice, I busied myself with starting research with Associate Professor Fiona Simpson – an incredible woman with a passion for working out “the why” and endless patience while I learnt the ropes of real science in between receiving immunotherapy.
The possibility of a career in surgery is now a reality – I am honoured to have been accepted onto General Surgery training. My path is filled with bumps and detours; however, I find pride in arriving here as my authentic self. I could never have navigated this path without the foundations laid by the wonderful women before me. Led by these women, I feel strongly about righting the misnomer that only ‘the best’ pinnacles of perfection are accepted in my field. Rather, I hope that the new role models in surgery and STEM are known for their innovation, their passion for their field and deep care for their patients and improving their outcomes.
STEM promotion and engagement has been a major priority throughout my time at the Translational Research Institute. Recently Associate Professor Fiona Simpson and myself presented on a panel at the TRI Town Hall. This presentation highlighted the benefits, barriers, and enablers of “Connecting Clinicians to TRI” and the power such relationships possess in progressing translational research projects. Furthermore, I’ve presented our collaborative work in breast cancer research in multiple forums: San Antonio Cancer Symposium; General Surgery Australia Annual Scientific Meeting (where I was awarded the Excellence in Research Award); Royal Australasian College of Surgeons Annual Scientific Congress; Lorne Cancer Conference; and Australian Society of Medical Research Conference (where I was awarded the People’s Choice Award for Long Talk Presentations).
The translational aspect of research and its prevalence in maintaining a patient first ethos has constantly sparked my passion. As a medical student in the Sunshine Coast Hospital and Health Service I acted as a research assistant to GIFTR (Giving InFormation to Research) pilot. This involved surveying patients, attending the HHS, on their willingness to provide their medical information for low risk and non-international health research. This lay the foundation for the GIFTR initiative that is currently utilised by Queensland Health.
Throughout my medical career I have constantly found satisfaction in providing mentorship and assistance to medical students. As a medical student I undertook work as a Medical Sciences tutor for earlier year medical students; additionally, as a junior doctor I have involved myself within formal medical student teaching via the University of Queensland. I volunteer myself to assess the final OSCE examinations and have participated in their Intern Preparedness program via the Mater Hospital. I have provided formal General Surgery teaching to 3rd year medical students at both Mater and Toowoomba Base Hospital. Furthermore, I have also provided General Surgery teaching and suturing lessons to Interns and junior medical staff at the aforementioned hospitals.
Additionally, I assisted in facilitating and teaching at the Supporting Women in Medicine (SWIM) Clinical Exam Tutorials and Professional Development Workshops – a subject I have displayed constant passion and interest for. Similarly, I have extended this passion to local public speaking at Brisbane girls’ schools to promote and advertise the medical journey and its endeavours.
Every year since my diagnosis with MS I have participated in the May50K – an endeavour to walk 50km over the course of May to raise money for MS Research Australia. The team I am a member of, “Walk a Myelin My Shoes”, has successfully raised over $10,000. In addition to the financial benefit, this fundraising also helped me connect with affected by MS. Raising awareness of this condition has provided me with an overwhelming sense of pride; however, it acts as a constant fuel to my ambitions of improving the medical field and offering my utmost effort to my profession.