Holy Grail: Restoring anti-tumour immunity in NSCLC

Lung cancer

27 Jun 2022

First up: can you describe the aim of your research in 10 words? 

To reinvigorate anti-tumour immunity by reprogramming immunosuppressive myeloid cells.

A lot of your work involves haematopoietic cell kinase (HCK). Can you tell me what that is, what you’ve learned about it so far and how it fits into your anti-tumour immunity research?

HCK is a member of the SRC kinase family and is expressed in myeloid cells. Elevated HCK expression is observed in most solid cancers and correlates with poor patient survival.

My research (Poh et al. Cancer Cell 2017, Cancer Immunology Research 2020, Science Advances 2022) is the first to show that aberrant HCK activity promotes gastrointestinal tumour growth in mice by enhancing the immunosuppressive activity of myeloid cells. Immunosuppressive myeloid cells are a major component of solid cancers and play a critical role in tumour development and metastasis by contributing to fibrosis, angiogenesis, immune exhaustion and drug resistance.

My colleagues and I have also shown that genetic ablation or therapeutic inhibition of HCK reduces tumour growth and metastasis in mice by ‘reprogramming’ immunosuppressive myeloid cells towards an immune-stimulatory (inflammatory) endotype. In turn, this reduces tumour fibrosis and angiogenesis, and re-invigorates anti-tumour immunity by enhancing the recruitment and activation of cytotoxic CD8 T-cells and natural killer cells. Importantly, therapeutic HCK inhibition also improves the efficacy of chemotherapy and immunotherapy across a range of tumour types, including stomach, colon, breast and skin cancer. These results are exciting because they demonstrate the broad applicability of HCK as a therapeutic target.

You recently won a grant to explore how targeting HCK in non-small cell lung cancer (NSCLC) can improve therapy responses (congratulations!). Can you tell me a bit about that work?

Up until now, my research has mainly focused on gastrointestinal cancers, but this two-year grant will enable the project to extend laterally into lung cancer so my team and I can identify additional tumour types that may benefit from anti-HCK drugs. We are particularly interested in NSCLC because it is the most common type of lung cancer, and most patients respond poorly to standard-of-care therapy. This is largely attributed to a ‘cold’ tumour microenvironment, which is dominated by immunosuppressive myeloid cells.

The first aim of this project is to establish a strong clinical rationale for developing HCK as a drug target in NSCLC. We will analyse an extensive repository of epidemiological data and patient samples, including clinically-annotated tumour microarrays and fresh tumour biopsies to understand how excessive HCK activation influences local/distant relapse, treatment response and overall prognosis. We are also interested in identifying patient subtypes who are most likely to benefit from anti-HCK drugs in future translational studies.

Our second aim is to validate HCK as an adjuvant therapy to improve the potency of standard-of-care chemotherapies and immunotherapies in orthotopic mouse models of NSCLC. This research complements our ongoing efforts in collaboration with industry partnerships to develop and optimise proprietary small molecule HCK inhibitors with better specificity and efficacy. Further, we’re interested in understanding the immunological mechanisms that underpin reduced tumour growth and enhanced drug synergy following therapeutic inhibition of HCK.

Lots of ground to cover. How did this grant come about and how will it support your research?

The idea for this grant was spurred by initial observations in HCK knock-in mutant mice that have been genetically engineered to express constitutive kinase activity. Approximately 20% of these mice develop lung adenocarcinomas due to excessive lung inflammation, suggesting a link between aberrant HCK activity in myeloid cells and lung cancer.

Because I’m still new to the lung cancer field, I’ve teamed up with Dr Sagun Parkh, who is a consultant medical oncologist and Head of the Lung Oncology Clinic at Austin Health. Dr Parakh is passionate about improving treatment outcomes in lung cancer, and has an amazing track-record in the development and translation of novel therapies into the clinic. We both saw an opportunity to combine our complementary research and clinical expertise to see whether HCK would be a viable therapeutic target in NSCLC.

We are extremely grateful to the Lung Foundation Australia and Cancer Australia for co-funding this project, which will be co-led by myself and Dr Parakh. This grant is invaluable to our development as early-career researchers, and will enable us to purchase critical resources and reagents to continue our work on developing HCK as a drug target in cancer. We will also be supported by an amazing team of clinicians, senior researchers, and consumer advocates to maximise the translational impact of our research.

How long before your work reaches the clinic?

Our research is still at an early, pre-clinical stage, but has the potential to create new treatment options for cancer patients, and improve progression free survival and quality of life. There is also potential for HCK to be developed as a prognostic biomarker.

On average, it takes almost two decades to bring a new treatment from initial discovery into the clinic because of rigorous testing to ensure efficacy, reproducibility, and safety at a pre-clinical level before moving on to clinical trials in patients. The Olivia Newton-John Cancer Research Institute specialises in “bench to bed-side” and “bed-side to bench” research to speed up the process of developing new cancer treatments. This enables us to accelerate the translation of lifesaving drugs to patients who will benefit most from them.

What aspect of your research excites you the most?

I really love collaborative research, and the opportunity to work with scientists, clinicians and research advocates from all around the world on a collective goal. I love the shared excitement of solving a problem, obtaining promising data, and the animated discussions that usually follow both these outcomes.

What’s your Holy Grail — the one thing you’d like to achieve in your research career?

I’ve been guided by incredibly supportive mentors throughout my career, and I’ve learnt a lot about myself through their encouragement and advice. It’s been a true labour of love. My Holy Grail is to pay it forward and help others in a similar way.

What is your biggest research hurdle?

Securing funding is a major hurdle that scientists (including myself) constantly worry about. Australia is home to the best health and medical researchers, but we are losing more and more skilled and talented scientists every year due to insufficient funding.

For example, the current success rate for the National Health and Medical Research Council (NHMRC) Ideas grants scheme is only 9%. Moreover, a third of all Ideas grants in 2021 scored by peer review as “Outstanding by international standards” were unfunded. This has significantly impacted the progress of fundamental and translational research.

In order to continue making significant contributions to health and wellbeing, the Australian science and medical research sector needs an urgent boost in funding to offer better long-term career perspectives, and clearer pathways for commercialisation of research findings. This will empower scientists with the resources to effectively respond to current and future health challenges.

Ok, last one. What new hobby have you picked up during COVID?

Like most people, I jumped on the sourdough/baking bandwagon at the start of the pandemic, but didn’t stick with it for too long. I also dabbled in pottery and leather craft, which were extremely fun but were more once-in-a-while hobbies. I finally found my happy medium with paint-by-numbers and jigsaw puzzles, which are both great ways to unwind and relax. Snapping a jigsaw piece into the right place is one of the best feelings in the world.

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