Tackling the challenges of chemotherapy resistance
We talk to Dr Sarah Spear about her latest findings from her Ovarian Cancer Action funded project. Her work aims to understand if the tumour genetics control how the immune system reacts to the tumour, and if we can develop drugs to alter this for the better.
Dr Sarah Spear is a post-doctoral researcher that previously worked in the Ovarian Cancer Action Research Centre, investigating why some ovarian cancers are more aggressive than others, and if the immune system plays a role.
In conversation with Dr Sarah Spear
Can you talk us through your project - what was the challenge?
Not all women respond to chemotherapy the same way, and unfortunately, some see their cancer return. My project investigates whether the genetic makeup of tumours affects the immune system and drives aggressive forms of ovarian cancer.
We’re particularly interested in the PTEN gene, which is different (mutated) in some ovarian cancer patients.
Our goal is to understand how PTEN mutations impact the immune system and explore potential ways to reverse these effects.
What is PTEN?
PTEN stands for phosphatase and tensin homolog and is a gene that helps regulate cell growth.
A fault or mutation in this gene can cause problems with cancer cell growth.
Why is PTEN important to ovarian cancer treatment?
It works by turning off the PI3K pathway—a process that tells cells to grow and divide.
Every time cells receive a signal to grow and divide they switch on the PI3K pathway and this allows them to grow.
However, quite quickly PTEN shuts this pathway down again and the cell stops growing.
But when PTEN is mutated, this "off switch" stops working, causing cells to grow uncontrollably.
There are drugs which can switch off the pathway again, these are called PI3K pathway inhibitors, however the signalling is so complex the cells often find a way to grow and adapt to the drugs.
What are the outcomes of the research?
We focused on the immune cell called a macrophage.
Macrophages are all over the body and help our organs stay healthy, repairing any damage that occurs and removing any bacteria that find their way in. They are vital to our health.
However, in ovarian cancer the number of macrophages in tumours increases dramatically compared to the healthy tissues.
What is a macrophage?
Macrophages are immune cells that help keep tissues healthy by repairing damage and removing bacteria. In ovarian cancer, however, macrophages can play a double role—some attack the tumour, while others help it grow.
Macrophages are thought to make up to 50% of the cells in tumours. However, removing them is not that simple because the cancer changes them into different types or flavours.
Some macrophages are trying to remove the tumour and attack, whilst others are helping it grow.
We analysed all the macrophages in tumours with and without PTEN-mutations in ovarian cancer and found that a specific type of macrophage is only found in PTEN-mutated tumours.
We learned this specific macrophage had high levels of an enzyme called HMOX1. This enzyme should only be found in your liver and spleen, and its used to break down old red blood cells and recycle iron.
What does the HMOX1 enzyme have to do with ovarian cancer?
Its unusual to find this enzyme in a tumour.
When macrophages use this enzyme to break down blood - they also become immunosuppressive and they shut down any attacking cells around them. This normally helps them peacefully breakdown blood in the liver and spleen without causing any problems.
However, if they are doing this inside ovarian cancer - this will shut down the immune system inside and prevent it from attacking the tumour.
We looked in patient samples and found that patients with high levels of these HMOX1 macrophages have a lower chance of survival and that their tumours are also more immunosuppressive.
How finding HMOX1 can help women with ovarian cancer
Imagine a bustling city where rubbish trucks (macrophages) play a crucial role in keeping the streets clean and recycling waste (removing damage and bacteria).
Normally, these trucks operate efficiently, ensuring the city runs smoothly.
Now, picture one part of the city where something has gone wrong—a factory (the tumour) is pumping out toxic waste at an alarming rate. The rubbish trucks sent to this area start malfunctioning. Instead of clearing the waste, they begin recycling it into harmful materials that fuel the factory’s growth.
This is what happens with HMOX1 in PTEN-mutated tumours. Macrophages, which should protect the body, start producing an enzyme (HMOX1) that breaks down blood in a way that suppresses the immune system. Instead of attacking the tumour, they unintentionally help it grow, creating a vicious cycle that allows cancer to thrive.
By blocking this enzyme, women with ovarian cancer may be able to live longer by giving the immune system a better chance to attack the tumour or slow tumour growth.
What are the next steps in your research?
We now want to understand what makes the macrophages start using HMOX1 and what exactly the cells are doing as a result, we want to use this information to try and develop a treatment strategy that could target this process in patients.
Why is ovarian cancer research so important?
While chemotherapy helps so many people, unfortunately, many women with ovarian cancer stop responding and become resistant to treatment.
It's at this point that research is so vital. We urgently need to identify new drug options, for those women who have stopped responding. As well as improve the existing treatment regimens for all women with ovarian cancer.
Did you always want to be a scientist?
In short: yes!
From a young age, I was fascinated by science. I loved learning about how the body works and understanding diseases, which led me to study Biomedical Science and eventually specialise in tumour immunology during my PhD.
Today, I have the privilege of working as a scientist every day, seeking answers to how cancer works and how we can fight it.
What do you dream of achieving?
I would like to see personalised treatments for every patient, based on their tumour genetics. In this way, every woman would receive exactly the drug combination their tumour will respond to, rather than receiving drugs that may not work.
How you can help us fund early-career researchers to build breakthroughs
For women diagnosed with ovarian cancer, chemotherapy often provides hope. But for many, this hope is cut short when their cancer becomes resistant to treatment.
New research steps in as a lifeline.
The goal is clear: discover new drug options for women who no longer respond to existing treatments and enhance current therapies for all patients.
At Ovarian Cancer Action, we’re committed to funding early-career researchers whose work has a tangible impact on improving outcomes for women.