Target validation and DNA damage response team

Breast cancer isn’t just one disease. There are many diverse types, and each one needs to be investigated and often treated differently. Some breast cancers develop because of a strongly inherited genetic cause that prevents our cell’s ability to repair damage to their DNA, and keep their instructions accurate. These cancers also have a weakness or “Achilles heel” associated with this failure of DNA repair that we can target. Another challenge in treating breast cancer is that treatments may work well at first, but the cancer can learn how to resist the treatment and return.

To find kinder and smarter treatments, we need to better understand the disease, as well as the genes and proteins that sometimes it uses and relies on to spread, thrive, and resist our current best treatments.

Professor Andrew Tutt and his team have two main areas of interest. They have led major developments in chemotherapies and PARP inhibitors treatments for those inheriting changes in BRCA1/BRCA2 or PALB2 genes (5-10% of breast cancer). As well as continuing to improve other treatment options in familial breast cancer. They also focus on identifying and targeting the processes that drive the 15% of all breast cancers that are triple negative, a group that has generally had fewer targeted treatments than other breast cancer types.

Certain changes in genes can lead to the cancer resisting treatment. Andrew’s team wants to understand why, so they can design better treatments. These treatments aim to selectively target breast cancer cells, without damaging healthy cells. They’d also have fewer side effects. Andrew is a breast cancer oncologist and he and his laboratory now work jointly with that of Professor Chris Lord bringing together their skills to most effectively target breast cancer.

Andrew and his team have 4 project areas on which they also work very closely with Professor Chris Lord:

1. Improving treatments for breast cancers with BRCA gene changes
   
   Treatments that target the way that DNA repairs itself can be very effective against breast cancer cells with changes to their BRCA genes. Two examples of this type of treatment are platinum-based chemotherapies and PARP inhibitors. But these treatments don’t work for everyone. And some cancers can become resistant to these treatments over time.

   The team is researching how cancer can become resistant to platinum-based chemotherapy and PARP inhibitors. They also want to understand how often different types of resistance happen. They can then use this information to design new, more effective treatments.

2. Understanding the roles of HORMAD1 and PUM3 in triple negative breast cancer
   
   Andrew’s team has found that high levels of 2 proteins are often involved in breast cancer, especially triple negative disease. These proteins are called HORMAD1 and PUM3.
   
   Like the BRCA proteins, HORMAD1 and PUM3 are involved in DNA repair and maintaining the stability of our chromosomes. These are the packages of DNA instructions that our cells must keep accurate when they are copied and then allocate them evenly to our new cells when they grow. Andrew’s team is investigating what advantage high levels of these proteins can bring to breast cancer cells. The researchers are studying if high HORMAD1 and PUM3 levels reveal a weakness in the breast cancer cells. This weakness could then be targeted with a drug.
   
   
3. Studying a potential new drug target, GPR89
   
   Andrew’s team has discovered that a “pump” protein that controls acid/alkali balance called GPR89 is often moved from its normal location to the major protein production and energy production areas of breast cancer cells, particularly in triple negative breast cancer. They also found a possible way in which it helps the tumour to grow. Now, they want to find out how cancers with the re-localised GPR89 “pump” could be treated.

   The researchers want to detect the cancers who transfer the GPR89 pump and which of these types of breast cancer need GPR89 more than others to grow. They are seeking to learn how to best block or remove the pump from its new location and therefore selectively kill the cancer cells.

   To do this, they’ll use samples of tissue donated by people with breast cancer. Using lab methods, they’ll stop or limit GPR89 production, both in mice with breast cancer and in 3D mini-tumours grown in the lab. They are also working with drug discovery groups to see how to best design drugs to target the GPR89 pump.

4. Creating ways to study breast cancers in the lab using cells donated by people with breast cancer
   
   Sometimes, discoveries made in the lab don’t work when they are used in clinical trials. That’s why we need better ways to study in the lab the breast cancers that really occur in the clinic.

   Andrew’s team are using tumour samples donated by people being treated at both the Royal Marsden Hospital and Guy’s Hospital. Some of these samples will be used to grow 3D mini-tumours in the lab, and others will be used to develop models of breast cancer in mice. Their aim is to reduce the reliance on mice if we can more successfully grow 3D mini-tumours in culture dishes.

   By working with patients and the wider clinical team they aim to be able to capture and “model” the different types of breast cancer, at different stages of the disease. Some of the samples will come from people whose cancer has already become resistant to certain treatments. This will allow researchers to test ways to reverse the resistance, or find a way around it. In their own work Andrew’s lab works with his clinical and clinical trials practice to develop models of changes in BRCA1/BRCA2, PALB2 genes and triple negative breast cancer.

Ultimately, this research could help people with breast cancer to live well, and improve their chances of survival.

As well as being a researcher, Andrew is also a clinician. This means he is in a good position to understand what needs to be done and to translate what he and his team have found in the lab to benefit people affected by breast cancer.

The work he’s doing at our research centres is focused on finding kinder, more effective treatments for BRCA1/BRCA2 and PALB2 breast cancer as well as triple negative breast cancers. But these findings could bring new treatments to people with other forms of breast cancer too.