Healing the Incurable: Teaching an Old Drug New Tricks to Fight...

IIn May, PhD students funded by the Medical Research Council (MRC) were invited to participate in the Max Perutz Science Writing Award 2020 and explain to the public “why your research matters”. Of the many entries received, the 10 that were shortlisted covered a variety of topics, including motor neuron disease, self-harm, babies’ pain experiences and bone loss as a result of space travel.

The essays were judged by the observerIan Tucker, Roger Highfield from the Science Museum, Prof. Fiona Watt from MRC, Andy Ridgeway from Bristol University and the journalist and broadcaster Samira Ahmed.

In a virtual ceremony last Tuesday, the winner, Sarah Taylor of the MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, was awarded the £ 1,500 prize for her article on her research into the effects of proteins on chemotherapy efficacy presented.

Here we publish the winning article, which Samira Ahmed describes as a “great and fascinating story”.

She is sitting in the small consulting room I’m waiting one more time to hear the news of your last scan. It has been a difficult journey since she last sat in that chair before starting her final session. Over a month full of exhaustion, vomiting, pain, sleepless nights and the inevitable hair loss. This time, however, the chemotherapy was unsuccessful. After all the side effects, all the pain she’s endured, her tumor is still growing, a dark mass on her ovary. Where does she go from here? What can she do when the treatment she had hoped for just doesn’t work anymore?

This situation is all too common in women with high-grade serous ovarian cancer (HGSOC), a devastating form of ovarian cancer. Only 35% survive more than five years after their diagnosis. While chemotherapy and surgery are highly effective for initially shrinking tumors, the cancer continues to fight back. Over time, the tumor changes, with cells that survive treatment predominating and replicating, passing on the protective traits that give them this survival benefit. The tumor becomes completely resistant to chemotherapy and there is no barrier left to prevent it from spiraling out of control and overwhelming the body.

However, there are groups of patients whose cancers are much more sensitive to chemotherapy than others who can be completely cured by chemotherapy. Key to this are DNA repair proteins, the tools all cells use to protect their DNA from damage. Think of this DNA as an instruction manual for a cell, detailing how all the proteins are built that the cell needs to live and perform various functions. Cancer cells often have defective DNA repair proteins because they can adapt and grow so quickly. As strange as it sounds, this can be a good thing from our perspective! Chemotherapy kills cancer cells by attacking their DNA, and those lacking DNA repair proteins have essentially forgotten to bring a first aid kit – they cannot repair themselves and move on. This means that chemotherapy can completely kill the cancer, allowing the patient to survive. This shows gaps in this cancer’s armor that we can use to help the women who need it most.

Even within a certain type like HGSOC, no two cancers are the same. Some have fully functional DNA repair proteins. Some initially have defective proteins, but can adjust and repair them. Others may make excessive amounts of the proteins to fight the effects of chemotherapy and survive. I hope that by learning what happens to these proteins when a cancer cell becomes resistant to chemotherapy, I can create new drugs to prevent the critical DNA repair proteins from working, which allows chemotherapy to kill cancer cells more effectively.

The first question I asked was which, if any, of these proteins are actually important in HGSOC’s response to chemotherapy. I have used cells taken from tumors of HGSOC patients and adapted to be easily grown in the laboratory, called cell lines, which have similar properties to an actual tumor in a patient. By using cell lines from a selection of patient tumors, scientists can create a picture of the similarities and differences between patient tumors. I started by looking at the growth of various cell lines when they were treated with a drug called carboplatin, the standard chemotherapy used to treat HGSOC. The slower the cells grow, the more effective it is as a treatment. I found that sensitivity to carboplatin varied widely between different cell lines – not surprising as one of the biggest challenges in cancer research is how many differences there are between individual tumors and even between different parts of the same tumor.

Next, I set out to find the reason for these differences and look for changes in the DNA repair proteins. I examined a database of ovarian cancer patients to look for clues as to what might be going on and found that tumor cells were often producing abnormally high or low levels of certain DNA repair proteins. So I decided to measure the amount of repair proteins made by my cell lines. I found that the cell line most sensitive to chemotherapy was almost completely missing one of these repair proteins! This is a really good indicator that this protein could be an important factor in repairing the damage caused by chemotherapy.

So I had identified a protein that may be involved in the effectiveness of chemotherapy. What now? I wanted to confirm that this protein works as I suspected it would in cancer cells. I blocked the cell lines from making the protein I was interested in and saw again how sensitive the cancer cells were to chemotherapy. This confirmed my initial suspicions – removing the protein made the cancer cells much more susceptible to chemotherapy!

With this project only in my first year, there is still a lot to do, but this is an exciting place to start. I definitely think it’s very exciting! My plan is to investigate the mechanism by which these cancer cells alter the amount of this repair protein and how intelligent the cancer cells are – cheating on chemotherapy by producing more of this protein to keep the cells from being killed ? Does this lead to a chemotherapy-resistant tumor? Most importantly, I want to identify patients whose cancers are high in this repair protein, where conventional chemotherapy may be less effective, and focus on how I can help them. To address this problem, I want to test drugs that prevent this protein from repairing DNA damage, rendering the cancer powerless, and unable to repair the damage caused by chemotherapy. My dream is that one day more women will be able to leave the consulting room and feel victorious, have exceeded their chances and shut the door for good on the way out.