Cure Incurable Diseases: Teaching Old Drugs New Trick to Fight Ovarian Cancer | Science

In In May, a PhD student funded by the Medical Research Council (MRC) Max Perutz Science Writing Award 2020 And tell the public “why your research is important”. From the many entries received, 10 It became a candidate list We covered a variety of topics, including motor neuron disease, self-harm, baby pain experiences, and bone loss due to space travel.

The essay was judged by ObserverIan Tucker, Roger Highfield of the Science Museum, Professor Fionawat of MRC, Andy Ridgeway of the University of Bristol, Journalist and Broadcaster Samira Ahmed.

£ 1,500 award to Sarah Taylor, winner of the University of Edinburgh’s Institute for MRC Genetic and Molecular Medicine, for her article on her work on the effects of proteins on the effectiveness of chemotherapy at a virtual ceremony last Tuesday. Was presented.

Here, we publish an award-winning article that Samira Ahmed described as “a horrifying and intriguing story.”

She is sitting in a small doctor’s office Waiting to hear the news of her latest scan again. It was a difficult journey since she last sat in this chair and before the recent treatment began. Over a month of malaise, vomiting, pain, sleepless nights, and inevitable hair loss. But this time, chemotherapy has not been successful. After all the side effects, all the pain she has endured, her tumor is still growing and there is a black mass in the ovaries. Where does she go from here? What can she do when all the treatments she wants don’t work?

This situation is very common in women with high-grade serous ovarian cancer (HGSOC), a devastating form of ovarian cancer. Only 35% survive more than 5 years after diagnosis. Chemotherapy and surgery are very effective in initially shrinking the tumor, but the cancer continues to fight back. Over time, tumors change, and cells that survive treatment predominantly replicate and inherit the protective properties that give them a survival edge. Tumors are completely resistant to chemotherapy, leaving no barriers to prevent the tumor from growing out of control and overwhelming the body.

However, there are groups of cancer patients who are far more sensitive to chemotherapy treatment than other cancers that can be completely cured by chemotherapy. One key to this is the DNA repair protein. This is the tool that every cell uses to protect DNA from damage. Think of this DNA as a cell instruction manual. It details how cells build all the proteins they need to live and perform different functions. Cancer cells adapt and grow rapidly, so DNA repair proteins are often defective. It may sound strange, but this is good from our point of view! Chemotherapy kills cancer cells by attacking the DNA of the cancer cells, and cells that are deficient in DNA repair proteins have essentially forgotten to bring a first aid kit. This means that the patient can survive because chemotherapy can completely kill the cancer. This can be used to reveal this cancer armor gap and help women who need it most.

Even for certain types, such as HGSOC, the two cancers are not exactly the same. Some have fully functional DNA repair proteins. Some initially have defective proteins, which can be adapted and corrected. Others can make excess amounts of protein to survive the effects of chemotherapy. By learning what happens to these proteins as they become resistant to chemotherapy, important DNA repair proteins work so that chemotherapy can kill cancer cells more effectively. I think we can make a new drug to prevent this.

The first question I asked was which of these proteins was really important to the way HGSOC responded to chemotherapy. I used cells called cell lines that were taken from the tumors of HGSOC patients and adapted for easy growth in the laboratory. It has properties similar to the patient’s actual tumor. By using cell lines taken from selected patient tumors, scientists can build images of similarities and differences between patient tumors. I started by assessing the growth of various cell lines when treated with a drug called carboplatin, the standard chemotherapy used to treat HGSOC. The slower the cells grow, the more effective the treatment. We found that susceptibility to carboplatin varied widely among different cell lines. It’s not surprising, because one of the main challenges in cancer research is how many differences there are between individual tumors, and even in different parts of the same tumor.

Then I found the reason for these differences and started looking for changes in DNA repair proteins. A search of a database of ovarian cancer patients looking for clues as to what is happening reveals that tumor cells typically produce abnormally large or small amounts of certain DNA repair proteins. It was. Therefore, I decided to measure the amount of repair protein produced by my cell line. It was found that one of these repair proteins was almost completely deficient in the most chemotherapy-sensitive cell lines. This is a very good indicator that this protein may be an important factor behind repairing the damage caused by chemotherapy.

Therefore, we identified proteins that may be involved in the effectiveness of chemotherapy. What’s next? I wanted to make sure that this protein works like I suspected in cancer cells. I blocked the cell line from producing the protein of interest and re-examined how sensitive cancer cells are to chemotherapy. This confirmed my first suspicion-removing protein made cancer cells much more sensitive to chemotherapy!

I’ve only been working on this project for the first year, so there’s still a lot to do, but this is an exciting starting point. Certainly very exciting! I plan to study the mechanisms these cancer cells use to alter the amount of this repair protein and see how smart they are. Are you fooling chemotherapy by producing more of this protein to prevent the cells from being killed? Does this result in chemotherapy-resistant tumors? Most importantly, I want to identify patients whose cancer has high levels of this repair protein and may be ineffective with conventional chemotherapy, and focus on how I can help them. I think. To address this issue, I would like to test drugs that prevent this protein from performing DNA damage repair, neutralize cancer, and cannot repair the damage done by chemotherapy. My dream is that one day this will allow more women to win the office, have no chance of winning, and close the door on their way out.