2021 Recipient — Bojana Stefanovska, PhD

Dr. Bojana Stefanovska

Bojana Stefanovska, PhD

APOBEC3B and DNA Repair as Synthetic Lethal Combinations in CCOC

Project Summary

Clear Cell Ovarian Carcinoma (CCOC) is one of the most clinically challenging types of ovarian cancer. The current standard-of-care consists in surgical resection and platinum therapy. The latter is a type of chemotherapy that causes changes in the DNA structure that result in cancer cell death. Unfortunately, platinum-based therapies are toxic and tumors frequently develop resistance to this type of treatment, leaving no good therapeutic alternatives. Thus, there is an urgent need for innovative research in this area.

Recently published data from our lab has led to the identification of a subset of CCOC patients that express high levels of an enzyme called APOBEC3B and are exquisite responders to platinum therapy. APOBEC3B is usually active as a part of our natural defense against viral infections. It attacks the genome of viruses by mutating their DNA, which in turn corrupts viral proteins and impairs virus replication and pathogenesis. However, in CCOC and other cancer types, APOBEC3B becomes activated without a viral infection and starts to attack and damage cellular chromosomal DNA. The cells in our body are equipped with machinery that recognizes this DNA damage and tries to repair it, yet many lesions escape repair and accumulate as mutations and DNA structural changes. Therefore, in CCOC tumors treated with platinum therapy there is a toxic accumulation of DNA damage caused by both the treatment and APOBEC3B activity. This simultaneous perturbation results in preferential death of the CCOC tumor cells (i.e. synthetic lethality). Thus, I hypothesize that the aberrant activation of APOBEC3B in CCOC makes these tumors dependent upon the proper functioning of cellular DNA repair machinery. Thus, inhibition of this machinery is predicted to lead to the selective death of CCOC tumor cells expressing APOBEC3B.

In this proposed research project, I will pursue two goals: Aim 1- Identify inhibitors (already in drug development pipelines) of the DNA repair machinery that kill CCOC tumor cells even more efficiently than platinum therapy when APOBEC3B is active. Aim 2- Identify the components of the DNA repair machinery responsible for the accumulation of DNA damage in CCOC patients treated with platinum therapy and active APOBEC3B. The results of these studies have the potential to identify new therapeutic opportunities for CCOC.


Dr. Bojana Stefanovska grew up in Bitola, North Macedonia. In 2010, she moved to Italy to attend the prestigious University of Padova where she completed Bachelor and Master’s Degree in molecular biology. In 2014, she obtained an ERASMUS grant to conduct her Master’s Thesis research in the laboratory of Professor Fabrice André at the Gustave Roussy Cancer Center in Villejuif, France, where she was conducting research on rare breast cancer subtypes. She continued the graduate studies in André’s lab where she worked on the PI3K/AKT/mTOR signaling pathway in breast cancer, focusing on the mechanisms of resistance to mTOR inhibitors.

She was awarded her PhD in 2019 from the University of Paris Saclay.

Currently she is a Postdoctoral Associate in the laboratory of Professor Reuben Harris at the University of Minnesota and her current research focuses on identifying synthetic lethal combinations of DNA repair genes and APOBEC3B in clear cell ovarian carcinoma.

Spotlight: Meet a Scientist

Photo: Dr. Bojana Stefanovska, in a research lab, wearing a lab coat and holding on to research equipment
Dr. Stefanovska in the lab

Dr. Bojana Stefanovska, at University of Minnesota Twin Cities, is a 2021 recipient of OCRA's Ann and Sol Schreiber Mentored Investigator Award. Her project, "APOBEC3B and DNA Repair as Synthetic Lethal Combinations in CCOC," explores DNA repair as a potential treatment avenue for clear cell ovarian carcinoma (CCOC).

What initially sparked your interest in science?

My dad is a medical oncologist. When I was a child, he was doing his residency and I always thought what he was doing was so cool. We were hearing stories about people suffering from cancer all the time, and he was like a superhero to me.

I believe I was in middle school when he explained to me in words that I could understand about the Hallmarks of Cancer paper by Weinberg and Hanahan published in the 2000s. That sparked my curiosity, and I knew that I wanted to do something related to cancer. But rather than treating patients, I was more interested in understanding the biology behind this disease. Driven by that, I started my bachelor’s degree in molecular biology. And since the first day, I knew that I wanted to pursue a master’s degree and then a PhD, and I was certain that it had to be in cancer research.

What drew you to the field of ovarian cancer research?

I was always driven to learn more about cancers that affect the female population. My PhD work was completely based on breast cancer. And for my postdoc, I wanted to focus more on ovarian cancer, which is exclusively feminine cancer.

The major thing that drew me to ovarian cancer research is how sneaky this kind of cancer is. The symptoms are vague and non-specific, and women may feel them on any given day. Since they go unrecognized, that often results in delays in diagnosis and treatment. On the other hand, the treatments available are not perfect. And even though targeted therapies are already available that exploit unique features of cancer cells to attack them, there is so much more that can be done. There is still a lot to learn about the biology of ovarian cancer and how we can use that knowledge to effectively kill the cancer cells.

Can you explain your research project?

We all have this gene called APOBEC3B that is used to produce a protein that protects us when there is a particular viral infection. We don’t exactly know when and how, but in certain types of cancers, including ovarian cancer, it gets ‘woken up’ and instead of attacking the virus it attacks the human DNA by changing one of its building blocks. When that happens the structure of the DNA is damaged, and it needs to be repaired.

We all have very complex machinery that can identify the damage to the DNA and repair it. Try to think about it as bringing a broken car to the mechanics' shop. They can typically spot the damage, repair it, and give it back to you ready to go. However, if the damage is too serious, the mechanics cannot do much and you will need to get rid of the car. Similar things can happen to your DNA. If there is too much DNA damage, the cells cannot repair. Instead, they surrender and die. In my project, I’m trying to use this feature in disfavor of the cancer cells. When they have their DNA damaged because they were attacked by APOBEC3B, I want to identify which “mechanic” can repair that damage, and then fire it, so that the cancer cells won’t be able to repair the damage and they will die.

What motivates you to persist in your research?

The act of discovery is my biggest motivation. I find it fascinating that I can contribute to the understanding of the biology of cancer by discovering something that no one has ever discovered before and that it can complement the current understanding of things. It is like a never-ending story, but in a good way. The more knowledge you find, the more you realize that there is so much to be discovered, the more you want to do it. And if some of my discoveries can help change the practice of treating cancer one day, there won’t be a better reward than that.

What is your hope for the field of ovarian cancer research?

I hope that in the following years we will find ways to improve screening and detection of ovarian cancer, but also improve and personalize the treatments even more.

If you had the opportunity to personally thank someone from the OCRA community who supported your work, what would you say?

I am very grateful that by investing in my project you believe that my research can change the way we treat ovarian cancer. This opportunity is very humbling and motivates me to work even harder to change for the better the future of patients suffering with ovarian cancer.

See more OCRA-funded research projects focused on DNA repair and analysis, and clear cell ovarian carcinoma.