Searching for drug targets in triple negative breast cancer - Sedef Iskit

In the “From the lab to…” series, we highlight our team’s scientific expertise by providing the spotlight to colleagues with a background in research. For the second edition, we learn from Life Science Consultant, Dr. Sedef Iskit, about her journey through academia. During a six-year research career Sedef specialized in research into new therapeutic strategies for the treatment of triple negative breast cancer.

“Targeted therapy strategies for triple negative breast cancer patients presents a large gap in cancer research”

Triple negative breast cancer (TNBC) is one of the nastier forms of breast cancer and constitutes 15-20% of all breast cancers. In other forms of breast cancer, certain molecules are overexpressed by cancerous cells, which can then be targeted with drugs. For instance, ER+ breast cancers overexpress estrogen receptor and the survival of these ER+ breast cancer cells is heavily dependent on this molecule. Drugs that are designed to inhibit this molecule work well in treating ER+ breast cancer.

TNBC takes its name from the fact that these breast cancer cells do not overexpress any of the three molecules that are commonly overexpressed and act as the main survival mechanisms of breast cancers. In fact, TNBC cells do not commonly overexpress any targetable molecules. That is why TNBC patients can only be treated with chemotherapy, radiotherapy, and surgery. Sometimes these work at first but most TNBCs are aggressive, so they eventually relapse, and the available therapy options do not work anymore. Therefore, development of targeted therapy strategies for TNBC patients represents a large gap in cancer research.

Searching for drug targets in triple negative breast cancer

During Sedef’s PhD, she worked for 6 years at one of Europe’s most competitive research institutes specialized in cancer research, the Netherlands Cancer Institute. One of Sedef’s main research topics was investigating new targeted therapies for triple-negative breast cancer. Sedef describes how this meant focusing on finding vulnerabilities in TNBC cells:

“During my PhD, I investigated TNBC cells to find vulnerabilities that we could exploit. I found that combining inhibitors targeted against two proteins, EGFR and ROCK, effectively killed TNBC cells. To generate clues towards the mechanistic basis of this cell death, I collaborated with the Proteomics Research Group at Utrecht University.”

Together, they were able to scan the entire profile of proteins expressed by TNBC cells, to identify how protein expression differed in TNBC cells that were treated with the inhibitory drugs. With this knowledge, they could better understand the exact mechanism that leads to TNBC cell death. The results of this part of the adventure were published in February 2020, with the title “Combined EGFR and ROCK Inhibition in Triple-negative Breast Cancer Leads to Cell Death Via Impaired Autophagic Flux”. Their findings demonstrated that simultaneously blocking (inhibiting) EGFR and ROCK deregulates a vital cellular process called autophagy, which normally clears damaged or aged cellular components.  

Translatable research

All scientists in this field know how unlikely it is to see the results from their research applied in the clinic within their lifetime. In fact, a great majority of the research is never translated into clinical use. For the remaining minority, it may take decades before the results impact any human’s health. However, in this project, Sedef and her supervisor took a practical approach: by selecting target molecules based on the presence of commercially available drugs, they could ensure that any clinically relevant findings would be easily translatable.

The selection of suitable target molecules was based on a previous publication from their group:

“Our research was based on logical and practical strategies of narrowing down potential targets to a handful of druggable proteins.” Sedef explains.

A common trait of cancers is that they eventually become unresponsive to drugs. Cancer patients often need to receive two or more treatments sequentially or in combination. Thus, their finding that EGFR and ROCK inhibitors – both already in-use in the clinic for various indications, and with established Phase I safety data – are an effective combination against TNBC cells is promising. With further supporting in vivo data, Sedef’s findings could translate into a real treatment strategy for TNBC patients.

Sedef continues, “With this project, I felt for the first time how my research could truly impact human health, something we all strive for. I do get excited every time I think about it.”

Through an invaluable learning experience in research

While reflecting on her PhD, Sedef highlights an experience rich in learning opportunities, and describes how she grew to be resilient in her work: “The entire PhD experience taught me a lot, mostly what not to do rather than what to do. After all, scientific research is very much trial-and-error-based. On the technical side, I had a lot of failed experiments. But also on the soft skills side, I had several planning and communication failures. These cost me time and sleep.”

Sedef continues, “Doing a PhD, you are on the same boat with a bunch of other PhD students with similar challenges. But it is also a very lonely process because the teamwork aspect is minimal. Everybody has their own projects that they are responsible for. Because of the publication pressure, true teamwork examples are scarce. That taught me to work independently and be resilient.”  

From the lab to life sciences consultancy… the intersection of science and entrepreneurship

Sedef’s strong interest in scientific communication led her from the lab, where she conducted and published highly translatable research, to consultancy, where she translates brilliant ideas into feasible, fundable projects. Today, she is at the intersection of science and entrepreneurship, a position that fuels her passion for innovative ideas: “Of course, the cutting edge, sometimes wild-sounding, ideas we are exposed to at Catalyze are very exciting and motivating. But my ever-lasting interest is in telling a good story, one that flows right and fits the grant’s scope and expectations. This requires that we give sufficient technical depth, which varies from grant to grant, and think about the broader implications of a given technology.”

Working at such an innovative intersection is a hugely challenging task, but as Sedef points out, her research background demanded a similar skill: comprehension. “One of the most important skills I carried from my PhD to my consultant role at Catalyze was asking the right questions to understand a subject. I know how to teach myself new things and I know what kind of basis I need to build on. So I can quickly put things into perspective, whatever the subject is.”

Lastly, Sedef touches on a particularly special aspect of her role at Catalyze, collaborating with our bold and inspired clients: “Working at Catalyze puts us in direct contact with the clients and I love the spark our clients bring to the game: they are so full of ambition and energy to fully develop their product and reach the people who can benefit from it, it is contagious.”

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