Kasper Karlssons project aims to fight cancer in children. The goal is to find targeted therapies that complement the standard treatment of neuroblastoma patients and thereby help more children beat cancer.
Assistant Professor Kasper Karlsson, Karolinska Institutet, has been awarded the prestigious European Research Council (ERC) starting grants. He receives EUR1.5 million over five years for projects that aim to identify which combination of drugs most effectively kill neuroblastoma cells, a type of cancer that mainly affects children.
Cell barcoding to model tumor subclone evolution
– I recently did a Postdoc at Stanford where we tried to model the occult process of early tumor evolution in vitro. Remarkably some aspects of tumor evolution could be recapitulated using organoids. As part of that process, we developed a cell barcoding strategy to track individual tumor subclones: we put in a random stretch of DNA into individual cells’ genome, thereby making them unique and distinguishable from other cells. Since the barcode is in the genome, the daughter cells will inherit the barcode, which means they can start thinking about cells with different barcodes as part of different tumor subclones.
– During my postdoc I used this to study dynamics of early tumor evolution. Now I want to take this in a translational direction. Specifically, I work with a new concept using cell barcodes to evaluate drug combinations.
Precision Lethality
We work with cancer, which is a heterogenous disease. This is one of main reasons we use drug combinations to treat cancer. One subclone may be resistant to a particular drug, and we need a second drug to target that subclone or the patient would not be cured. However, the main way drug combinations are evaluated today if they are good or not is by drug synergy. Drug synergy assess how potent a particular drug combination is to eradicate the average cell, it will not identify rare subpopulations that are resistant to multiple drugs.
– We believe that our ability to follow specific tumor subclones will make it possible to identify subclones that are sensitive to the standard of care drug treatments today and also identify drugs that specifically target these resistant populations.
This strategy has been developed before by Peter Sorger lab at Harvard (https://sorger.med.harvard.edu/people/peter-sorger-phd/), but it has not been tested at scale.
– I think it has a lot of potential, and we plan to evaluate the this extensively for neuroblastoma. We have also rebranded this concept of using cell barcoding to target different subpopulations with different drugs into Precision Lethality.
What do you hope to attain?
– My main hope is to improve cure rates for children with cancer, initially focusing on neuroblastoma. High-risk neuroblastoma patients are given harsh treatments including chemotherapy, radiotherapy, surgery and stem cell transplantation.
Initial treatment is often quite effective, but around 50% of high-risk patients will experience a relapse, with very limited chances of survival. In order to increase cure rates, we need to find the right drugs to eradicate the rare metastatic cells that survive standard of care today, to prevent relapses from occurring.
Different strategies to overcoming metastatic heterogeneity
– Here we believe Precision Lethality could be useful, instead of finding drugs that efficiently target all cells, Precision Lethality allows us to focus in and find drugs that specifically target the rare cells that have a high chance of resisting standard of care.
They also use a very different approach, called radiopharmaceutical therapy, to achieve the same goal of overcoming metastatic heterogeneity. Here a radioisotope is attached to a molecule that specifically targets tumor cells, which allows them to get tumor specific radiation that also reach metastatic cells.
– The main reason we are so excited about radiopharmaceutical therapy is due to the crossfire effect. If a molecule with a radioisotope binds to a tumor cell, it will exert radiation not only to that tumor cell, but also to surrounding tumor cells. Thus, not all cells in a metastatic cluster need to express the correct receptor to receive a lethal dose of radiation, a kind of brute force strategy to overcome heterogeneity. Our hope is that either of these approaches will make a difference for children with high-risk neuroblastoma.
Which challenges do you face?
– I would say the main challenge is the sheer amount of challenges, and I think this is common not only for me but for most new PI in science. There are many things to keep track of and expectations to meet, including budgeting, financing, lab safety, recruitment, co-financing, setting up lab and then science and finding time for that. Each one is fine by itself, but combined the time runs out. There are many “oughts” that starts to fall off the to-do list.
How does receiving an ERC change the possibility of reaching your goal?
– The ERC grant has been super important! If I hadn’t received that I hadn’t been sure if I would be able to do science after February 2025 when my current salary would end. Now I get five more years to stay on. It gives time and resources for science instead of writing grants. It’s a proof that what I do is important. It opens up new doors, new possibilities and gives credibility.
What advantages are there of being a researcher at Karolinska Institutet and SciLifeLab?
– This is an amazing place to be in! So many possibilities for networks, infrastructures, core facility and lots of smart people within a relatively small place. I also like that it makes it so much easier to work across borders, you need input from many different fields in order to solve new questions. Working at SciLifeLab in Solna makes is easy to engage with researchers from SU, KTH and KI and to initiate multidisciplinary project.
Which is your favorite spot in Hagastaden?
– Perhaps a bit morbid for a cancer researcher, but I do like to occasionally take a walk around Norra Begravningsplatsen. It gives a bit of peace and serenity and helps to put some distance to the things I’m working on daily.
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