RESCUER

WP 1. COMBINATION TRIALS (DE) 1a. Peter Fasching 1b. Olav Engebråten 1c. Jürgen Geisler 1d. Jon Amund Kyte 1e. Shridar Ganesa 1f. Aleix Prat 1g. Hanna Hübner

WP 8. DATA MANAGEMENT & BIOINFORMATICS (FI) 8a. Sampsa Hautanemi 8b. Eivind Hovig WP 3. MICE XENOGRAFTS (NO) 3a. Gunhild Mælandsmo 3b. Marina Cihova

WP 2. INTEGRATIVE OMICS (SE) 2a. Janne Lehtiö 2b. Vessela Kristensen

WP 5. SINGLE-CELL ANALYSIS (SE) 5a. Diether Lambrechts 5b. Xavier Tekpli

WP 7. IMAGING ANALYSIS (IL) 7a. Zohar Yakhini 7b. Therese Seierstad WP 4. MECHANISTIC MODELLING (NO) 4a. Arnoldo Frigessi 4b. Alvaro Köhn-Luque

WP 11.

PERTURBATION SYSTEMS &

RESISTENCE MECHANISMS (ES) 11a. Toni Hurtado 11b. Jörg Tost

WP 1. DATA GRENERATION & NEW TRIALS (DE) 1a. Patricia Oppelt 1b.Charles Vaske WP 6. TUMOR ORGANOIDS (FI) 6a. Juha Klefström 6b. Pauliina Munne

WP 10. LARGE-SCALE DRUG SCREENING (NO) 10a. Kjetil Tasken 10b. Jorrit Enserink

WP 9. DRUG

SYNERGY PREDICTION (UK) 9a. Sylvia Richardson 9b. Manuela Zucknik

Bottom Up

(from models to trials)

RESCUER project takes aim at breast cancer

There are many sub-types of breast cancer and a wide variety of treatment options are available, so in some cases it can be difficult for clinicians to identify what treatment is best for each patient. We spoke to Professors Vessela Kristensen, Arnoldo Frigessi, Gunhild M. Mælandsmo and Kjetil Tasken about the work of the RESCUER project where the researchers are using the power of computers to search for improved treatments.

The majority of breast cancer cases are of the estrogen receptor positive (ER+) type, fuelled by the hormone estrogen which attaches to cells via receptors, leading to the activation of signalling pathways and changes within cells. This type of breast cancer is fairly well understood, says Professor Vessela Kristensen, Head of the Cancer Genome Variation Research Group at Oslo University Hospital. “There is the hormone, the receptor and the signalling pathways. We know what the receptor does to de-regulate signalling and to make the cell abnormal,” she outlines. There is no such clear modus operandi with the estrogen receptor negative (ER-) type however, in which cells don’t have an estrogen receptor, so these two types of breast cancer are treated differently. “With the ER+ type, there are several ways to block estrogen receptor signalling, for example by reducing the production of estrogen. There are also some homologues of the estrogen receptor that can fool cells and block estrogen receptor signalling,” says Professor Kristensen. “It’s more complicated with the ER- cases, because we don’t know what to block.”

RESCUER project

This is one of the issues Professor Kristensen and her colleagues in the RESCUER project are working to address. The project consortium brings together researchers from a wide variety of disciplines, spanning basic science and more translational fields, with the goal of developing more effective methods of treating breast cancer, building on data from clinical trials. “We have a large number of clinical collaborators who are key members in the project, creating the design of clinical trials,” says Professor Kristensen. These partners manage the collected biomaterial and have performed different types of molecular analysis on tumour samples, work which Professor Kristensen says has generated large volumes of data from clinical biobanks. “We recently gathered for our Consortium meeting at Erlangen University Hospital, where Professor Peter Fasching and his team run a biobank of 65000 patients with close to 1 million biological specimens. We have isolated DNA from tumours, conducted nextgeneration sequencing, and also isolated tissue slices from the tumour. Together with other consortium members, the group of Diether Lambrechts in Leuven, they have also worked on spatial transcriptomics, isolating RNA from the tumour, and done single RNA sequencing,” she explains. “Our goal is to synthesise the information in this data, and to identify what signatures are particularly important in terms of an individual’s response to treatment.”

The next step is to develop mechanistic mathematical models, based on the molecular data available in the biobank, which can then be used to test whether

different treatments lead to improved outcomes. The idea is to essentially make a computer-based copy – or digital twin – of the main characteristics of an individual tumour, then researchers can test out different treatments. “This is a way of searching for the optimal personalized treatment,” says Professor Arnoldo Frigessi, leader of the Oslo Center for Biostatistics and Epidemiology and work package 4 in RESCUER. In some cases, tumours may be resistant to certain types of treatment, another topic of interest in the project. To identify treatment options for tumours that have developed resistance, the researchers use patient-derived xenografts (PDXs) where the patient tumour tissue continues to grow in mice. “The PDXs help to keep a tumour alive a little bit longer than it otherwise would be. If you already know that this tumour has been resistant in the patient, you can use a PDX to try to find out why it has been resistant,” outlines Gunhild Mælandsmo, who leads this work at Oslo University Hospital (OUH). “We also experiment with explant cultures. With explant cultures we take cells or tissue from the tumour and keep it alive in a petri dish. The

With the ER+ type of breast cancer, there are several ways to block estrogen receptor signalling, for

example by reducing the production of estrogen. It’s more complicated with the ER- cases because

we don’t know what to block.

tumour is not sustained by a living organism like a mouse but by artificial matrices, which are constantly improving. This allows us to spare animals,” adds Professor Kristensen.

Researchers in the project are also developing organoids, which involves essentially taking the tissue then allowing single cells to grow back and self-organise, opening-up the possibility of looking at smaller structures. The wider aim in this research is to help clinicians assess what course of treatment is most likely to be effective for a particular patient. “There are very clear treatment guidelines for most breast cancer patients, and in the majority of cases this works very well. There are however still patients that clinicians don’t know exactly how to treat,” says Professor Kristensen. This is an issue at the heart of the RESCUER project, with work package 10 in the project dedicated to large-scale drug screening, which could ultimately lead to the discovery of effective new drug combinations. “This could be achieved by testing single drugs, and also by using AI-approaches to predict synergies and/or by testing combinations in the cancer drug sensitivity screening,” explains Professor Kjetil Tasken, leader of the Institute for Cancer Research at OUH and the work package.

This is part of the project’s work in providing clear and relevant information to clinicians, which can then inform and guide decisions on treatment. Clinicians typically draw on their own knowledge and experience when deciding on the right course of treatment for a patient, and the RESCUER tools are designed to add to that, keeping the needs of clinicians at the forefront. “The project is led by clinicians and is for clinicians,” stresses Professor Kristensen. Technology can help doctors identify possible treatment options, but Professor Kristensen is clear that the ultimate decision will always lie with clinicians. “The clinician has a connection with the patient, an awareness of their personality, their overall health profile or characteristics, and they can judge whether they will tolerate a particular treatment,” she says. “We’re not trying to replace that clinical expertise. However, with breast cancer, and for other forms of cancers and some rare diseases, there is the potential to develop new combinatorial treatments.”

Data management

A large amount of information has already been generated and collected in RESCUER, with researchers from a wide variety of disciplines, including bioinformatics, mathematics, pathology and surgery, all contributing to the project’s overall agenda. There is a risk of over-loading clinicians with too much information, so Professor Kristensen says it’s important to identify what information is the most relevant. “One of the goals in the project is to prioritise effectively and to identify those parameters that will be most likely to help doctors,” she outlines. The project is still at a relatively early stage, and while research has been disrupted by the Covid-19 pandemic, Professor Kristensen says progress is being made. “We have had four consortium meetings so far and work packages are becoming well integrated, all enjoying great communication science and social-wise. We also hold regular zoom meetings which are well attended, and we’ve already had a couple of papers published,” she says.

RESistance Under Combinatorial Treatment in ER+ and ER- Breast Cancer

Project Objectives

The objective of RESCUER is to develop a new approach and identify mechanisms of resistance at systems level, exploring how the treatment is affected by patient- and tumour-specific conditions. The project will integrate longitudinal multidimensional data from ongoing clinical trials and novel systems approaches, which combine subcellular/cellular and organ-level in silico models to discover molecular signatures of resistance and predict patient response to combinatorial therapies. This new knowledge will be used to identify already approved drugs with a high curative potential of new personalised drug combinations.

Project Funding

The RESCUER project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement No. 847912.

Project Partners

https://www.rescuer.uio.no/the-team/partners/

Contact Details

Project Coordinator, Professor Vessela Kristensen, University of Oslo, Institute for Clinical Medicine, Kirkeveien 166, Laboratoriebygget, 0450 Oslo T: +4792068432 E: v.n.kristensen@medisin.uio.no W: https://www.rescuer.uio.no/

Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial - Nature Medicine. https://www.nature.com/articles/s41591-022-02126-1 Prof. Vessela Kristensen

Vessela N. Kristensen is Director of Research and Head of Research and Development at the Department of Medical Genetics, OUS and Professor at the Medical Faculty of the University in Oslo (UiO). Previously she worked at the Department of Clinical Molecu§§lar Biology and Lab science (EpiGen), Akershus university hospital, and Group Leader at the Department of Genetics, IKF, Det Norske Radiumhospital. She is currently visiting professor at Princeton University, and has served as Professor II at the Centre for Integrative Genetics, University of Life Sciences, assistant professor at the Advanced Technology Center at NCI, NIH, Bethesda as well as the Berzelius Laboratory at Karolinska Institute.