cliniCIN: Targeting the roots of chromosomal instability in cancer
Lead Research Organisation:
University of Cambridge
Department Name: Cancer Research UK Cambridge Institute
Abstract
GOAL: Overcoming the genomic complexity of cancers with high chromosomal instability by using signatures of ongoing mutational processes as biomarkers for drug response.
BACKGROUND: Chromosomal instability is a hallmark of most lethal cancers. Highly unstable tumours have few biomarkers to guide treatment decisions and patient survival has not improved for decades. My team pioneered approaches to dissect chromosomal instability using genome-wide DNA copy number patterns, so called CIN signatures, which are characteristic for different types of instability and underlying mutational processes. In pilot studies we found that CIN signatures predict drug response. Signature analysis focuses on the cause, rather than the consequence of chromosomal instability, and thus represents a radical departure from previous personalised medicine approaches.
APPROACH: Here, I am building on genomic and computational technologies I have developed to design biomarkers for treating cancers with high chromosomal instability. I propose a novel single cell DNA sequencing approach to identify ongoing mutational processes from unique events in individual cells. This pharmacogenomic test is a major advance, because it allows to separate ongoing mutational processes, which are actively contributing to cancer development, from extinct mutational processes, which left marks in the genome but are no longer active. I will systematically identify robust and predictive biomarkers of drug response in a comprehensive experimental plan across five highly unstable cancers (esophageal, lung, pancreatic, ovarian and triple negative breast cancer) and measure the heterogeneity of CIN across tumour microenvironments in patients undergoing neo-adjuvant treatment.
IMPACT: This pioneering project will result in fundamental insights into how cancers with different types of chromosomal instability react to drugs and how to exploit genomic complexity for patient benefit in cancers of unmet clinical need.
BACKGROUND: Chromosomal instability is a hallmark of most lethal cancers. Highly unstable tumours have few biomarkers to guide treatment decisions and patient survival has not improved for decades. My team pioneered approaches to dissect chromosomal instability using genome-wide DNA copy number patterns, so called CIN signatures, which are characteristic for different types of instability and underlying mutational processes. In pilot studies we found that CIN signatures predict drug response. Signature analysis focuses on the cause, rather than the consequence of chromosomal instability, and thus represents a radical departure from previous personalised medicine approaches.
APPROACH: Here, I am building on genomic and computational technologies I have developed to design biomarkers for treating cancers with high chromosomal instability. I propose a novel single cell DNA sequencing approach to identify ongoing mutational processes from unique events in individual cells. This pharmacogenomic test is a major advance, because it allows to separate ongoing mutational processes, which are actively contributing to cancer development, from extinct mutational processes, which left marks in the genome but are no longer active. I will systematically identify robust and predictive biomarkers of drug response in a comprehensive experimental plan across five highly unstable cancers (esophageal, lung, pancreatic, ovarian and triple negative breast cancer) and measure the heterogeneity of CIN across tumour microenvironments in patients undergoing neo-adjuvant treatment.
IMPACT: This pioneering project will result in fundamental insights into how cancers with different types of chromosomal instability react to drugs and how to exploit genomic complexity for patient benefit in cancers of unmet clinical need.
Organisations
People |
ORCID iD |
| Florian Markowetz (Principal Investigator) |
Publications
Morrill Gavarró L
(2025)
A Dirichlet-multinomial mixed model for determining differential abundance of mutational signatures.
in BMC bioinformatics
| Description | We are building on our expertise with copy number signatures and combine novel computational and experimental approach's to define signatures of chromosomal instability on a single cell level: the key output will be predictors of drug response that recognise which mutational processes are currently active rather than historic. |
| Exploitation Route | The key output will be predictors of drug response that recognise which mutational processes are currently active rather than historic |
| Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
| Description | Chromosomal instability is one of the key factors of the hardest to treat cancers. Because of chromosomal in fertility, these cancers are characterized by genomic chaos. There are almost no recurrent events and so far no biomarkers to guide treatment decisions. As a result, cancers with chromosomal instability at very low survival rate. In this project we try to change this. We have developed computational approaches to decode genomic chaos, and in this project, we're bringing them from a bulk level to a single-cell level. This will allow us to differentiate between mutational processes that have been active in the past. And mutational processes which are currently active. Our hypothesis is that signatures of currently active mutational processes are better predictors of drug response than signatures of historic processes, and this project will test the hypothesis. |
| Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Policy & public services |
| Description | 17th IPSCC 2024 Berlin |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | Since 2007, the IPSCC has brought together senior PhD students from top cancer research institutes across Europe. The focus of the conference is on basic and translational cancer research but we also welcome researchers who are focusing on clinical, epidemiological, and other areas of cancer research as the whole spectrum of cancer research will contribute to our better understanding of cancer and better treatments for cancer patients. The conference is tailored to attract scientists, professionals, translational researchers, applied scientists and clinicians with all levels of experience and expertise interested in cancer research. |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://www.mdc-berlin.de/news/news/student-cancer-conference-max-delbruck-center |
| Description | Cambridge Computational Oncology Meeting |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Friday, September 1, 2-5pm @CRUK_CI Speakers: Marta Milo @marta_milo Paula Martin Gonzalez @paulittamg Sarah Aitken @S_J_Aitken |
| Year(s) Of Engagement Activity | 2023 |
| URL | https://linkprotect.cudasvc.com/url?a=https%3a%2f%2fforms.office.com%2fe%2fiRW1Eak3t6&c=E,1,HKFlhVoC... |
| Description | Cambridge Computational Oncology Meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | This event was held on 5 February 2025 and the speakers were PhD student Greta Markert, Drs Marta Milo and Martin Miller |
| Year(s) Of Engagement Activity | 2025 |
| Description | Cambridge University Society Talk |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Florian was the keynote speaker for their yearly conference. |
| Year(s) Of Engagement Activity | 2025 |
| Description | EMBO EMBL Symposium: AI and Biology |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Artificial intelligence (AI) is transforming virtually all areas of science, and the life sciences are no exception. AI-based methods are pushing the limits of what is possible in experimental design, data analysis, simulation, and modelling. The aim of this symposium is to catalyse synergistic interactions between AI researchers in different subfields of biology by exploring shared theoretical approaches, cross-domain experiments, and data integration, as well as shared topics in dissemination of tools and collaboration with experimental labs. Furthermore, we will look into the future and discuss how the concerted actions of AI and life science communities can enable both fields to exploit the full potential of the ongoing data deluge and find new application areas ripe for disruption by AI. AI-based analytics is subject to active research in at least three major application areas: sequencing, imaging and structural biology. While all three domains are experiencing very fast growth, the development of AI-based analysis is largely happening independently. The aim of our symposium is to bring these communities together to discuss topics of mutual interest to make progress, including on the theoretical/methodological side and on the more strategic issues of identifying the next areas of high potential. |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://www.embl.org/about/info/course-and-conference-office/events/ees24-01/ |
| Description | Invited Speaker at PCUK Discovery and Translation Meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | "Collaborations are essential because we can't all be expert in everything" Last month we gathered together members of the UK pancreatic cancer research community at our Discovery & Translational Research Forum, in the beautiful surroundings of Oxford. In order to make progress in pancreatic cancer research, we need to have a thorough understanding of the processes involved in disease initiation and development. Over two days, we discussed the priority challenges faced by discovery and translational pancreatic cancer researchers in the UK, and how we can work together to overcome them. Crucially, this forum also brought researchers together to develop networks and collaborations. These are so important to help us maximise the potential and efficiency of the pancreatic cancer research community, especially after two years of uncertainty where there have been limited opportunities to meet each other face-to-face. Across the two days, there were some overall themes of discussion that cut across all of the sessions. |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://www.pancreaticcancer.org.uk/for-researchers/pancreatic-cancer-uk-discovery-and-translational... |
| Description | Invited to Chair at Cancer Research UK Data-driven cancer research conference |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Florian co-chaired a Debate on how much added value AI tools have for patient benefit at this Data Conference. |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://www.convergencesciencecentre.ac.uk/news-events/events-calendar/evnets-archive/2024/02/27/def... |