From Instability to Opportunity: Therapeutic Targeting of CIN in Cancer

Lead supervisor: Associate Professor Eileen Parkes

Co-supervisor: Dr Parinaz Mehdipour

Commercial partner: Dark Blue Therapeutics

Background: Chromosomal instability (CIN) is a defining hallmark of aggressive cancers and is strongly associated with poor prognosis and resistance to conventional treatments, including chemotherapy, radiotherapy, and immunotherapy. CIN is particularly prevalent in high-mortality cancers such as oesophagogastric cancer, uveal melanoma, ovarian cancer, triple-negative breast cancer, and bladder cancer. Despite its clinical significance, there are currently no approved therapies that directly target CIN or exploit CIN-associated vulnerabilities, representing a major gap in cancer treatment.

Our group has developed robust experimental systems to address this challenge, including isogenic human and mouse models of CIN, and a transcriptomic signature that quantitatively scores CIN status. Using this signature, we have mined large-scale functional genomic datasets (e.g. DEPMAP), generating a shortlist of candidate therapeutic vulnerabilities enriched in CIN-high tumours. We have also shown that CIN can be detected in a clinically tractable manner through quantification of cGAS-positive micronuclei, providing an opportunity to stratify patients most likely to benefit from CIN-targeted approaches.

Project Aims: This project will systematically identify, validate, and mechanistically dissect therapeutic targets associated with CIN, while establishing translational pipelines to accelerate the development of CIN-targeted therapies.

The aims are:

1.Identification of CIN-associated vulnerabilities

Integrate large-scale functional screens with our CIN signature to prioritise candidate targets in pathways such as the DNA damage response, replication stress, and mitotic checkpoint. 

2.Validation in preclinical models

Test candidate targets in 2D and 3D patient-derived models and organoids.

Apply the cGAS-micronuclei assay to stratify CIN-high versus CIN-low tumours.

Explore combinatorial strategies with existing therapies.

3.Mechanistic investigation

Define how validated hits exploit CIN-specific biology (e.g. dependence on replication stress tolerance, defective cytokinesis).

Use transcriptomic and proteomic profiling to uncover downstream effects and potential resistance mechanisms.

4.Translational development

Partner with Dark Blue Therapeutics to evaluate lead compounds and biomarkers.

Align discoveries with industrial pipelines to accelerate progress towards first-in-human applications.

Relevance to MRC remit: This project directly addresses an urgent unmet clinical need: improving outcomes for patients with aggressive, treatment-resistant cancers. By combining functional genomics, translational biomarkers, and industrial expertise, it exemplifies the MRC remit of driving discovery science into health impact. The integration of biomarker-driven stratification with novel therapeutic approaches reflects the growing emphasis on precision oncology and aligns with UK priorities in life sciences innovation.

Benefits of the Collaboration: The collaboration brings together complementary strengths. The Oxford academic team provides state-of-the-art cancer biology, functional genomic expertise, and preclinical models that enable systematic discovery of CIN-specific targets. Dark Blue Therapeutics contributes a robust drug discovery platform, industrial assay development, and deep expertise in translating biological insights into oncology therapeutics. For the academic team, this collaboration ensures that findings are rapidly channelled towards clinical application, maximising patient benefit. For Dark Blue Therapeutics, access to unique CIN models and signatures accelerates their pipeline of first-in-class cancer therapies, while training the next generation of translational scientists.

Overall, this interdisciplinary, academia–industry partnership transforms chromosomal instability from a marker of poor prognosis into a therapeutic opportunity, with the potential to deliver tangible benefits for patients with aggressive cancers.

Apply using course: DPhil in Oncology