Faithful eucaryotic cell division requires spatio-temporal orchestration of multiple sequential events. Among the crucial steps to providing the daughter cells with identical set of chromosomes is the DNA replication. During this phase, cells coordinate the speed of DNA synthesis with the length of the cell cycle to ensure genome integrity. To do so, growth factors and metabolic signals are integrated primarily by D-type Cyclins. Indeed. their deregulation can directly lead to some of the hallmarks of cancer by causing proliferation that is independent of normal extracellular cues. We previously demonstrated that aberrant accumulation of Cyclin D1 results in a faster cell cycle, with uncontrolled speed of DNA replication fork progression and genome instability (Maiani & Milletti et al., 2021). Despite, frequently altered in many tumors (Musgrove et al., 2011), a unifying theory that clarify how Cyclin D1 promote cancer transformation is still lacking. In the lab of Prof. Jiri Bartek, it was previously shown that PARP1 inhibition increases replication fork speed (Maya-Mendoza et al., 2018). PARP1i uncouples the leading and lagging DNA synthesis resulting in fast fork speed and genome instability. However, it is currently unknown whether the aberrant accumulation of Cyclin D1 has similar effect on DNA synthesis as PARPi. Furthermore, it is also undetermined whether aberrant levels of Cyclin D1 could trigger metabolic changes that accelerate the speed of DNA synthesis. Taking advantage of our previous observations, we aim with this proposal to: i) identify metabolic signatures that can predict dis-regulated DNA synthesis in response to cell cycle alterations; ii) define the molecular mechanism of how cyclin D1 accumulation induces accelerated fork speed; iii) identify new metabolic genes involved in the control of S phase progression and the speed of DNA synthesis by CRISPR-Cas9 screening technology; iv) suggest druggable targets that could be used in cancer therapy.

Breast and ovarian cancer constitute serious health challenges in the EU. To identify new improved cancer therapeutic approaches, we will pursue a multi-facetted synthetic lethal approach, which takes advantage of the inherent genetic instability of cancer cells. Most mutations acquired by cancer cells do not cause lethality, but the very same mutations may cause cell death when a second gene in a redundant pathway is inactivated. Thus, targeting a gene that is synthetic lethal together with a cancer-specific mutation will kill only cancer cells while sparing normal cells. Synthetic lethal approaches have been clinically pioneered by members of our consortium, by combining cancer-promoting mutations (e.g. in BRCA2) with inactivating combinations of DNA repair genes. We will use this approach as the scientific frame for our ETN (SYNTRAIN) consisting of 9 academic and 1 SME beneficiary as well as 3 partners. We aim to identify synthetic lethal interactions and exploit them to innovate future breast and ovarian cancer treatments through compound screening and development. SYNTRAIN consists of World leading researchers with complementary knowledge in genome maintenance and stress response pathways, and a critical mass of expertise for providing an excellent training in screening methodologies, mechanistic investigations, and drug discovery. We will offer a structured training program that exceeds the capacities of each individual member. We will educate a future generation of cancer researchers with a high innovative capacity and skills that enhances their career prospects in both academia and industry. Our aims are to train young researchers: i) in techniques preparing for a career in cancer research, ii) in complementary skills relevant for work in academia and the pharma industry and iii) to become creative and entrepreneurial, capable of bridging the gap between basic and applied research.

The 5-year survival for children with cancer increased from 30% in the 1970s to more than 80% at present. There are up to 300,000 childhood cancer survivors in Europe and this number is increasing. Years after treatment, childhood cancer survivors are at high risk for developing health and psychosocial late effects, resulting in excess morbidity and mortality compared the general population. The impact on the quality of life (QoL) of survivors and their families, as well as the societal and economic burdens, are significant. However, these impacts can be reduced by long-term survivorship care to detect treatable disease at an early phase and start timely interventions to preserve health, improve QoL, as well as coordinate specialised care and empower survivors. Implementing follow-up care, especially for young adult and adult survivors of childhood cancer, has proven challenging across Europe. These survivors have left paediatric care and most of them have no opportunity to visit experts in survivorship care. To improve survivorship care for these survivors across Europe, PanCareFollowUp will conduct a prospective cohort study to assess effectiveness, value, cost effectiveness and feasibility of the PanCareFollowUp Care intervention, a person-centred approach to survivor follow-up care based on international clinical guidelines for surveillance of late effects. PanCareFollowUp also includes the development and assessment of a personalised, guideline-based eHealth lifestyle intervention. Ensuring that the PanCareFollowUp interventions are used in the real world is paramount to achieving enduring improvements to survivorship care. Hence, the project includes the development of materials to support sustainable maintenance and replication of the PanCareFollowUp interventions. The PanCare network will become the guardian of the interventions after the project, ensuring that the intervention materials are openly available, sustainably maintained and widely shared.