Within our ERC CoG grant, RSHEALTH, our group has contributed to the to the preclinical development of chemical inhibitors of the ATR kinase as anticancer agents, that are now in clinical trials by several companies. During the course of our investigations, we also made important advances in developing inhibitors of SETD8, another interesting cancer-related target. SETD8 is a histone methyltransferase known to play important roles in DNA replication and repair. Evidence indicating that targeting SETD8 could be interesting for cancer therapy has been building up in recent years. For instance, SETD8 is overexpressed in a wide range of cancers, and recent works identified SETD8 as a specific vulnerability in High-Risk Neuroblastoma or MYC-driven Medulloblastomas. Unfortunately, all available SETD8 inhibitors have low potency and poor pharmacological properties, and none has progressed to the clinic. We here propose to capitalize in our strengths in academic drug development, and our experience in transferring our inhibitors to the industry, in order to facilitate the clinical development SETD8 inhibitors. Our proposal includes objectives that will help us improve the quality of our inhibitors, valorise them in preclinical cancer models and develop companion biomarkers that would be used for patient stratification. All of this would be integrated within a business plan that should facilitate a coherent development of this line of work oriented towards the clinical development of SETD8 inhibitors for the benefit of cancer patients.

Glioblastoma multiforme (GBM) is one of the most common and aggressive forms of brain tumour, affecting 2-3 per 100,000 adults per year, and with a usual survival time of 14-18 months after diagnosis with only a 10% of the patients living up to 5 years after it. Because of its location, early detection of the tumour and surgical removal may be complicated. Furthermore, its fast growth rate and migration capacity makes it extremely aggressive. Aditionally the presence of glioma cancer stem cells contribute to radio- and chemioresistance of GBM. Because of all this, a deeper understanding about its genetical, biochemical and microenviromental nature is needed. In order to gain more insight into the formation and development of glioma, in this proposed project we hypothesize that the heterogeneous nuclear ribonucleoprotein K (hnRNPK) and the mechanically activated ion channel Piezo1 constitute an axis that promotes the onset and progression of glioma. HnRNPK is a multifunctional protein that influences transcription, translation and RNA stability amongst other function, and it exerts its function depending on its phosphorylation state, which is modulated by kinases such as ERK, JNK or PKC. Piezo1 is a stretch-activated cation channel, that activated upon mechanical cues allowing the influx of calcium in the cell and activation of multiple cascades, such as ERK or PKC pathways, as well as in apoptosis and migration. Both hnRNPK and Piezo1 are upregulated in gliomas and preliminary data suggests a relation in their regulation. Here, we proposed that there is a regulation between Piezo1 and hnRNPK, and that this axis promotes the onset of gliomas cancer stem cells and contributes to its aggressiveness. With this project, we aim to investigate how this axis could contribute to the formation and aggressiveness of gliomas, and how its modulation can contribute to its control, therefore turning Piezo1 and hnRNPK into a new promising target for glioma treatment.

Relapse and metastasis in cancer are driven by cancer stem cells (CSC) which self-renew, give rise to tumor cell heterogeneity and are more resistant to chemotherapy. The RANK signalling pathway is implicated in a number of cancers and notably in breast carcinogenesis and metastasis. Inhibition of this pathway reduces CSCs decreasing both recurrenceRelapse and metastasis in cancer are driven by cancer stem cells (CSC) which self-renew, give rise to tumor cell heterogeneity and are more resistant to chemotherapy. The RANK signalling pathway is implicated in a number of cancers and notably in breast carcinogenesis and metastasis. Inhibition of this pathway reduces CSCs decreasing both recurrence and metastasis. RANKL inhibitors are used in breast cancer clinical trials and studies focused on RANK signalling in carcinogenesis are needed to identify patients who would benefit from treatment. RANK mediates many of its effects on cell survival, migration and chemoresistance via the PI3K/AKT pathway, activation of which confers enhanced proliferation, survival, metastatic potential and resistance to therapy in cancer. AKT is a central node in PI3K signalling and AKT isoforms play important and differential roles in carcinogenesis. RANK is also regulated by CD44, a marker of stemness and a key player in cell migration, proliferation, differentiation, survival, stem cell maintenance and chemoresistance. CD44 alternative splicing plays a pivotal role in cancer development in breast and other tissues. However, the role of CD44 and AKT isoforms in cancer is not clearly defined. In this MSCA project, I will investigate the role of the CD44-RANK-AKT crosstalk in tumorigenesis and identify CD44 and AKT isoforms regulating cancer stemness, metastasis and resistance to therapy. I hypothesize that the interplay between CD44, RANK and AKT regulates cancer stemness and the metastatic potential of breast tumor cells, and specific CD44 and AKT isoforms have vital roles in this process.

Precision Oncology has revolutionized cancer therapeutics, mostly by matching genomic alterations with molecularly targeted agents. Yet, current predictive capacity is imperfect even in best-case scenarios (tumors driven by oncogene addiction against which a targeted agent exists). To push the field forward, we propose to exploit recent technological advances to analyze longitudinal profiles of cancer patients that encompass dimensions beyond the genetic profile: physiological monitoring, e-health records, patient-reported outcomes, medical imaging, and multi-omics. The integration of this multi-dimensional data with personalized genomics will allow an unprecedented level of understanding of cancer processes, identifying the features that drive patient disease trajectories, eliciting truly precision interventions. The goal of this project is to use this approach to improve the current predictive ability and break current efficacy plateaus in advanced breast cancers. I will integrate longitudinal data of a cohort of 100 hormone receptor-positive metastatic breast cancer patients in first line of treatment with CDK4/6 inhibitors and hormone inhibitors, monitored until disease progression or treatment failure. This constitutes the largest high-definition medicine study in advanced breast cancer patients to date. I will use data across 10 different modalities to establish disease trajectories, relate molecular features to clinical outcomes and build predictive models for prognosis. This integrative project combines translational and clinical oncology, engineering, and data science, to transition from the current genomics-centered precision oncology approach to high-definition oncology, a model in which deep longitudinal patient monitoring achieves a comprehensive personalized oncology.