EPICAN · Inhibiting tumor cell plasticity by targeting the epigenome in breast cancer
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-05-01 → 2022-04-30
- EU contribution
- €191,149
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Inhibiting tumor cell plasticity by targeting the epigenome in breast cancer
Breast cancer is the second leading cause of cancer death in women and 2.1 million new patients are diagnosed each year with this disease, reported by the World Health Organization (WHO) in 2020. My EPICAN research project aimed at understanding the origin of intra tumor heterogeneity in breast cancer. Despite its clonal origin, cancer is heterogeneous by nature, due to the intrinsic genetic and epigenetic alterations and the multi clonal evolution of the disease, and due to the crosstalk between the cancer cells and their micro-environment. Such tumor heterogeneity is an important source of fitness for cancer, and constitute a major hurdle to develop efficient anti-cancer therapies. In this project, I aim at understanding how oncogenic activation of the PI3K pathway (e.g., PIK3CAH1047R…), hyperactive in more than 70% of breast cancers, increases tumor cell plasticity to generate tumor heterogeneity. Breast cancer is the leading cause of cancer death among females, with 685,000 deaths annually. Breast cancer has dramatic effects on quality of life and socio-economics factors, and is clearly a major society issue worldwide, regardless of the index of development. This research project, despite its fundamental rationale, is of major interest for breast cancer patients. Indeed, there is a crucial need to identify new predictive biomarkers and novel therapeutic targets, to improve patient stratification and to develop efficient anti-cancer therapies to block disease progression. Genetic mutations conferring oncogenic activation of the PI3K pathway are among the most frequent in breast cancer together with TP53 deletions. Besides, the first targeted therapy (Alpelisib) for patients bearing PIK3CA mutations has recently been approved, thus raising great hopes for better care of breast cancer patients (SOLAR-1 Trial). However, as mechanisms of resistance frequently emerge following targeted therapy administration, cancer cells may escape the therapeutic pressure imposed by Alpelisib. It is therefore of paramount clinical interest to anticipate such phenomenon and to investigate the molecular mechanisms promoting tumor cell heterogeneity, in order to enhance the efficacy of such targeted therapies and prevent relapses. This is the goal the of my research project.
Data: CORDIS, © European Union
Project objective
Breast cancer is a heterogeneous disease which is classified into different histological and molecular subgroups presenting different clinical outcomes. Also, the diversity of genetic/epigenetic alterations in cancer cells and their interactions with the microenvironment enhance cell plasticity and result in intra-tumor heterogeneity. While tumor heterogeneity is a major hurdle to anti-cancer therapy, its underlying molecular mechanisms remain ill-defined. The Phosphoinositide 3-kinase (PI3K) pathway, which is hyperactive in more than 70% of breast cancers mostly due to oncogenic activating mutations (PIK3CA-E545K & PIK3CA-H1047R), is a major driver of cell transformation. Using spatio-temporal conditional expression of the mutant PIK3CAH1047R combined with in situ lineage tracing in transgenic mice, recent studies demonstrated that the PIK3CA-H1047R oncogene reprograms lineage-committed mammary epithelial progenitors into a multipotent state, giving rise to heterogeneous mammary tumors. However, the mechanisms by which the PIK3CA-H1047R oncogene reactivates multipotency in breast cancer remain unknown. An increasing number of studies demonstrates that epigenetic regulators participate downstream of PI3K/AKT kinases to regulate the epigenome and contribute to tumor malignancy. Given the importance of epigenetic regulation for cell fate, I hypothesize that the effects of PIK3CA-H1047R signaling on tumor cell plasticity are mediated by epigenetic regulators. Because single inhibition of the PI3K pathway often results in resistance, it is of paramount interest to identify new targets whose inhibition can synergize with PI3K inhibitors to block tumor outgrowth, reduce tumor heterogeneity and prevent resistance. The overarching goal of this proposal is to identify epigenetic regulators downstream of oncogenic activation of the PI3K pathway leading to tumor cell plasticity, and to validate them as new targets in breast cancer.
Original text from CORDIS.
Participants
- UNIVERSITAT BASEL · BaselCoordinatorSwitzerland
Links
Data: CORDIS, © European Union