Periodic Reporting for period 1 - EPICAN (Inhibiting tumor cell plasticity by targeting the epigenome in breast cancer)
Reporting period: 2020-05-01 to 2022-04-30
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.
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.
Within the period covered by the report, the main results have been achieved so far:
- Characterization of the tumorigenesis induced by the PI3KCAH1047R oncogene in vivo
- Profiling of the neoplastic mammary gland using multi-OMICS approaches
- Development of a surrogate 3D organoid model to investigate the molecular mechanisms generating tumor cell plasticity upon oncogenic PI3KCAH1047R signaling
- OMICs profiling of the 3D organoid model
- Identification of the molecular mechanisms responsible for increase tumor cell plasticity and generation of intra tumor heterogeneity
- Identification of novel candidates acting downstream of the PI3KCAH1047R oncogene potentially involved in generating intra tumor heterogeneity.
- Selection of several candidates for pharmacological inhibition in a mini drug screen approach on the 3D organoid model.
- Ongoing work: validation of the candidates in pre-clinical models
Additional goals achieved:
- Mentoring of two PhD students with the host laboratory
- Publication of a scientific review
- Publication of a collaborative research article
- Submission of 3 additional research articles including one co-first authorship
- Characterization of the tumorigenesis induced by the PI3KCAH1047R oncogene in vivo
- Profiling of the neoplastic mammary gland using multi-OMICS approaches
- Development of a surrogate 3D organoid model to investigate the molecular mechanisms generating tumor cell plasticity upon oncogenic PI3KCAH1047R signaling
- OMICs profiling of the 3D organoid model
- Identification of the molecular mechanisms responsible for increase tumor cell plasticity and generation of intra tumor heterogeneity
- Identification of novel candidates acting downstream of the PI3KCAH1047R oncogene potentially involved in generating intra tumor heterogeneity.
- Selection of several candidates for pharmacological inhibition in a mini drug screen approach on the 3D organoid model.
- Ongoing work: validation of the candidates in pre-clinical models
Additional goals achieved:
- Mentoring of two PhD students with the host laboratory
- Publication of a scientific review
- Publication of a collaborative research article
- Submission of 3 additional research articles including one co-first authorship
The primary research goal of my project was to identify the molecular mechanisms underpinning generation of intra tumor heterogeneity and to identify novel promising therapeutic targets in breast cancer. Indeed, intra tumor heterogeneity is a major hurdle to implement efficient anti-cancer therapies, as distinct breast cancer cells may have distinct drug responsiveness and therefore better resist therapies. It is therefore key to identify novel factors promoting such plasticity and fueling intra tumor heterogeneity. In this project, we identified several candidates whose pharmacological inhibition is currently being tested in pre-clinical model, in vivo as well as in ex vivo 3D primary mammary organoid models. We hope to identify therapeutic target(s) whose inhibition can synergize with the PI3KCA inhibitor Alpelisib to better eradicate breast cancer cells and residual disease. The impact of such finding can potentially be important as we are currently discussing the possibility of translating our finding to the clinics. Indeed, we are considering setting up a clinical cohort study in collaboration with medical oncologists in Basel to assess whether our novel dual combination may benefit to breast cancer patients bearing PIK3CA mutations. Indeed, clinical translation has always been the connecting thread of my post-doctoral research.
Beyond my main research project, my MSCA fellowship enabled me to the publish a scientific review on tumor heterogeneity, phenotypic plasticity and metastatic colonization in Trends in Cell Biology. It also enabled me to contribute to collaborative studies, which are either already available or soon to be published.
Beyond my main research project, my MSCA fellowship enabled me to the publish a scientific review on tumor heterogeneity, phenotypic plasticity and metastatic colonization in Trends in Cell Biology. It also enabled me to contribute to collaborative studies, which are either already available or soon to be published.