Acute loss of PTEN induces senescence response both in vitro and in vivo, termed PICS. We aim to identify novel enhancers involved in modulating PICS. Even though senescence is demonstrated to restrict tumorigenesis in vivo, prolonged accumulation of such senescent tumor cells, have been reported to have a negative impact on the tumor microenvironment allowing its progression. We aim to identify compounds that can selectively eliminate senescent-tumor cells.
Our final aim is to implement, in tandem, a ‘Pro-senescence approach’ followed by ‘Senolytic therapy’.
The immune-research program of the Alimonti lab seeks to identify novel treatment modalities based on the dual-enhancement of senescence and immune response in prostate cancer. We have recently demonstrated that tumor-infiltrating GR1+ myeloid cells can antagonize chemotherapy-induced senescence in a model of prostate cancer (Di Mitri et al. Nature 2014). These findings have paved the way for the development of treatments that combine different immunotherapies with pro-senescence compounds.
The research of the Cell Signaling group is focused on the characterization of the molecular mechanisms involved in prostate cancer development and progression. We demostrted that loss PTEN, drives Pten loss induced cellular senescence (PICS) that dampen tumor progression. Ptenpc-/- and Ptenpc-/-; Trp53pc-/- murine models of prostate cancer allowed us to focus our research on molecular targets involved in senescence induction. By these studies, multiple preclinical mouse model of prostate cancer were generated and we are currently investigating the molecular mechanisms driving escape of senescence in order to develop new therapeutic strategies.
We have opened 2 clinical trials to text in the clinic our hypothesis that inhibition of MDSCs will block tumor growth in metastatic prostate cancer (Di Mitri, Nature 2014). The first trial is a phase I/II clinical trial that will assess the tolerability and efficacy of a combination of a CXCR2 antagonist with enzalutamide in metastatic castration resistance prostate cancer.
The second trial will assess whether a JAK2 inhibitor administered prior surgery will promote the inhibition of MDSCs in patients with high-risk prostate cancer with an increased NLR.