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Exploiting neutrophil heterogeneity as mediator of synthetic lethality in breast cancer

People

 

Calcinotto A.

(Responsible)

Baggiolini A.

(Project partner)

Abstract

About 80% of breast cancers are hormone dependent. Although, anti-hormonal therapy remains a treatment mainstay, a considerable fraction of these patients does not respond to the therapy and ultimately progress with advanced cancer. It has been shown that neutrophils highly infiltrate the breast cancer microenvironment and we have recently demonstrated that these neutrophils support the growth of hormone-driven cancers such as breast and prostate cancer. In addition, recent results from my lab identified a subset of immature neutrophils named Neutrophil Progenitors (NePs) that can proliferate in the tumors of Luminal B breast cancer patients, an aggressive tumor type characterized by poor prognosis. As demonstrated, these NePs can promote genetic instability by releasing, in the tumor microenvironment, an oncometabolite that impairs homologous DNA repair.

Poly(ADP-ribose) polymerase-1 (PARP) is involved in a number of cellular processes such as DNA repair and PARP inhibitors (PARPis) are licensed for use exclusively in a subclass of cancer patients that harbor germline DNA-repair defects. Mounting evidence also suggests that patients without these genetic defects also benefit, however, a biological explanation for this observation has not been offered yet. We have now collected preliminary evidence that NePs induce dependence of the cells on alternative DNA repair mechanisms mediated by PARP. Thus, suggesting that the presence of NePs in the tumor may sensitize the tumors to PARPis.

Whether tumor-infiltrating neutrophils regulate sensitiveness to PARPis and play as mediators of synthetic lethality in the tumor microenvironment of hormone-dependent breast cancer patients is unexplored and a hot topic in the field.

Goal of this application is to demonstrate that NePs increase suscetibility to PARPis by modulating DNA repair mechanisms. Therapeutically, we will perform a pre-clinical trial to assess the efficacy of PARPis in tumors enriched by NePs and exploit the tumor cell death induced by PARPis to empower tumor immunogenicity and revert immune-desert breast cancers in tumors that respond to immune-checkpoint inhibitors.

To achieve these goals, my team has set up innovative state of the art methodologies and will use different in vivo mouse models of breast cancer.

Expected outcomes of this application will be:

1) to identify novel and unexplored mechanisms by which neutrophils modulate PARP transcription,

2) to understand whether NePs can sensitize the tumor cells to PARPis,

3) to assess whether PARPis reprogram the tumor immune response by killing immunosuppressive neutrophils and/or favoring immunogenic cell death in ER+ breast cancers.

Results of this project will thus explain the mechanisms behind the efficacy of PARPis in patients who do not harbor germline DNA-repair defects. Additionally, our preclinical work will provide the basis for testing novel therapeutic drug combination to improve response to endocrine therapy and checkpoint inhibitors in hormone-dependent breast cancer patients.

Additional information

Start date
01.01.2024
End date
31.12.2027
Duration
48 Months
Funding sources
SNSF
Status
Active
Category
Swiss National Science Foundation / Project Funding / Life Sciences (Division III)