Saturday, April 20, 2024
4/20/2024
SUMMARY Background. Triple-negative breast cancers (TNBCs) present with advanced histological grade and aggressive clinical behavior. They are overwhelmingly unresponsive to conventional systemic treatments, and patients with refractory disease have increased recurrence and dismal 5-year survival rates. Reliable biomarkers and targeted therapies for TNBC are therefore critically needed, but remain to be defined. Preliminary findings. We found that PTX3 was particularly abundant in TNBC specimens and in patient- derived xenografts (PDX), and that its levels positively and specifically correlated with adverse TNBC patient survival. We show that PTX3 propagated cancer-stem-cell (CSC) -like traits, that it promoted cancer cell growth in suspension, and that it promoted multifold increase in TNBC metastasis. In addition, we demonstrate that PTX3 activated anti-apoptotic pathways and de-sensitized TNBC cells to chemotherapy. Genetic suppression of PTX3 inhibited oncogene-induced cell growth, and quelled malignant features of TNBC cells, such as migration and anchorage-independent growth. Importantly, we show that circulating levels of PTX3, which is secreted by TNBC cells, associated with tumor burden in preclinical models and were particularly elevated in TNBC patients. Finally, we show that antibody neutralization of PTX3 caused TNBC cell death. Hypotheses. We hypothesize that PTX3 is a critical biomarker for risk stratification of TNBC patients, and that it is a decisive functional driver of malignancy and a tractable therapeutic target of translational utility in TNBC management. Specific aims and study design. We will establish PTX3 as a prognostic biomarker in clinical TNBC (aim 1), determine how PTX3 regulates malignant progression (aim 2), and establish PTX3 as a TNBC therapeutic target (aim 3). To this end, we will correlate tumoral and circulating levels of PTX3 to patient survival in retrospective analyses of a large TNBC patient cohort using PCR-, -in situ, and ELISA-based approaches (aims 1.1 and 1.2). We will then determine the role of PTX3 in regulating self-renewal and tumor-initiating functions of CSCs (aim 2.1), identify the metastatic steps facilitated by PTX3 (aim 2.2) and assess its contributions to chemoresistance in vitro and in vivo (aim 2.3). Finally, we will determine the essentiality of PTX3 to the initiation (aim 3.1), survival, and growth of established metastases (aim 3.2) using xenograft models, as well as investigate the ability of anti-PTX3 neutralizing antibodies to suppress tumorigenic growth using patient-derived xenograft and syngeneic murine cancer models (aim 3.3). Impact. Our sought results will introduce novel theranostics of potential groundbreaking utility in managing aggressive and difficult-to-treat breast cancers for which targeted therapies are sorely needed.
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