STAT activation, a key mediator of inflammatory signaling across cancer types, constitutes a target for the prevention of cancer progression and disease recurrence following initial cancer removal.
Background & Significance
Activation of STAT family transcription factors, particularly STAT3, constitutes a key molecular component of an inflammatory cytokine-related signaling network that regulates progression of a variety of solid tumors, including squamous cell and BC49. Hence, STAT inhibition may constitute an effective approach to prevent tumor progression across cancer types, by virtue of its role as a primary tumor driver or by activating bypass signaling to revert drug sensitivity. Our preliminary experiments with primary patient-derived squamous cell tumor cultures, indicates that STAT3 activation is tumor-specific. This implies that the use of STAT inhibitors to prevent tumor progression should be diagnostically assessed.
This project will develop assays to measure the activation and targeting of STAT proteins, so to translationally assess STAT’s candidacy as a target for cancer prevention. ESR13 will combine the use of novel STAT inhibitors (B. Page, co supervisor) with an analysis of STAT-related biological read-outs, to develop diagnostic tools for personalized analysis of ex vivo tumor cultures.
ESR13 will access an established collection of cultures derived from chemotherapy naive clinical squamous and BC tumors, with associated drug sensitivity response data, serving as a starting point, expand this collection and determine the mutation status of common driver genes by sequencing;
determine the sensitivity of newly-derived cultures to single or combination targeted compounds, using a high-throughput screening approach established at UHel;
determine the activation status of the STAT pathway, and other oncogenic signaling pathways, both at baseline and following treatment with compounds that show efficacy;
measure responses (viability, apoptosis, long-term colony formation assays) to known vs novel STAT inhibitors, in cultures that show STAT activation, as well as in slice explants50 from primary squamous tissue;
integrate all data to assess the diagnostic value and biomarkers of STAT inhibitors for prevention of tumor progression.
Enrolment in Doctoral degree(s):
- University of Helsinki