Emmy Verschuren – Laboratory of Lung Cancer Model Systems – PhD project 13

The prevention of cancer recurrence in patients following primary disease treatments is defined as tertiary cancer prevention. Our research team has developed a set of ex vivo functional assays, including primary cultures and tissue slice explants[1], to understand how tumor cells within phenotypically diverse microenvironments can be targeted. We aim to translate the fundamental findings from both pre-clinical and clinical sample-based research to help identify more effective treatments for cancer patients. One PhD position is available to test whether STAT proteins constitute a target for cancer prevention across solid tumor types, using our experience in lung cancer diagnostics as a basis. This ESR will work as part of a collaborative team to explore novel inhibitors of the inflammatory Stat signaling pathway as a translational approach, to indicate its promise for the tertiary prevention of solid tumor progression.

Project 13 – Translational assessment of STAT3 as a target for cancer prevention

Hypothesis: 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 and 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 Breast Cancer (BC). 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, warranting diagnostic assessment.

Objectives: 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 (provided by 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. (1) 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; (2) determine the sensitivity of newly-derived cultures to single or combination targeted compounds, using a high-throughput screening approach established at UHel; (3) determine the activation status of the STAT pathway, and other oncogenic signaling pathways, both at baseline and following treatment with compounds that show efficacy; (4) 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 explants from primary squamous tissue; (5) integrate all data to assess the diagnostic value and biomarkers of STAT inhibitors for prevention of tumor progression.

Related readings

[1] Nagaraj, A. S. et al. Establishment and Analysis of Tumor Slice Explants As a Prerequisite for Diagnostic Testing. J Vis Exp, (2018).

[2] Yu, H., et al. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14, 736-746 (2014).