# Research Project 2: Targetin Tumor-Initiating Cell (TIC) Heterogeneity To Overcome Chemotherapy Resistance

> **NIH NIH U54** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $467,134

## Abstract

PROJECT SUMMARY 
We and others have shown that a subset of tumor cells capable of regenerating new tumors, termed variously 
as tumor-initiating cells (TIC) or “cancer stem cells” (CSC), are comparatively resistant to current systemic 
chemo- and radio-therapies relative to the bulk of the tumor. As such, the guiding premise for our work over the 
past decade, is that therapeutic targeting of processes required for survival or function of TIC will allow 
elimination of such cells at both the primary and metastatic sites, thereby enhancing response to current 
systemic therapies. However, it has become clear from several laboratories using current cell surface markers, 
enzymatic activity markers, and lentiviral signaling reporters for Wnt, Hedgehog, and STAT3-mediated 
signaling, that TIC are heterogeneous not only across tumors, but also show different behaviors, treatment 
responses, and reporter gene expression at the primary and metastatic sites within a given tumor model. Thus, 
it is critical to understand the diversity of TIC types both within and across tumors, as well as to understand 
how such cells differ in function between the primary and metastatic site, in order to target them effectively – 
particularly in “triple-negative” breast cancer (TNBC), for which there are no approved targeted therapies. 
We hypothesize that there exist molecularly distinct classes of TIC in TNBC. As a consequence, differential 
responses to individual chemotherapies depend, in part, on the class(es) of TIC present in a given tumor. If 
true, we further assert that identifying and targeting class-specific TIC functions may help overcome 
chemotherapy resistance. 
In order to identify candidate regulatory genes or pathways functioning in a spectrum of PDX-derived TIC 
isolated from primary and metastatic sites, we propose to determine first whether TIC derived from either the 
primary or metastatic site show identical, or different, patterns of activation of signaling networks implicated in 
TIC function using lentiviral fluorescent reporters specific for signaling pathways and transcription factors 
implicated in TIC function. We will then identify candidate molecular mechanisms required for TIC activity at 
the population and single cell levels using RNAseq. 
In order to determine whether in vivo targeting of TIC-related genes/pathways can augment response to 
carboplatin, and lead to elimination of different classes of TIC at both the primary and metastatic sites, we will 
evaluate the ability of FDA-approved agents targeting TIC to augment treatment response alone or in 
combination with carboplatin at the primary and metastatic sites, and assay the effect of treatment on TIC 
function in vivo. Results may be used to guide planning and execution of human clinical trials and inform 
precision medicine efforts.

## Key facts

- **NIH application ID:** 10005244
- **Project number:** 5U54CA224076-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Michael T. Lewis
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,134
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005244

## Citation

> US National Institutes of Health, RePORTER application 10005244, Research Project 2: Targetin Tumor-Initiating Cell (TIC) Heterogeneity To Overcome Chemotherapy Resistance (5U54CA224076-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10005244. Licensed CC0.

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