# Mechanisms and therapeutic targeting of colon cancer stem cell plasticity

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $352,275

## Abstract

ABSTRACT:
Tumor-initiating or cancer stem cells (CSCs) have been implicated in drug resistance, metastasis, and relapse,
making CSCs a major impediment for the effective treatment of cancer. Recent studies have unequivocally
established that the adult stem cell marker LGR5 (leucine-rich repeat-containing, G protein-coupled receptor 5)
is highly expressed in primary colon tumors and only LGR5-positive colon CSCs are capable of driving tumor
growth and metastasis. However, the function and mechanism of LGR5 in CSCs is still relatively unknown. We
generated LGR5-targeted antibody-drug conjugates (ADCs) incorporating the toxin monomethyl-auristatin E
and showed they could destroy colon cancer cells and xenografts, yet tumors eventually recurred.
Furthermore, selective genetic ablation of LGR5-positive colon CSCs failed to completely eradicate tumors
since LGR5-negative cancer cells were able to rapidly regenerate LGR5-positive cells after treatment was
terminated, indicating a high degree of cancer cell plasticity. Therefore, to develop therapies that completely
eradicate primary colon tumors and metastatic disease, it is critical to identify LGR5-mediated functions and
signaling pathways involved in CSC plasticity. We reported that LGR5 binds R-spondin growth factors and
functions to potentiate Wnt/beta-catenin signaling, an essential pathway that is activated in CSCs. Recently,
we have found that LGR5 interacts with the scaffold protein IQGAP1 (IQ Motif Containing GTPase Activating
Protein 1) to increase cell-cell adhesion in colon cancer cells and knockdown of LGR5 significantly enhanced
drug resistance and activation of proteins associated with survival signaling. Loss of LGR5 induced expression
of adhesion G-protein-coupled receptor GPR56, which is highly upregulated in colon tumors. In Aim 1, we will
determine the roles and mechanisms of LGR5 in the control of stemness and drug resistance of CSCs. We will
investigate how LGR5 knockout (KO) compared to elimination of LGR5-positive CSCs affects tumor growth,
metastasis, drug resistance, and cancer cell signaling using patient-derived xenograft (PDX) organoids models
ex vivo and in vivo. The role of LGR5-IQGAP1 interaction in regulating the different properties that define
CSCs will also be examined. In Aim 2, we will develop unique bispecific ADCs to target CSC plasticity. We will
test safety, efficacy and establish proof-of-concept for dual-targeted therapeutics to simultaneously destroy
both LGR5-positive CSCs and LGR5-negative cancer cells. In Aim 3, we will characterize and validate GPR56
as a novel target for colon cancer by delineating its roles in tumor growth and drug resistance using GPR56
KO colon cancer cell lines and PDX models. This study will uncover the function and mechanism of LGR5 in
CSCs and generate innovative therapeutic leads to target stemness and plasticity for the treatment and
eradication of colon cancer.

## Key facts

- **NIH application ID:** 9896787
- **Project number:** 5R01CA226894-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Kendra S. Carmon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,275
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896787

## Citation

> US National Institutes of Health, RePORTER application 9896787, Mechanisms and therapeutic targeting of colon cancer stem cell plasticity (5R01CA226894-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9896787. Licensed CC0.

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