Wednesday, January 15, 2025
1/15/2025
ABSTRACT: Tumor heterogeneity and cancer stem cell (CSC) plasticity present a significant challenge to the effective treatment of colorectal cancer (CRC). Several studies have established that Leucine-rich repeat containing, G protein-coupled Receptor 5 (LGR5) marks CSCs and is highly upregulated in CRC. Plasticity of LGR5+ CSCs has been shown to promote therapy resistance, tumor progression, and metastasis. CRC is also dependent on the epidermal growth factor receptor (EGFR) and EGFR-targeted antibodies such as cetuximab (CTX) are routinely used for the treatment of metastatic CRC. However, the clinical efficacy of EGFR-targeted treatment has been limited to a subset of patients that do not harbor KRAS mutations. Antibody-drug conjugates (ADCs) have experienced a recent surge in success within the past few years and several have now been approved for solid tumor indications. The objective of this project is to develop a novel bispecific ADC (BsADC) directed against LGR5 and EGFR and evaluate antitumor and antimetastatic efficacy in patient-derived models of CRC. We propose leveraging the dual-targeting capabilities of an LGR5-EGFR bispecific antibody combined with the ability of ADCs to exert potent drug effects irrespective of tumor mutational status, while minimizing systemic toxicity. In Aim 1, we will generate a lead LGR5-EGFR BsADC with high potency and specificity in vitro. In Aim 2, we will evaluate tolerability and therapeutic efficacy of the lead LGR5-EGFR BsADC in subcutaneous and orthotopic patient-derived tumor models of CRC. Results from this study will lead to the development of a unique dual-targeted ADC and determine if it can overcome therapy resistance due to tumor heterogeneity and CSC plasticity and prevent metastasis. Moreover, an LGR5-EGFR BsADC has the potential to treat other tumor types that express high levels of either tumor antigen.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).