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Bispecific drug-conjugates for treating colorectal cancer

Award Number: R21CA282378
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Bispecific drug-conjugates for treating colorectal cancer - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $215,308 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	2	6/6/2025	NON-COMPETING CONTINUATION	$21,531
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	1/8/2025	NON-COMPETING CONTINUATION	$193,777
														Subtotal = $215,308

Issue Date FY: 2024 ( Subtotal = $178,843 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	1/26/2024	NEW	$178,843
														Subtotal = $178,843

Grand Total All Awards = $394,151

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Bispecific drug-conjugates for treating colorectal cancer

Award Number: R21CA282378

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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