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Novel Antibody-Drug Conjugate Combination Therapy for Treating Colorectal Cancer

Award Number: R21CA270716
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Novel Antibody-Drug Conjugate Combination Therapy for Treating Colorectal Cancer - ABSTRACT: Colorectal cancer stem cells (CSCs) are believed to mediate therapeutic resistance and relapse of residual disease due to their increased capacity for survival and ability to self-renew and differentiate into heterogeneous lineages of tumor cells. Recent therapeutic efforts have been focused on the targeting of CSCs to improve treatment efficacy. However, due to the plastic nature of CSCs and tumor heterogeneity, it is becoming more apparent that in order to successfully eliminate colorectal cancer (CRC), treatment may require a dual- or multi- targeted approach. Several reports have established that LGR5 (Leucine-rich repeat containing, G protein- coupled Receptor 5) is highly upregulated in CRC and marks highly plastic CSCs. The dynamic interconversion of LGR5-positive CSCs to LGR5-negative cancer cells has been shown to be essential during tumor progression and metastasis. We and others generated LGR5-targeted antibody-drug conjugates (ADCs) that were highly effective in eliminating LGR5-positive colorectal tumors without major adverse effects, however a fraction of tumors eventually relapsed. These findings suggest that targeting LGR5-positive CSCs alone may not be sufficient to eliminate colorectal tumors due to their plasticity. Epiregulin (EREG) is a cell surface expressed, EGFR ligand that is upregulated in CRC and highly expressed on both LGR5-postive CSCs and LGR5-negative cancer cells. EREG was also shown to drive colitis-associated CRC and be predictive of CRC-associated liver metastasis. Interesting, EGFR-targeted therapies have been shown to increase LGR5 expression in CRC models and LGR5 knockdown in CRC cells increased EREG levels. Thus, therapeutic targeting of both LGR5 and EREG/EGFR may be a more effective strategy to eliminate LGR5-positive CSCs and overcome plasticity. In Aim 1, we will generate anti-EREG ADCs and evaluate safety and therapeutic efficacy against multiple CRC models. In Aim 2, we will determine if ADC combination treatment can improve therapeutic response and overcome cancer cell plasticity. We will characterize different EREG monoclonal antibodies and screen different linker-payloads to develop an optimal anti-EREG ADC with high specificity, affinity, and potency. Anti-EREG ADCs will be tested as a monotherapy and in combination with anti-LGR5 ADCs linked to the same or different payloads against patient-derived xenograft models of CRC. ADCs will also be evaluated in combination with other EGFR-targeted therapies. This project will lead to the generation of unique ADCs and an innovative ADC combination therapy to potentially overcome CSC plasticity and resistance for the improved treatment of CRC.


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 = -$3,478 )
2025	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	4/29/2025	NON-COMPETING CONTINUATION	-$3,478
														Subtotal = -$3,478

Issue Date FY: 2023 ( Subtotal = $214,414 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	1/26/2023	NON-COMPETING CONTINUATION	$214,414
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	002	2	1/31/2023	NON-COMPETING CONTINUATION	$214,414
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	2	1/30/2023	NON-COMPETING CONTINUATION	-$214,414
														Subtotal = $214,414

Issue Date FY: 2022 ( Subtotal = $182,325 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	1/14/2022	NEW	$182,325
														Subtotal = $182,325

Grand Total All Awards = $393,261

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Novel Antibody-Drug Conjugate Combination Therapy for Treating Colorectal Cancer

Award Number: R21CA270716

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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