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Optimizing HER2 modulation in HER2-low breast tumors to enhance ADC therapy

Award Number: R01CA309209
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Optimizing HER2 modulation in HER2-low breast tumors to enhance ADC therapy - PROJECT SUMMARY/ABSTRACT - In patients with breast tumors who are clinically classified as HER2-low, the antibody-drug conjugate (ADC) trastuzumab-deruxtecan (T-DXd) prolongs progression-free and overall survival compared to single-agent chemotherapy. However, not all breast tumors classified as HER2-low benefit from T-DXd, or even those that initially respond, inevitably develop resistance over time. Complementary biomarkers and novel therapeutic approaches are therefore needed to identify patients who will respond and to overcome resistance to HER2-targeting ADC therapies. Our data demonstrate that biological processes of caveolin-1 (CAV-1)-mediated HER2 internalization and recycling associate with tumors' response to ADCs. Among patients treated with trastuzumab, those with CAV-1-high tumors have lower survival outcomes compared to patients with CAV-1-low tumors. Lovastatin-mediated CAV-1 depletion enhanced T-DXd efficacy, and statin use was associated with longer survival in retrospective studies of patients treated with trastuzumab or T-DXd. Here, we will evaluate antibody positron emission tomography (immunoPET) using zirconium-89 (89Zr)-trastuzumab together with HER2 and CAV-1 protein levels as a complementary biomarker to predict early response of T-DXd, and to optimize T-DXd plus lovastatin in patients with HER2-low breast tumors. We will perform randomized imaging and therapeutic studies in HER2-low breast patient-derived xenografts (PDXs) resistant to T-DXd to optimize lovastatin co-treatment and restore sensitivity to T-DXd, as these clinically relevant models preserve tumor heterogeneity and are an intact living system required for PET imaging to evaluate whole-body T-DXd biodistribution and therapeutic response. We will test T-DXd in combination with lovastatin in a phase II clinical trial of patients with HER2-low advanced breast cancer. Aim 1 will use 89Zr-trastuzumab PET imaging to further investigate the role of CAV-1 in the regulation of HER2-ADC internalization and T-DXd efficacy. Our studies will show that 89Zr-trastuzumab PET and CAV-1 protein levels, combined with analyses at the tissue level, can detect different levels of early response to T-DXd therapy, providing a strong impact. Aim 2 will further establish PET to monitor the modulation of CAV-1 with lovastatin to enhance T-DXd efficacy. We will determine CAV-1 protein levels and 89Zr-trastuzumab uptake in HER2-low breast PDXs by PET in response to treatments that enhance T-DXd efficacy. In Aim 3, we will conduct a phase II clinical trial to evaluate the overall response rate of T-DXd plus lovastatin in patients with HER2-low advanced breast cancer and obtain impactful correlative studies, including 89Zr-trastuzumab PET imaging and tissue analyses. This project will provide a foundation for future investigations, including the clinical translation of imaging approaches to predict and monitor tumor response to ADCs and the potential broader application to enhance uptake of other ADCs through modulating membrane receptor density, ADC internalization, and improving understanding of heterogeneous antigen expression. This project will lead to a novel combination therapy to treat HER2-low advanced breast tumors.


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: 2026 ( Subtotal = $645,323 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Detection and Diagnosis Research	000	1	7/10/2026	NEW	$645,323
														Subtotal = $645,323

Grand Total All Awards = $645,323

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Optimizing HER2 modulation in HER2-low breast tumors to enhance ADC therapy

Award Number: R01CA309209

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/10/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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