Project 2: Rational approaches to improve treatment outcomes of patients with breast cancer brain metastases

$277,223P50FY2025CANIH

Dana-Farber Cancer Inst, Boston MA

Investigators

Linked publications & trials

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Abstract

Project Summary/Abstract Brain metastases are a devastating complication with few effective therapies. Recently, antibody drug conjugates (ADCs) have markedly improved outcomes for patients with metastatic breast cancer and other cancers. However, patients with active brain metastases have been systematically excluded from most ADC trials. Substantial preclinical and clinical data suggest ADCs may be effective against brain metastases due to their ability to cross the disrupted blood-tumor barrier (BTB) in these lesions, unlike the intact blood brain barrier (BBB). The compromised BTB in brain metastases enables entry of molecules including large biologics like ADCs. Additionally, given our recent finding that PI3KÎ² inhibition enhances anti-tumor immunity in PTEN- deficient tumors, we will target immune evasion in PTEN-deficient brain metastases by evaluating PI3KÎ² inhibitors in combination with immunotherapy. Given frequent PTEN loss in breast cancer brain metastases (BCBM), this approach has strong potential to improve outcomes for BCBM patients. We will leverage patient- derived xenografts (PDXs) and genetically engineered models (GEMMs) to develop rational ADC-based combination therapies for BCBM. In Aim 1, we will test combination approaches to increase the efficacy of the HER2-targeted ADC, trastuzumab deruxtecan (T-DXd), in HER2+ and HER-low BCBM and evaluate PI3KÎ² blockade to enhance anti-tumor immunity. We will conduct clinical trials with T-DXd in patients with HER2+ and HER2-low BCBM. In Aim 2, we will investigate the TROP2 targeted ADC, datopotamab deruxtecan (Dato-DXd) in triple negative (TN) BCBM and evaluate combinations of Dato-DXd with PI3KÎ² blockade in PTEN-deficient TN BCBM. We will also pursue clinical translation of Dato-DXd in patients with TN BCBM. Our overarching goals are to rigorously develop novel ADC-based therapies which are active intracranially in the preclinical setting to enable rapid clinical advancement for this patient population with tremendous unmet medical need.

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