The incidence of esophagogastric (EG) cancer is increasing rapidly, notably among young men. In patients clinically classified as HER2-positive (ERBB2 amplification and/or 2+/3+ protein overexpression), the combination of the therapeutic anti-HER2 antibody trastuzumab and standard cytotoxic therapy prolongs progression-free and overall survival. However, intrinsic tumor resistance or mechanisms of resistance developed during treatment limit the clinical benefit in 32% of patients, and other anti-HER2 therapeutic antibodies failed in clinical trials to treat EG cancer. Complementary biomarkers and methods are therefore needed to treat such patients. Guided by preclinical data suggesting that caveolin-1 (CAV1) ? the main protein of cholesterol-rich invaginations of the plasma membrane ? reduces trastuzumab binding to HER2-positive EG tumors, we initiated retrospective clinical analyses to validate CAV1 as a complementary biomarker of HER2. Remarkably, Kaplan-Meier survival analyses demonstrated that HER2+ EG tumors expressing high CAV1 (IHC 2+/3+) had worse overall survival than those expressing low CAV1 (IHC 0/+1) after trastuzumab therapy. These promising preliminary results prompted us to pharmacologically deplete CAV1 (which is present in cholesterol membrane domains) with lovastatin, a cholesterol-depleting drug. Here, we will perform retrospective analyses of patients with HER2-positive EG tumors to assess HER2 expression and heterogeneity, ERBB2 amplification, CAV1 staining and the presence of genetic alterations (copy number variations) associated with trastuzumab resistance. We will analyze medical records to determine if concurrent statin use is associated with enhanced response to trastuzumab. In addition to retrospective analyses, we will perform randomized imaging and therapeutic preclinical studies using patient-derived EG xenografts (PDXs) representing HER2+/CAV1High and HER2+/CAV1Low tumor populations. We will determine the molecular imaging profile (89Zr-Trastuzumab PET) and therapeutic efficacy in PDXs treated with (1) control saline, (2) trastuzumab alone, (3) lovastatin alone, or (4) the combination of trastuzumab with lovastatin, to identify molecular features that confer drug sensitivity and resistance to this promising investigational combination.
Aim 1 will validate CAV1 as a complementary biomarker to HER2, Aim 2 will determine the potential dosimetric impact of the statins on clinical imaging and identify EG tumor populations that benefit from the trastuzumab/lovastatin combination, and Aim 3 will validate the use of a statin as a new pharmacologic approach to HER2-targeted imaging and systemic radionuclide therapy (endoradiotherapy) capable of reducing off-target radiation doses. All three aims will generate important new preclinical data on the use of statins to improve trastuzumab efficacy, which should provide an excellent foundation for many future investigations, including clinical translation of trastuzumab/statin combination therapy and potential broader application to other HER2+ cancers. The long-term translational objectives are to establish the foundation for a clinical trial combining statin with trastuzumab to prevent or delay the emergence of drug resistance in patients with HER2+ EG cancer.
This proposal seeks to validate caveolin-1 as a complementary biomarker of HER2 and to determine sensitivity or resistance of the tumor-targeting anti-HER2 antibody trastuzumab when administrated in combination with the common cholesterol-depleting drug lovastatin in the treatment of esophagogastric cancer. Retrospective clinical and preclinical analyses will be performed using patient HER2+ tumor samples and patient-derived EG xenografts treated with statin alone, trastuzumab alone, or the combination of the two. The long-term goal will be to inform future therapeutic strategies that can prevent or delay the emergence of trastuzumab resistance.
