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Temporal Modulation of HER2 Membrane Availability Increases Pertuzumab Uptake and Pretargeted Molecular Imaging of Gastric Tumors.

ABSTRACT: Human epidermal growth factor receptor 2 (HER2) is used as a tumor biomarker and therapeutic target. Pertuzumab is an anti-HER2 antibody, and its binding to tumor cells requires HER2 to be present at the cell membrane. However, the cellular distribution of HER2 protein in gastric tumors is dynamic, and HER2 internalization decreases antibody binding to tumor cells. These features preclude the use of pretargeted strategies for molecular imaging and therapy. We explored the pharmacological modulation of HER2 endocytosis as a strategy to improve pertuzumab uptake in HER2-positive gastric tumors and allow the use of a pretargeted imaging approach. Methods: We conducted in vitro and in vivo studies with NCI-N87 gastric cancer cells to determine how HER2 endocytosis affects pertuzumab binding to tumor cells. Lovastatin, a clinically approved cholesterol-lowering drug, was used to modulate caveolae-mediated HER2 endocytosis. Results: Administration of lovastatin to NCI-N87 cancer cells resulted in significant accumulation of non-activated HER2 dimers at the cell surface. Pretreatment of NCI-N87 cells with lovastatin increased in vitro specific accumulation of membrane-bound 89Zr-labeled pertuzumab. Lovastatin-enhanced pertuzumab tumor uptake was also observed in NCI-N87 gastric cancer xenografts, allowing tumor detection as early as 4 h and high-contrast images at 48 h after tracer administration via PET. Temporal enhancement of HER2 membrane availability by lovastatin allowed imaging of cell surface HER2 with transcyclooctene-conjugated antibodies and 18F-labeled tetrazine. Conclusion: Temporal pharmacological modulation of membrane HER2 may be clinically relevant and exploitable for pretargeted molecular imaging and therapy in gastric tumors.

SUBMITTER: Pereira PMR

PROVIDER: S-EPMC6836866 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Temporal Modulation of HER2 Membrane Availability Increases Pertuzumab Uptake and Pretargeted Molecular Imaging of Gastric Tumors.

Pereira Patrícia M R PMR Mandleywala Komal K Ragupathi Ashwin A Carter Lukas M LM Goos Jeroen A C M JACM Janjigian Yelena Y YY Lewis Jason S JS

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20190606 11

Human epidermal growth factor receptor 2 (HER2) is used as a tumor biomarker and therapeutic target. Pertuzumab is an anti-HER2 antibody, and its binding to tumor cells requires HER2 to be present at the cell membrane. However, the cellular distribution of HER2 protein in gastric tumors is dynamic, and HER2 internalization decreases antibody binding to tumor cells. These features preclude the use of pretargeted strategies for molecular imaging and therapy. We explored the pharmacological modulat ...[more]

PMID: 31171598

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Project description:BackgroundIn patients with metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (HER2), progression-free survival was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel. Overall survival was significantly improved with pertuzumab in an interim analysis without the median being reached. We report final prespecified overall survival results with a median follow-up of 50 months.MethodsWe randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination. The secondary end points of overall survival, investigator-assessed progression-free survival, independently assessed duration of response, and safety are reported. Sensitivity analyses were adjusted for patients who crossed over from placebo to pertuzumab after the interim analysis.ResultsThe median overall survival was 56.5 months (95% confidence interval [CI], 49.3 to not reached) in the group receiving the pertuzumab combination, as compared with 40.8 months (95% CI, 35.8 to 48.3) in the group receiving the placebo combination (hazard ratio favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Results of sensitivity analyses after adjustment for crossover were consistent. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed. Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained.ConclusionsIn patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination. (Funded by F. Hoffmann-La Roche and Genentech; CLEOPATRA ClinicalTrials.gov number, NCT00567190.).

Project description:BackgroundPertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer.MethodsWe randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo.ResultsIn the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).ConclusionsPertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann-La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877 .).

Dataset Information

Temporal Modulation of HER2 Membrane Availability Increases Pertuzumab Uptake and Pretargeted Molecular Imaging of Gastric Tumors.

Publications

Temporal Modulation of HER2 Membrane Availability Increases Pertuzumab Uptake and Pretargeted Molecular Imaging of Gastric Tumors.

Similar Datasets

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