Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Abstract

Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.treatment resistance | tumor-stroma interaction | targeted therapy | tumor microenvironment | antiangiogenesis

ANG4043, a Novel Brain-Penetrant Peptide–mAb Conjugate, Is Efficacious against HER2-Positive Intracranial Tumors in Mice

“…The small increase in median survival for the native mAb is consistent with the low concentrations observed in brain, while the increased survival conferred by ANG4043 suggests that the higher brain concentrations provide additional benefit. In previous studies in mice with intracranial tumors, trastuzumab was reported to have no significant effect on survival at doses between 4 and 10 mg/kg, administered either daily or twice weekly (15,16,47). In our study, we did observe a slight increase in survival with unconjugated anti-HER2, but the effect was significantly smaller than that observed with ANG4043.…”

“…Mice (n ¼ 10) in the survival studies were monitored daily for body weight loss and were euthanized if a reduction of 20% or greater from the maximum weight was observed. For the native mAb, median survival was somewhat higher than for vehicle (6%, P ¼ 0.028), with vehicle and anti-HER2 median survival of 47 days [95% confidence interval (CI), [40][41][42][43][44][45][46][47][48][49][50] and 50 days (95% CI, 45-56), respectively (Fig. 6A).…”

“…Median survival in the ANG4043 group was 60 days (95% CI, 50-63). In a follow-up study to determine the effect of increasing dose, intravenous treatment with 15 mg/kg ANG4043 increased median survival by 78% (P ¼ 0.0003), with survival of 45 days (95% CI, [40][41][42][43][44][45][46][47][48][49] in the vehicle group and 80 days (95% CI, 62-89) in the ANG4043 group (Fig. 6B).…”

Interdisciplinary management of central nervous system metastasis and neoplastic meningitis: recent developments and future perspectives

“…By adding anti-VEGFR2 antibodies, however, tumor growth in the brain was better controlled, leading to improved survival, especially with a combination of lapatinib, trastuzumab, and anti-VEGFR2 antibody treatment. [20] Second, astrocytes are intimately involved in maintaining normal homeostasis of the brain microenvironment, accomplished through transport of nutrients to the neurons and facilitation of neural signal transduction. In fact, activated astrocytes induced upregulation of survival genes.…”

A murine–human chimeric IgG antibody against vascular endothelial growth factor receptor 2 inhibits angiogenesis in vitro

“…As a result, angiogenesis inhibitors have been developed to target VEGFR2 on vascular ECs and block angiogenesis that is required for tumor growth. These inhibitors include antibodies (Wicki et al 2012;Kodack et al 2012), immunotoxins (Behdani et al 2013), ribozymes (Tao et al 2007), soluble receptors , and small molecule tyrosine kinase inhibitors (Shen et al 2012). Some of them have demonstrated significant therapeutic efficacy both in preclinical animal models and in clinical trials in patients with cancer.…”