Fig. 4

Statin treatment increases tumor uptake and efficacy of trastuzumab. a Representative coronal and MIPs PET images and b biodistribution data at 4, 8, 24, and 48 h p.i. of [⁸⁹Zr]Zr-DFO-trastuzumab in athymic nude mice bearing s.c. gastric tumors. Lovastatin (8.3 mg kg⁻¹ of mice) was orally administrated 12 h prior and at the same time as the tail vein injection of [⁸⁹Zr]Zr-DFO-trastuzumab (8.14–10.18 Mbq, 80–100 μg protein). Bars, n = 4 mice per group, mean ± S.E.M. MIPs maximum intensity projection. %ID g⁻¹, percentage of injected dose per gram. Scale bars: 5 mm. c Uptake (upper panel) and autoradiography (lower panel) of [⁸⁹Zr]Zr-DFO-trastuzumab in organotypic cultures of non-tumor and tumor human bladder tissues. Organotypic cultures were incubated with 25 μM of lovastatin for 4 h prior and at the same time as the addition of [⁸⁹Zr]Zr-DFO-trastuzumab. Slices were harvested at 3 h after incubation with [⁸⁹Zr]Zr-DFO-trastuzumab. Bars, n = 3, mean ± S.E.M, *P < 0.05 based on a Student’s t-test. CPM counts per minute. Scale bars: 500 μm. d Superior in vivo therapeutic efficacy of trastuzumab combined with lovastatin when compared with trastuzumab in nu/nu female mice bearing NCIN87 gastric and BT474 breast xenografts, and NSG mice bearing gastric PDXs (n ≥ 8 mice per group). Intraperitoneal trastuzumab administration 5 mg kg⁻¹ weekly (during 5 weeks) was started at day 0. Lovastatin (4.15 mg kg⁻¹ of mice) was orally administrated 12 h prior and at the same time as the intraperitoneal injection of trastuzumab. e Ability of trastuzumab to mediate in vitro ADCC as determined with peripheral blood mononuclear cells (PBMCs) from healthy donors, in Scr and CAV1-depleted cancer cells (upper panel). Bars, n = 5, mean ± S.E.M, **P < 0.01 based on a Student’s t-test. Trastuzumab IC₅₀ response as determined with engineered Jurkat cells stably expressing the FcγRIIIa receptor, in Scr and CAV1-depleted cancer cells (lower panel)