Abstract
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Introduction: The glycoprotein non-metastatic melanoma B (gpNMB) is a transmembrane protein identified as a promising therapeutic target for many malignancies including 30 - 41% of triple negative breast cancer (TNBC), and is associated with metastasis, recurrence and shorter overall survival of patients with breast cancer. Glembatumumab vedotin (CDX-011) is an antibody drug conjugate that binds to gpNMB and delivers a microtubulin inhibitor to kill the cancer cell. Previous preclinical studies found that kinase inhibitors such as dasatinib can induce increased gpNMB expression and may enhance the efficacy of tumor cell killing by CDX-011 or other anti-gpNMB therapeutics. [89Zr]ZrDFO-CR011 was previously developed as a companion diagnostic imaging agent for CDX-011, and shown to distinguish different levels of cell surface gpNMB expression.The primary aim of this study was to evaluate the ability of [89Zr]ZrDFO-CR011 to monitor the upregulation of gpNMB induced by treatment with dasatinib in preclinical models of TNBC, to define the optimal timepoint for CDX-011 administration. The secondary aim was to explore the therapeutic efficacy of combination treatment with both dasatinib and CDX-011 in comparison with either single agent therapy.
Methods: Mice with MDA-MB-468 xenografts, which have moderate level of gpNMB expression, were treated with dasatinib (n=16), vehicle (n=6), or CDX-011 (n=8), respectively, for two weeks. Mice treated with dasatinib were then separated into two groups (n=8 each), one continued on with dasatinib alone while the other received dasatinib in combination with CDX-011, for another two weeks. [89Zr]ZrDFO-CR011 was injected via tail vein of the mice, PET imaging was performed 7 days p.i. before treatment (baseline), and at 2 and 4 weeks after treatment to monitor changes in gpNMB expression in vivo. The mean standardized uptake values (SUVmean) of tumor was calculated based on the decay-corrected radioactivity and mice weight. Tumor volumes were measured and the percent change in tumor volume (% CTV) was calculated over time every 5 days, and at the end of the 4-week experiments. Levels of gpNMB and biomarkers of response to dasatinib (Src and p-Src) were analyzed via western blot.
Results: Compared with baseline (SUVmean= 3.2 ± 0.3), the dasatinib group has significantly higher tumor accumulation of [89Zr]ZrDFO-CR011 at 2 (SUVmean = 4.9 ± 0.6) and 4 weeks (SUVmean= 4.6 ± 0.2) after treatment. The SUVmean in the CDX-011 group were significantly lower at 2 (2.0 ± 0.3) and 4 weeks (1.3 ± 0.1) compared with that at baseline (2.8 ± 0.5). For the combination group, the SUVmean increase from 3.1 ± 0.4 to 4.3 ± 0.5 after two weeks of dasatinib, and then decrease to 2.2 ± 0.3 after the added treatment with CDX-011. Dasatinib-treated tumors displayed significantly increased gpNMB, decreased pSrc (Y416), and retained total Src levels compared with the vehicle group (Fig 2). In the groups treated with CDX-011 (with or without dasatinib), there was a significant negative correlation between tumor uptake of the tracer at 2 weeks after treatment and the corresponding percent change in tumor volume (r = -0.787, p = 0.0205) (Fig 3). The CDX-011 and dasatinib combination group showed the highest tumor regression after treatment with %CTV of -54 ± 13 compared with the vehicle group (+102± 27), CDX-011 group (-25 ± 9.8), and dasatinib group (-23 ± 11) (Fig 4).
Conclusions: PET imaging with [89Zr]ZrDFO-CR011 can be used to measure gpNMB upregulation in response to dasatinib treatment. Two weeks is the optimal time point that upregulated gpNMB for CDX-011 therapy. Further, combination therapy with dasatinib and CDX-011 appears to be a promising therapeutic strategy for TNBC.
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