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Fig. 1 | Journal of Hematology & Oncology

Fig. 1

From: VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status

Fig. 1

Cediranib potentiates the antitumor activity of olaparib in OC-PDXs. A OC-PDXs (N = 10) were transplanted subcutaneously in nude mice and treatment started when tumors reached approximately 300 mg. Olaparib (OLA 100 mg/kg) and cediranib (CED 3 mg/kg), as single agents or in combination (OLA + CED), were given orally by gavage once a day (QD) 5 days on and 2 days off (Q1 × 5). The change in tumour volume (compared with the tumour volume at treatment start, baseline for each mouse) after 4 weeks of treatment is shown in the waterfall plots (each vertical bar = one tumour): vehicle N = 100, CED N = 86, OLA N = 90, OLA + CED N = 98. RECIST category was determined/ as follow: change of tumour volume between + 25% and -30% was considered stable disease (SD), while below -30% was considered regressive disease (RD). The difference in objective response rate (ORR = the sum of RD and SD) of the combination therapy and olaparib monotherapy (81% vs 50%, respectively) was statistically significant (P < 0.0001; Wald test for logistic regression model) with an odds ratio of 3.9 (95% CI 2.05–7.41). Colours associated to each OC-PDX reflect the HRR mutational status (specified in Additional file 1: Fig. S1): tumours carrying a biallelic inactivating mutations in BRCA1 or BRCA2 genes (MNHOC154, MNHOC500, MNHOC508, MNHOC511, MNHOC513) are bluish; tumours being HRR wild-type (MNHOC124) or carrying heterozygous mutations in some HRR genes (MNHOC18, MNHOC94/2-C, MNHOC143, MNHOC182) are reddish. Sensitivity to cisplatin (DDP; cis-diaminedichloroplatinum) is also indicated: platinum-sensitive (T/C < 10%) light grey; marginally platinum-sensitive (T/C 10–50%) dark grey, platinum-resistant (T/C > 50%) black. B-D Treatment effects on MNHOC182 and MNHOC18 as exemplificative cases. Treatment effects on tumour growth of MNHOC182 and MNHOC18 as exemplificative cases. B Tumor growth, graphs are median tumour volume (mm3) ± median absolute deviation (MAD, shaded area). Coloured bars at the bottom indicate the study dosing period. DDP response (tested in the same experiment) is reported in the insert at the side. MNHOC182: Vehicle N = 5, CED N = 4, OLA N = 4, OLA + CED N = 5; MNHOC18: Vehicle N = 6, CED N = 6, OLA N = 6, OLA + CED N = 6. Differences in tumour volume were analysed by ANOVA and Tukey’s post-test (or t test when only two groups were compared) the days of measurement. *P < 0.05; **P < 0.01. C Heatmap of mRNA expression in MNHOC182 (left panel) and MNHOC18 (right panel) treated for 4 weeks. Log2 normalized values of 3 independent tumors/mice are shown. D Quantitative analyses and representative images (magnification 200x) of immunohistochemistry (IHC) staining for microvessel density (number of CD31+ vessels per mm3) after 4 weeks of treatment. MNHOC182 (left panel) and MNHOC18 (right panel). Statistic by ANOVA and Tukey’s post-test. *P < 0.05; **P < 0.01; ****P < 0.001. (Detailed methods in Additional file 2)

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