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A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds

View Article: PubMed Central - PubMed

ABSTRACT

The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.

No MeSH data available.


Drug-Drug Combination Studies in PDTCs(A) Synergism of paclitaxel in combination with 17-AAG. (Top panel) Bliss independence model residuals for paclitaxel combinations are shown. The 95% percentile of these differences (in percentage) is plotted. For each drug combination, the expected response is compared to the observed response in all the dose ranges in the combination. (Middle panel) Boxplots of distribution of residuals (Bliss independence model) for paclitaxel and 17-AGG combination in each PDTC model tested are shown. (Bottom panel) Detailed analysis for HCI008 (from top to bottom: single drug curves, bivariate isotonic fit for the combination, and residuals of the Bliss model for each dose combination) is shown. Red shades, synergistic effects; blue shades, antagonistic effects.(B) Synergism of IGF-1R/IR inhibitor (BMS-754807) with PI3K/mTOR inhibitor (NVP-BEZ235). Panels are the same as in A (bottom panel: detailed analysis for STG201).
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fig5: Drug-Drug Combination Studies in PDTCs(A) Synergism of paclitaxel in combination with 17-AAG. (Top panel) Bliss independence model residuals for paclitaxel combinations are shown. The 95% percentile of these differences (in percentage) is plotted. For each drug combination, the expected response is compared to the observed response in all the dose ranges in the combination. (Middle panel) Boxplots of distribution of residuals (Bliss independence model) for paclitaxel and 17-AGG combination in each PDTC model tested are shown. (Bottom panel) Detailed analysis for HCI008 (from top to bottom: single drug curves, bivariate isotonic fit for the combination, and residuals of the Bliss model for each dose combination) is shown. Red shades, synergistic effects; blue shades, antagonistic effects.(B) Synergism of IGF-1R/IR inhibitor (BMS-754807) with PI3K/mTOR inhibitor (NVP-BEZ235). Panels are the same as in A (bottom panel: detailed analysis for STG201).

Mentions: Combination therapy is increasingly being used as an approach to combat development of resistance in cancer treatment. To test the use of PDTC models in high-throughput drug-drug combination assays, we designed a 5 × 5 matrix with standard of care chemotherapy agents (cisplatin and paclitaxel) and six clinically relevant targeted compounds (Figure S7A). Single-agent drug responses in these drug-drug combination assays were highly correlated with those obtained from the 108 individual compound screen (Pearson correlation 0.84), further confirming the robust and reproducible performance of our PDTX/PDTC platform (Figure S7B). The Bliss model (see STAR Methods), an approach that does not require precise estimates of IC50s, was used to compute synergy and antagonism. The performance of the Bliss model was validated by showing in a Her2-positive model (HCI008) synergy of an Hsp90 inhibitor (17-AAG or tanespimycin) in combination with paclitaxel, which has been previously reported (Modi et al., 2011; Figure 5A). The testing of pairwise combinations using the six targeted compounds (Figure S7A) confirmed the rationally predicted synergistic effects of combining an IGFR1/INSR1 inhibitor (BMS-754807) with a dual PI3K/mTOR inhibitor (NVP-BEZ235) or an EGFR inhibitor (gefitinib/Iressa; Figure 5B).


A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds
Drug-Drug Combination Studies in PDTCs(A) Synergism of paclitaxel in combination with 17-AAG. (Top panel) Bliss independence model residuals for paclitaxel combinations are shown. The 95% percentile of these differences (in percentage) is plotted. For each drug combination, the expected response is compared to the observed response in all the dose ranges in the combination. (Middle panel) Boxplots of distribution of residuals (Bliss independence model) for paclitaxel and 17-AGG combination in each PDTC model tested are shown. (Bottom panel) Detailed analysis for HCI008 (from top to bottom: single drug curves, bivariate isotonic fit for the combination, and residuals of the Bliss model for each dose combination) is shown. Red shades, synergistic effects; blue shades, antagonistic effects.(B) Synergism of IGF-1R/IR inhibitor (BMS-754807) with PI3K/mTOR inhibitor (NVP-BEZ235). Panels are the same as in A (bottom panel: detailed analysis for STG201).
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037319&req=5

fig5: Drug-Drug Combination Studies in PDTCs(A) Synergism of paclitaxel in combination with 17-AAG. (Top panel) Bliss independence model residuals for paclitaxel combinations are shown. The 95% percentile of these differences (in percentage) is plotted. For each drug combination, the expected response is compared to the observed response in all the dose ranges in the combination. (Middle panel) Boxplots of distribution of residuals (Bliss independence model) for paclitaxel and 17-AGG combination in each PDTC model tested are shown. (Bottom panel) Detailed analysis for HCI008 (from top to bottom: single drug curves, bivariate isotonic fit for the combination, and residuals of the Bliss model for each dose combination) is shown. Red shades, synergistic effects; blue shades, antagonistic effects.(B) Synergism of IGF-1R/IR inhibitor (BMS-754807) with PI3K/mTOR inhibitor (NVP-BEZ235). Panels are the same as in A (bottom panel: detailed analysis for STG201).
Mentions: Combination therapy is increasingly being used as an approach to combat development of resistance in cancer treatment. To test the use of PDTC models in high-throughput drug-drug combination assays, we designed a 5 × 5 matrix with standard of care chemotherapy agents (cisplatin and paclitaxel) and six clinically relevant targeted compounds (Figure S7A). Single-agent drug responses in these drug-drug combination assays were highly correlated with those obtained from the 108 individual compound screen (Pearson correlation 0.84), further confirming the robust and reproducible performance of our PDTX/PDTC platform (Figure S7B). The Bliss model (see STAR Methods), an approach that does not require precise estimates of IC50s, was used to compute synergy and antagonism. The performance of the Bliss model was validated by showing in a Her2-positive model (HCI008) synergy of an Hsp90 inhibitor (17-AAG or tanespimycin) in combination with paclitaxel, which has been previously reported (Modi et al., 2011; Figure 5A). The testing of pairwise combinations using the six targeted compounds (Figure S7A) confirmed the rationally predicted synergistic effects of combining an IGFR1/INSR1 inhibitor (BMS-754807) with a dual PI3K/mTOR inhibitor (NVP-BEZ235) or an EGFR inhibitor (gefitinib/Iressa; Figure 5B).

View Article: PubMed Central - PubMed

ABSTRACT

The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.

No MeSH data available.