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Rapid screening of novel agents for combination therapy in sarcomas.

Cubitt CL, Menth J, Dawson J, Martinez GV, Foroutan P, Morse DL, Bui MM, Letson GD, Sullivan DM, Reed DR - Sarcoma (2013)

Bottom Line: Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984).We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines.Sorafenib and topotecan demonstrated a mixed response.

View Article: PubMed Central - PubMed

Affiliation: Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA ; Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.

ABSTRACT
For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984). A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies.

No MeSH data available.


Related in: MedlinePlus

MRI tumor volume and pathologic response to combination therapy in Ewing sarcoma. (a) Region of interest analysis of T2-weighted MR datasets yielding the percent change in tumor size compared with that shown at initial value on day 0. (b) Quantitative histological results from H&E sections for viability, necrosis, and fibrosis at day 13. (c) P values comparing tumor volumes between treatment groups. (d) P values comparing pathologic determinants of response between treatment groups.
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fig4: MRI tumor volume and pathologic response to combination therapy in Ewing sarcoma. (a) Region of interest analysis of T2-weighted MR datasets yielding the percent change in tumor size compared with that shown at initial value on day 0. (b) Quantitative histological results from H&E sections for viability, necrosis, and fibrosis at day 13. (c) P values comparing tumor volumes between treatment groups. (d) P values comparing pathologic determinants of response between treatment groups.

Mentions: As measured by MRI, the relative change in tumor volume demonstrated similar tumor growth rates for all animals initially (Figure 4(b)). On day 6, the untreated control group and the triciribine-treated mice showed notable increases in tumor growth versus that shown in the dasatinib and combination groups (Figures 4(a)–4(c)). In fact, after the fourth treatment on day 2, dasatinib demonstrated significantly smaller tumor volumes than triciribine at all time points throughout the course of the experiment. Similarly, the combination group also showed significantly lower tumor volumes following the treatment on day 6 versus that shown in the triciribine and control groups. By day 13, the dasatinib group appeared to display the smallest tumor volumes, whereas triciribine did not appear to affect tumor growth. These results also agree with the MRI volume results (Figure 4(b)) and the histology H&E stains (Figure 4(c)).


Rapid screening of novel agents for combination therapy in sarcomas.

Cubitt CL, Menth J, Dawson J, Martinez GV, Foroutan P, Morse DL, Bui MM, Letson GD, Sullivan DM, Reed DR - Sarcoma (2013)

MRI tumor volume and pathologic response to combination therapy in Ewing sarcoma. (a) Region of interest analysis of T2-weighted MR datasets yielding the percent change in tumor size compared with that shown at initial value on day 0. (b) Quantitative histological results from H&E sections for viability, necrosis, and fibrosis at day 13. (c) P values comparing tumor volumes between treatment groups. (d) P values comparing pathologic determinants of response between treatment groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824404&req=5

fig4: MRI tumor volume and pathologic response to combination therapy in Ewing sarcoma. (a) Region of interest analysis of T2-weighted MR datasets yielding the percent change in tumor size compared with that shown at initial value on day 0. (b) Quantitative histological results from H&E sections for viability, necrosis, and fibrosis at day 13. (c) P values comparing tumor volumes between treatment groups. (d) P values comparing pathologic determinants of response between treatment groups.
Mentions: As measured by MRI, the relative change in tumor volume demonstrated similar tumor growth rates for all animals initially (Figure 4(b)). On day 6, the untreated control group and the triciribine-treated mice showed notable increases in tumor growth versus that shown in the dasatinib and combination groups (Figures 4(a)–4(c)). In fact, after the fourth treatment on day 2, dasatinib demonstrated significantly smaller tumor volumes than triciribine at all time points throughout the course of the experiment. Similarly, the combination group also showed significantly lower tumor volumes following the treatment on day 6 versus that shown in the triciribine and control groups. By day 13, the dasatinib group appeared to display the smallest tumor volumes, whereas triciribine did not appear to affect tumor growth. These results also agree with the MRI volume results (Figure 4(b)) and the histology H&E stains (Figure 4(c)).

Bottom Line: Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984).We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines.Sorafenib and topotecan demonstrated a mixed response.

View Article: PubMed Central - PubMed

Affiliation: Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA ; Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.

ABSTRACT
For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984). A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies.

No MeSH data available.


Related in: MedlinePlus