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Selective small molecule Stat3 inhibitor reduces breast cancer tumor-initiating cells and improves recurrence free survival in a human-xenograft model.

Dave B, Landis MD, Tweardy DJ, Chang JC, Dobrolecki LE, Wu MF, Zhang X, Westbrook TF, Hilsenbeck SG, Liu D, Lewis MT - PLoS ONE (2012)

Bottom Line: Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs).Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model.Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors.

View Article: PubMed Central - PubMed

Affiliation: The Methodist Cancer Center, Houston, Texas, United States of America.

ABSTRACT
Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs). Previously, we have defined a CD44+/CD24-/low mammosphere-forming tumorigenic 493-gene signature in breast cancer. Stat3 was identified as a critical node in self-renewal based on an ongoing lentiviral shRNA screen being conducted in two breast cancer cell lines SUM159 and BT549. In corroborating work, targeting the SH2 domain of Stat3 with a novel small molecule decreased the percentage of cells expressing TIC markers (CD44+/CD24-/low and ALDH+) and mammosphere formation in p-Stat3 overexpressing human breast cancer xenografts in SCID-beige mice. Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model. Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors.

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Chemoresistant BCM2665 transplanted in the fat pad of SCID Beige mice responds to combination of Stat3 inhibitor+docetaxel treatment, with decrease in tumor volume and TIC markers by FACS and MSFE.(A) Tumor volume fold change over time + SEM in 4 treatment arms of the chemoresistant BCM2665 model for the treatment period of 14 days. Significant decrease in mean tumor volume was noted between vehicle and combination of C188+docetaxel, and between chemotherapy and combination treatment (p<0.05). (B) FACS analysis of 10,000 cells BCM2665 tumor cells for ALDF+. Statistically significant decreases were observed with C188 vs. control (p<0.05), C188 vs. chemotherapy (p<0.05), and combination of C188+chemotherapy vs. chemotherapy alone (p<0.05). Data depicted as Mean + SEM. (C) Mammosphere forming efficiency of tumor cells harvested and seeded at 20,000 cells/well. Statistically significant decrease with C188 treatment vs. control (p<0.05), and C188 treatment vs. chemotherapy was observed (p<0.05). (D) The epithelial compartment of the BCM2665 tumors treated with C188 or vehicle control was isolated using laser capture microscopy. pStat3 levels were determined using Western blot analysis (representative picture shown). (E) Immunohistochemical analysis of pStat3Stat expression in Vehicle vs C188Stat treated BCM2665 tumor tissue (representative picture shown).
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pone-0030207-g002: Chemoresistant BCM2665 transplanted in the fat pad of SCID Beige mice responds to combination of Stat3 inhibitor+docetaxel treatment, with decrease in tumor volume and TIC markers by FACS and MSFE.(A) Tumor volume fold change over time + SEM in 4 treatment arms of the chemoresistant BCM2665 model for the treatment period of 14 days. Significant decrease in mean tumor volume was noted between vehicle and combination of C188+docetaxel, and between chemotherapy and combination treatment (p<0.05). (B) FACS analysis of 10,000 cells BCM2665 tumor cells for ALDF+. Statistically significant decreases were observed with C188 vs. control (p<0.05), C188 vs. chemotherapy (p<0.05), and combination of C188+chemotherapy vs. chemotherapy alone (p<0.05). Data depicted as Mean + SEM. (C) Mammosphere forming efficiency of tumor cells harvested and seeded at 20,000 cells/well. Statistically significant decrease with C188 treatment vs. control (p<0.05), and C188 treatment vs. chemotherapy was observed (p<0.05). (D) The epithelial compartment of the BCM2665 tumors treated with C188 or vehicle control was isolated using laser capture microscopy. pStat3 levels were determined using Western blot analysis (representative picture shown). (E) Immunohistochemical analysis of pStat3Stat expression in Vehicle vs C188Stat treated BCM2665 tumor tissue (representative picture shown).

Mentions: Female SCID Beige mice (36 mice, 9 mice per treatment arm) were transplanted with small fragments (∼1 mm3) of BCM2665 tumors, which were allowed to grow to ∼100–1000 mm3. Resulting tumor-bearing mice were then randomized into the four arms, namely vehicle, docetaxel (20mg/kg), Stat3 inhibitor (C188) (12.5 mg/kg), and the inhibitor+docetaxel combination. Tumor volume was monitored twice weekly using caliper measurements. Neither the Stat3 inhibitor nor docetaxel as single agents showed any reduction in tumor volume, relative to vehicle treated controls (Fig. 2A). However, the combination group showed a statistically significant decrease in tumor volume as compared to vehicle or chemotherapy.


Selective small molecule Stat3 inhibitor reduces breast cancer tumor-initiating cells and improves recurrence free survival in a human-xenograft model.

Dave B, Landis MD, Tweardy DJ, Chang JC, Dobrolecki LE, Wu MF, Zhang X, Westbrook TF, Hilsenbeck SG, Liu D, Lewis MT - PLoS ONE (2012)

Chemoresistant BCM2665 transplanted in the fat pad of SCID Beige mice responds to combination of Stat3 inhibitor+docetaxel treatment, with decrease in tumor volume and TIC markers by FACS and MSFE.(A) Tumor volume fold change over time + SEM in 4 treatment arms of the chemoresistant BCM2665 model for the treatment period of 14 days. Significant decrease in mean tumor volume was noted between vehicle and combination of C188+docetaxel, and between chemotherapy and combination treatment (p<0.05). (B) FACS analysis of 10,000 cells BCM2665 tumor cells for ALDF+. Statistically significant decreases were observed with C188 vs. control (p<0.05), C188 vs. chemotherapy (p<0.05), and combination of C188+chemotherapy vs. chemotherapy alone (p<0.05). Data depicted as Mean + SEM. (C) Mammosphere forming efficiency of tumor cells harvested and seeded at 20,000 cells/well. Statistically significant decrease with C188 treatment vs. control (p<0.05), and C188 treatment vs. chemotherapy was observed (p<0.05). (D) The epithelial compartment of the BCM2665 tumors treated with C188 or vehicle control was isolated using laser capture microscopy. pStat3 levels were determined using Western blot analysis (representative picture shown). (E) Immunohistochemical analysis of pStat3Stat expression in Vehicle vs C188Stat treated BCM2665 tumor tissue (representative picture shown).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412855&req=5

pone-0030207-g002: Chemoresistant BCM2665 transplanted in the fat pad of SCID Beige mice responds to combination of Stat3 inhibitor+docetaxel treatment, with decrease in tumor volume and TIC markers by FACS and MSFE.(A) Tumor volume fold change over time + SEM in 4 treatment arms of the chemoresistant BCM2665 model for the treatment period of 14 days. Significant decrease in mean tumor volume was noted between vehicle and combination of C188+docetaxel, and between chemotherapy and combination treatment (p<0.05). (B) FACS analysis of 10,000 cells BCM2665 tumor cells for ALDF+. Statistically significant decreases were observed with C188 vs. control (p<0.05), C188 vs. chemotherapy (p<0.05), and combination of C188+chemotherapy vs. chemotherapy alone (p<0.05). Data depicted as Mean + SEM. (C) Mammosphere forming efficiency of tumor cells harvested and seeded at 20,000 cells/well. Statistically significant decrease with C188 treatment vs. control (p<0.05), and C188 treatment vs. chemotherapy was observed (p<0.05). (D) The epithelial compartment of the BCM2665 tumors treated with C188 or vehicle control was isolated using laser capture microscopy. pStat3 levels were determined using Western blot analysis (representative picture shown). (E) Immunohistochemical analysis of pStat3Stat expression in Vehicle vs C188Stat treated BCM2665 tumor tissue (representative picture shown).
Mentions: Female SCID Beige mice (36 mice, 9 mice per treatment arm) were transplanted with small fragments (∼1 mm3) of BCM2665 tumors, which were allowed to grow to ∼100–1000 mm3. Resulting tumor-bearing mice were then randomized into the four arms, namely vehicle, docetaxel (20mg/kg), Stat3 inhibitor (C188) (12.5 mg/kg), and the inhibitor+docetaxel combination. Tumor volume was monitored twice weekly using caliper measurements. Neither the Stat3 inhibitor nor docetaxel as single agents showed any reduction in tumor volume, relative to vehicle treated controls (Fig. 2A). However, the combination group showed a statistically significant decrease in tumor volume as compared to vehicle or chemotherapy.

Bottom Line: Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs).Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model.Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors.

View Article: PubMed Central - PubMed

Affiliation: The Methodist Cancer Center, Houston, Texas, United States of America.

ABSTRACT
Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs). Previously, we have defined a CD44+/CD24-/low mammosphere-forming tumorigenic 493-gene signature in breast cancer. Stat3 was identified as a critical node in self-renewal based on an ongoing lentiviral shRNA screen being conducted in two breast cancer cell lines SUM159 and BT549. In corroborating work, targeting the SH2 domain of Stat3 with a novel small molecule decreased the percentage of cells expressing TIC markers (CD44+/CD24-/low and ALDH+) and mammosphere formation in p-Stat3 overexpressing human breast cancer xenografts in SCID-beige mice. Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model. Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors.

Show MeSH
Related in: MedlinePlus