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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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Chemosensitive MC1 transplanted in fat pad of SCID Beige mice, with non-significant decrease in TIC markers (ALDF, CD44+/CD24−, and MSFE) with Stat3 inhibitor compared to chemotherapy alone.(A) Tumor volume fold change over time (14 days). Decrease in mean tumor volume + SEM was observed with chemotherapy alone (chemosenstive tumor line). (B) FACS analysis of 100,000 cells MC1 tumor cells for CD44+/CD24−, ALDF. Data were depicted as Mean + SEM. Non-significant decrease in TIC markers (ALDF, CD44+/CD24) with Stat3 inhibitor compared to chemotherapy alone was observed. (C) Mammosphere forming efficiency of tumor cells seeded at 10,000 cells/ml. Data depicted as Mean + SEM. Non-significant decrease in MSFE with C188 compared to chemotherapy alone was observed.
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pone-0030207-g003: Chemosensitive MC1 transplanted in fat pad of SCID Beige mice, with non-significant decrease in TIC markers (ALDF, CD44+/CD24−, and MSFE) with Stat3 inhibitor compared to chemotherapy alone.(A) Tumor volume fold change over time (14 days). Decrease in mean tumor volume + SEM was observed with chemotherapy alone (chemosenstive tumor line). (B) FACS analysis of 100,000 cells MC1 tumor cells for CD44+/CD24−, ALDF. Data were depicted as Mean + SEM. Non-significant decrease in TIC markers (ALDF, CD44+/CD24) with Stat3 inhibitor compared to chemotherapy alone was observed. (C) Mammosphere forming efficiency of tumor cells seeded at 10,000 cells/ml. Data depicted as Mean + SEM. Non-significant decrease in MSFE with C188 compared to chemotherapy alone was observed.

Mentions: As with BCM2665, female SCID Beige mice were transplanted with MC1 tumors, which were allowed to grow to ∼200–700 mm3, and then randomized into the same four treatment arms. C188 had no effect on tumor growth as a single agent. With chemotherapy, there was a significant reduction in tumor volume relative to the other treatment groups (Fig. 3A), while the combination C188 and docetaxel showed an intermediate growth curve between the two single agent arms (Fig. 3A).


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)

Chemosensitive MC1 transplanted in fat pad of SCID Beige mice, with non-significant decrease in TIC markers (ALDF, CD44+/CD24−, and MSFE) with Stat3 inhibitor compared to chemotherapy alone.(A) Tumor volume fold change over time (14 days). Decrease in mean tumor volume + SEM was observed with chemotherapy alone (chemosenstive tumor line). (B) FACS analysis of 100,000 cells MC1 tumor cells for CD44+/CD24−, ALDF. Data were depicted as Mean + SEM. Non-significant decrease in TIC markers (ALDF, CD44+/CD24) with Stat3 inhibitor compared to chemotherapy alone was observed. (C) Mammosphere forming efficiency of tumor cells seeded at 10,000 cells/ml. Data depicted as Mean + SEM. Non-significant decrease in MSFE with C188 compared to chemotherapy alone was observed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412855&req=5

pone-0030207-g003: Chemosensitive MC1 transplanted in fat pad of SCID Beige mice, with non-significant decrease in TIC markers (ALDF, CD44+/CD24−, and MSFE) with Stat3 inhibitor compared to chemotherapy alone.(A) Tumor volume fold change over time (14 days). Decrease in mean tumor volume + SEM was observed with chemotherapy alone (chemosenstive tumor line). (B) FACS analysis of 100,000 cells MC1 tumor cells for CD44+/CD24−, ALDF. Data were depicted as Mean + SEM. Non-significant decrease in TIC markers (ALDF, CD44+/CD24) with Stat3 inhibitor compared to chemotherapy alone was observed. (C) Mammosphere forming efficiency of tumor cells seeded at 10,000 cells/ml. Data depicted as Mean + SEM. Non-significant decrease in MSFE with C188 compared to chemotherapy alone was observed.
Mentions: As with BCM2665, female SCID Beige mice were transplanted with MC1 tumors, which were allowed to grow to ∼200–700 mm3, and then randomized into the same four treatment arms. C188 had no effect on tumor growth as a single agent. With chemotherapy, there was a significant reduction in tumor volume relative to the other treatment groups (Fig. 3A), while the combination C188 and docetaxel showed an intermediate growth curve between the two single agent arms (Fig. 3A).

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