Limits...
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.

Show MeSH

Related in: MedlinePlus

Kaplan Meier recurrence free survival with the combination with high dose docetaxel and C188 vs. chemotherapy alone.Female mice were transplanted in one mammary fat pad with chemoresistant breast cancer xenograft 2665A (ER/PgR/HER2-negative and p-Stat3-positive). After 6 weeks, mice with ∼200 mm3 tumors were randomized and treated with either 2 cycles of docetaxel (60 mg/kg) combined with daily dose of C188 (12.5 mg/kg; solid line) at the start of treatment vs. docetaxel alone (– line). Mice were observed daily after the end of all treatment (all the tumors had receded at that time). Time to tumor recurrence as denoted by tumors being measured to be larger than 50mm3 was significantly improved with the combination vs. chemotherapy alone (p = 0.030).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3412855&req=5

pone-0030207-g004: Kaplan Meier recurrence free survival with the combination with high dose docetaxel and C188 vs. chemotherapy alone.Female mice were transplanted in one mammary fat pad with chemoresistant breast cancer xenograft 2665A (ER/PgR/HER2-negative and p-Stat3-positive). After 6 weeks, mice with ∼200 mm3 tumors were randomized and treated with either 2 cycles of docetaxel (60 mg/kg) combined with daily dose of C188 (12.5 mg/kg; solid line) at the start of treatment vs. docetaxel alone (– line). Mice were observed daily after the end of all treatment (all the tumors had receded at that time). Time to tumor recurrence as denoted by tumors being measured to be larger than 50mm3 was significantly improved with the combination vs. chemotherapy alone (p = 0.030).

Mentions: To evaluate the effect of Stat3 inhibition on recurrence, SCID Beige mice were transplanted with BCM2665 tumors and randomized to two groups (n = 6/group) at 6 weeks and treated with high dose docetaxel (60mg/kg) or the combination of high dose docetaxel and C188 for 14 days, per cycle, for two cycles. Complete tumor disappearance was observed in both arms at which time the treatment was stopped. The animals were then followed for tumor recurrence for a period of 20 days, and time to tumor recurrence was calculated using Kaplan Meier survival analysis. The time to recurrence was improved by ∼4-fold with the addition of Stat3 inhibitor to conventional chemotherapy compared to chemotherapy alone, with 30-day tumor recurrence rate of 20% (95% CI: 0.01–0.58) vs. 83% (95% CI: 0.27–0.97) (p = 0.03, Wilcoxon test) (Fig. 4), thus confirming that Stat3 inhibition decreased the TIC subpopulation and improved survival (Table S3).


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)

Kaplan Meier recurrence free survival with the combination with high dose docetaxel and C188 vs. chemotherapy alone.Female mice were transplanted in one mammary fat pad with chemoresistant breast cancer xenograft 2665A (ER/PgR/HER2-negative and p-Stat3-positive). After 6 weeks, mice with ∼200 mm3 tumors were randomized and treated with either 2 cycles of docetaxel (60 mg/kg) combined with daily dose of C188 (12.5 mg/kg; solid line) at the start of treatment vs. docetaxel alone (– line). Mice were observed daily after the end of all treatment (all the tumors had receded at that time). Time to tumor recurrence as denoted by tumors being measured to be larger than 50mm3 was significantly improved with the combination vs. chemotherapy alone (p = 0.030).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0030207-g004: Kaplan Meier recurrence free survival with the combination with high dose docetaxel and C188 vs. chemotherapy alone.Female mice were transplanted in one mammary fat pad with chemoresistant breast cancer xenograft 2665A (ER/PgR/HER2-negative and p-Stat3-positive). After 6 weeks, mice with ∼200 mm3 tumors were randomized and treated with either 2 cycles of docetaxel (60 mg/kg) combined with daily dose of C188 (12.5 mg/kg; solid line) at the start of treatment vs. docetaxel alone (– line). Mice were observed daily after the end of all treatment (all the tumors had receded at that time). Time to tumor recurrence as denoted by tumors being measured to be larger than 50mm3 was significantly improved with the combination vs. chemotherapy alone (p = 0.030).
Mentions: To evaluate the effect of Stat3 inhibition on recurrence, SCID Beige mice were transplanted with BCM2665 tumors and randomized to two groups (n = 6/group) at 6 weeks and treated with high dose docetaxel (60mg/kg) or the combination of high dose docetaxel and C188 for 14 days, per cycle, for two cycles. Complete tumor disappearance was observed in both arms at which time the treatment was stopped. The animals were then followed for tumor recurrence for a period of 20 days, and time to tumor recurrence was calculated using Kaplan Meier survival analysis. The time to recurrence was improved by ∼4-fold with the addition of Stat3 inhibitor to conventional chemotherapy compared to chemotherapy alone, with 30-day tumor recurrence rate of 20% (95% CI: 0.01–0.58) vs. 83% (95% CI: 0.27–0.97) (p = 0.03, Wilcoxon test) (Fig. 4), thus confirming that Stat3 inhibition decreased the TIC subpopulation and improved survival (Table S3).

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