Abstract LB-100: The Norton-Simon hypothesis and cancer stem cells: how cancer stem cells may explain the effectiveness of dose-dense chemotherapy

Abstract

Abstract Systemic therapies are effective initially in controlling and reversing tumor growth; however, residual cancers will invariably re-grow despite this initial response. We have published data from paired human breast cancer samples that standard therapy every three weeks kills dividing daughter cells but not tumor-initiating cells (TICs), so that samples obtained after therapy are enriched for CD44+/CD24−/low putative “tumor-initiating” or “cancer stem” cells. These data indicate that standard treatment regimens are missing the critical targets, TICS; thus, we are trying to identify novel therapeutic combinations and regimens that will eliminate these TICS that ultimately cause breast tumor recurrence and metastasis. Interestingly, we have recent data in human breast tumors that indicate that TICs may in fact be initially chemosensitive, with a decrease in TICs observed within three days of chemotherapy, but shortly thereafter, TICS are actually induced by chemotherapy. To evaluate TIC response to chemotherapy, mice with xenografted human breast tumors were treated with docetaxel (20 mg/kg) or vehicle, and then tumors were collected and dissociated for TICs assays either 3d or 14d after treatment. According to multiple assays for TICs, TICs were reduced compared to vehicle-treated at 3d post-docetaxel, and increased at 14d. This was evident in both primary and secondary mammosphere (MS) formation. Flow cytometric analyses for TICs markers (CD44+/CD24−/low and ALDH+) further corroborated these data. These results indicate TICs were initially responsive but became chemoresistant, or even activated by chemotherapy. To further define TICs response to chemotherapy, mice with xenografted human breast tumors were treated with vehicle, 10 mg/kg docetaxel, or 33 mg/kg docetaxel, and then tumors were collected and dissociated for TICs assays either 48h or 72h after treatment. Although BCM-2147 TICs did not significantly decrease at any time points or doses tested, they were induced by 72h post-treatment compared to control (ALDH+ 2- to 4-fold increased). In contrast, according to TIC markers and MS formation efficiency, BCM-2665 TICS were reduced by docetaxel compared to vehicle at 48h post 10 mg/kg docetaxel (4-fold decrease), and 48h and 72h post 33 mg/kg docetaxel compared to control (14- and 2-fold decrease, respectively). Furthermore, BCM-2665 ALDH+ cells showed 6-fold increased proliferation 72h post cisplatin compared to control, indicating that chemotherapy may inducing proliferation of TICs. When TICs are induced to proliferate, they may be more susceptible to traditional proliferative targets such as chemotherapy. These findings are consistent with the Norton-Simon Hypothesis in that chemotherapy regimens given more frequently may in fact eliminate TICs, thereby explaining the proven increased effectiveness of dose-dense chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-100. doi:10.1158/1538-7445.AM2011-LB-100