Background: The cancer stem cell hypothesis asserts that there is a small population of cells within a tumor that has the ability to self renew and differentiate, and that these cells drive tumor growth and metastasis but are resistant to conventional cytotoxic chemotherapy. Pathways involved in stem cell growth and differentiation are viable targets for new anticancer therapies. One such pathway, Notch, is inhibited by GSIs which prevent translocation of Notch intracellular domain to the nucleus. Inhibition of GS concurrent with chemotherapy might improve disease control by targeting both stem cells and differentiated cells within the tumor. This Phase Ib clinical trial was designed to determine the MTD of the GSI, MK-0752, in combination with docetaxel, and to evaluate an effect on stem cell markers in serial tumor biopsies. Methods: Eligible subjects had metastatic breast cancer or locally advanced breast cancer that did not respond to anthracycline therapy. Patients with disease that progressed on a taxane, or who had received a taxane within 6 months were excluded. MK-0752 was administered orally on days 1-3 of each 21-day cycle of therapy, in escalating doses. Dose levels (mg/day) 1=300; 2=450; 3=600; and 4=800. Docetaxel 80 mg/m2 IV was administered day 8, with pegfilgrastim day 9 each cycle. Treatment was continued until disease progression, unacceptable toxicity, or symptomatic deterioration. The trial was monitored using the Time to Event Continual Reassessment Method, targeting a 20% toxicity rate. Tumor biopsies were performed at baseline, after 1 cycle, and at treatment completion in a subset of patients. Results: 30 patients were enrolled between Mar 2008 and Jan 2010. Dose limiting toxicities of the combination included diarrhea, hand-foot syndrome, and LFT elevation. 20/30 patients experienced Grade 1 or 2 fatigue. The final estimates and confidence intervals for the probability of dose limiting toxicity at each dose level are summarized in the table: Probability = probability of dose-limiting toxicity 20 enrolled patients had measurable disease by RECIST criteria. Of these, 9 had PR, 8 SD, and 3 PD, for an estimated RR of 45% to the combination. 2 patients have been maintained on therapy in excess of 22 cycles. Conclusions: Dose level 3 was identified for further study in a Phase II randomized trial. Efficacy of docetaxel was not inhibited by MK-0752, as a 45% RR in patients with measurable disease was observed. There is intriguing long term disease stabilization in 2 patients. Evidence of an effect of the combination on the stem cell population was apparent on serial biopsies as presented at SABCS Dec 2009 (Abstract # 48); additional biopsy data will be presented. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-03.
The realization that many cancers, including breast cancer, are driven by cells which display stem cell properties has significant clinical implications. Furthermore, the demonstrated role of these cells in mediating tumor metastasis and treatment resistance suggests the need to develop strategies to specifically target CSC populations. Cancer stem cell self-renewal and survival pathways represent potential therapeutic targets. These self-renewal pathways are regulated by an interacting network of cell intrinsic pathways, as well as extrinsic factors from the tumor microenvironment. These mircroenvironmental factors include cytokines such as IL-6, IL-8 and TGFb. CSCs maintain the plasticity to transition between epithelial-like MET and mesenchymal-like EMT states, a process regulated by the tumor microenvironment through microRNA circuits. We have demonstrated that previously identified cancer stem cell markers are cancer stem cell state specific. CD44+/CD24- CSCs represent mesenchymal-like stem cells capable of tissue invasion which are largely quiescent. In contrast, Aldehyde dehydrogenase expression identifies a more epithelial-like cancer stem cell state associated with self-renewal. Reversible EMT/MET transitions play a crucial role in mediating tumor metastasis. Preclinical breast cancer models predict that the greatest efficacy of CSC targeting therapeutics will occur when they are used in the adjuvant setting, a concept supported by preclinical models and clinical trials. Tumor regression may reflect effects on bulk cell populations explaining the lack of correlation between tumor shrinkage and patient survival. In contrast, recurrence following adjuvant therapy may be mediated by CSCs, which possesses sufficient self-renewal to form clinically significant metastasies. The important role of HER2 signaling in regulating breast cancer stem cell self-renewal may account for the remarkable clinical efficacy of targeting HER2 in the adjuvant setting. Furthermore, the clinical benefit of such therapies in classically defined HER2-negative breast cancers may be due to selective expression of HER2 in CSCs in the absence of HER2 gene amplification. The clinical benefit of adjuvant trastuzumab in women whose breast cancers are currently classified as HER2-negative is currently being assessed in the randomized national clinical trial B47. These studies may demonstrate the need for reevaluating currently used clinical endpoints and clinical trial designs. Promising new technologies including the isolation and molecular characterization of circulating cancer stem cells may provide the opportunity for real time assessment of the efficacy of CSC targeting agents. A number of agents regulating BCSCs have entered early phase clinical trials which will determine whether effective targeting of CSCs improves patient outcome. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS01-2.
Background: Breast cancer stem cells (BCSC) have the ability to self renew and generate the full range of cells that make up a bulk tumor. Experimental models and retrospective clinical observations point to BCSC as responsible for tumor recurrence and metastasis. CXCR1, one of the receptors for CXCL8, has been identified on BCSC. Reparixin, an allosteric inhibitor of CXCR1, reduced BCSC in breast cancer xenografts (Ginestier C et al., JCI 2010) both as single agent and in combination with taxane chemotherapy. In a phase Ib trial in women with metastatic HER2-negative BC, the combination of escalating doses (400 to 1200 mg three times per day) of reparixin with weekly paclitaxel resulted in a low incidence and severity of adverse reactions, a sizeable response rate and time-to-progression, with some long-term responders (Schott AF et al., SABC 2014). Trial Design: In this randomized, double-blind phase 2 trial patients will be randomized (1:1) to paclitaxel 80 mg/m2 on days 1, 8 and 15 of 28-day cycles in combination with reparixin or placebo oral tablets 1200 mg three times daily on days 1-21. Treatment continues until disease progression, unacceptable toxicity or withdrawal of consent. An independent Data Monitoring Committee has been appointed to oversee the trial. An independent Radiology Review will be performed for analysis of primary and secondary endpoints. Disease response will be assessed every 8 weeks. Patients will be followed up to 12 months after last enrolled patient completes treatment. Eligibility Criteria: Patients must be female aged ≥18 years with untreated metastatic TNBC who have relapsed >12 and >6 months after the end of a taxane- or non taxane-based (neo)adjuvant chemotherapy regimen, respectively. They must have measurable disease, ECOG PS of 0-1, adequate organ function, and no history or evidence of brain metastases (brain CT or MRI required). Tumor tissue must be available from a metastatic site or from primary tumor for confirmation of diagnosis and correlative studies. Key exclusion criteria are pre-existing peripheral neuropathy G>1 and any disease significantly affecting gastrointestinal function. Specific Aims: Primary: to evaluate progression-free survival (PFS) rate by independent assessment. Secondary: to determine median PFS, overall survival (OS), objective response rates and safety of the combination treatment. Exploratory: to determine median time to new tumor metastasis (TTM), proportion of patients progressing with new metastatic lesions, incidence and severity of peripheral neuropathy, and to evaluate BCSC in metastatic tissue Statistical Methods: The trial design provides 80% power to detect an increase in 6 month PFS from 30% to 50% with a 2-sided 5% significance level (Chi-square test). Kaplan-Meier curves will be produced for median PFS, OS outcomes and exploratory median TTM. Appropriate descriptive statistics will be provided for safety variables. Present Accrual and Target Accrual: Target accrual is 190 patients. Patients will be enrolled internationally in US and Europe. Contact Information: info@dompe.com Citation Format: Chang JC, Schott AF, Wicha MS, Cristofanilli M, Ruffini PA, McCanna S, Goldstein LJ. A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for triple-negative breast cancer (fRida). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-07.
Background Endocrine therapy is the most effective therapies for estrogen receptor positive (ER+) breast cancer, but resistance is still a major clinical problem. Tumor initiating cells (TICs) in drug resistant tumors are believed to be part of the contributing factors for tumor relapse. Here we focused on the TICs and how they are related to HER2 expression and its downstream factors in acquired endocrine resistance models. Materials and Methods: We have established a panel of endocrine resistant cell models through long-term treatment with tamoxifen (Tam, 10−7M, >6 months). Resistance to tamoxifen treatment in cells (TamR) was confirmed by growth curve assays (Celigo, Cyntellect Inc., San Diego, CA). In vitro mammosphere assays were applied to assess the mammosphere forming ability of parental and resistant cells. Aldefluor assays (StemCell Technology) were performed to measure the aldehyde dehydrogenase (ALDH-1) expressing cell population as a marker of TICs. Flow analysis was performed to evaluate HER2 expression in the ALDH subpopulations of both parental and TamR cells. Immunofluorescence staining was further used to detect the expression of ER, HER2, phosphorylated STAT3, and β-catenin in sorted ALDH+/− subpopulations. Results: We found that endocrine resistant cells have a higher mammosphere forming ability than their parental counterparts. In addition, we showed that the ALDH+ subpopulation was significantly upregulated in all TamR derivative lines. Further analysis of the ALDH populations indicated that HER2, as well as downstream survival factors such as pSTAT3s727 and β-Catenin, are upregulated in the ALDH+ populations as compared to the ALDH-population, especially in TamR derivatives. Discussion: Our data suggest that deregulated HER or other growth factor receptor signaling can potentially lead to the enrichment of TICs as a potential contributor to endocrine resistance. We will further investigate the role and molecular signaling of TICs in endocrine resistance of breast cancer, as well as whether and to what extent more potent anti-HER inhibitors can improve endocrine sensitivity and circumvent resistance. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-02.
Breast cancer stem cells (BCSCs) maintain the plasticity to transition between quiescent mesenchymal- (M) and proliferative epithelial-like (E) states, but how this plasticity is regulated under metabolic/oxidative stress is poorly understood. Here, we show that M- and E-BCSCs exhibit markedly different sensitivities to the inhibitors of glycolysis and redox metabolism. Metabolic/Oxidative stress generated by 2DG/H2O2 or hypoxia promotes ROSlo M-BCSCs transition to their ROShi E-state. This transition is reversed by the antioxidant N-acetyl cysteine and facilitated by the activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust expression of NRF2/NFE2L2 and a wide variety of NRF2 downstream antioxidant responsive genes including the family of drug transporters and detoxification enzymes, NADPH production as well as the thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Suppression of NRF2 activity by a small-molecular inhibitor Trigonelline or shNRF2 mediated knockdown significantly decreased ALDH+ E- but not CD24-CD44+ M-BCSCs. This specific vulnerability of E-BCSCs to the inhibition of NRF2-mediated antioxidant defenses was also observed following inhibition of the downstream TXN and GSH antioxidant pathways, which promotes ROS-mediated differentiation and subsequent apoptosis of E-BCSCs. Co-inhibition of glycolysis and TXN/GSH pathways synergistically suppressed tumor growth and tumor initiating potential in two patient-derived xenograft models of triple negative breast cancer by eliminating both M- and E-BCSCs. Together, our studies reveal novel cellular and molecular mechanisms demonstrating how modulation of redox signaling regulates the equilibrium of two distinct BCSC states. These studies define the metabolic vulnerabilities of M- and E-BCSCs, and also provide a novel therapeutic approach to collectively target these distinct CSC states. As the CSC state equilibrium may be similarly regulated across a spectrum of tumors with diverse oncogenic drivers, this approach may have broad therapeutic applicability. Citation Format: Luo M, Shang L, Brooks M, Jiagge E, Zhu Y, Conley S, Fath MA, Harouaka R, Merajver SD, Spitz DR, Wicha MS. Targeting breast cancer stem cell state equilibrium through modulation of redox signaling [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-02-09.
Breast cancers contain cell populations that display hierarchical organization at the apex of which are cells that display stem cell properties. These cancer stem cells (CSCs) mediate metastasis and contribute to treatment resistance. CSC's display cellular plasticity , a property that allows them to transition between mesenchymal and epithelial states, facilitating metastasis. Although different therapeutic strategies have been developed for the treatment of the various molecular subtypes of breast cancer, CSCs driving these cancers may share common regulatory pathways including those maintaining cellular plasticity. This suggests that therapeutic strategies targeting these CSC pathways may be complementary to subtype specific therapeutic agents targeting bulk cell populations. Furthermore, since CSCs constitute a minor fraction of total tumor cell populations classical clinical endpoints such as tumor regression are inadequate to assess the efficacy of CSC targeting therapeutics. Neoadjuvant trial designs allow for the direct assessment of treatment on biological targets and as well as the therapeutic effectiveness of CSC targeting agents. Molecular analysis of circulating tumor cells at single cell resolution provides an alternative method of accessing the effects of CSC targeting therapies. CSCs are regulated by the tumor micro environment and recent studies suggest that the immune microenvironment plays a crucial role in CSC regulation. Immunotherapeutic approaches may provide a means to target heterogeneous CSC's as well as bulk tumor populations. Early phase clinical trials currently in progress have demonstrated the safety of CSC targeting agents. Future randomized trials will be required to determine whether addition of CSC targeting therapeutics to current agents targeting bulk cell populations improves the efficacy of these therapeutic agents. Citation Format: Wicha MS. Targeting breast cancer stem cells: Challenges and opportunities [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr DL-1.
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