sepantronium and Breast-Neoplasms

The objective of this study was to assess the efficacy and tolerability of YM155, a survivin suppressor, in combination with docetaxel, compared with docetaxel alone in patients with HER2-negative metastatic breast cancer. This phase II, multicenter, open-label, 2-arm study randomized patients (≥18 years) with histologically or cytologically confirmed stage IV HER2-negative metastatic breast cancer and ≥1 measurable lesion, to receive docetaxel alone or docetaxel plus YM155. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), time to response (TTR), biomarker assessment, and analysis of circulating tumor cells. Patients were women diagnosed with HER2-negative breast cancer; most had received prior drug therapies. The median PFS was 8.4 months with YM155 plus docetaxel (n = 50) and 10.5 months with docetaxel alone (n = 51; HR 1.53; 95 % CI 0.83, 2.83; P = 0.176). No statistically significant differences were observed for secondary endpoints, although slightly greater OS (630 vs 601 days; P = 0.768), CBR (84.3 vs 82.0 %; P = 0.855), DOR, and TTR were observed with docetaxel alone compared with YM155 plus docetaxel, whereas ORR was similar (25.5 vs 26.0). The most common TEAEs observed with YM155 plus docetaxel compared with docetaxel alone were neutropenia (83.3 vs 84.3 %), alopecia (62.5 vs 52.9 %), fatigue (50 vs 41.2 %), and nausea (37.5 vs 41.2 %). Although YM155 is a novel drug that suppresses survivin, YM155 plus docetaxel exhibited no statistically significant differences in endpoints compared with docetaxel alone. The combination regimen was well tolerated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Docetaxel; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Imidazoles; Lymphatic Metastasis; Middle Aged; Naphthoquinones; Receptor, ErbB-2; Taxoids; Treatment Outcome

Small molecule inhibitors (TKIs) of HER2 have demonstrated clinical benefit in HER2-positive breast tumors. One of them, lapatinib, is used once advanced tumors become refractory to the HER2 antibody trastuzumab. Another one, neratinib, has shown benefit in high-risk early-stage breast cancer after trastuzumab-based therapies. A common characteristic is that patients are formerly treated with trastuzumab. We have explored whether trastuzumab previous therapy affects its antitumoral action. Long time exposure of the HER2+ cell line BT474 to trastuzumab resulted in trastuzumab-insensitive cells (BTRH cells). While treatment of wild type BT474 cells with lapatinib or neratinib resulted in decreased viability, BTRH cells were resistant to the action of these TKIs. Analogous results were obtained using trastuzumab-resistant cells derived from a PDX. Functional transcriptomic analyses and biochemical studies demonstrated that the TKIs caused DNA damage and apoptosis in wild type cells, but not in BTRH. Moreover, previous treatment with trastuzumab impairs response to small TKIs, by eliminating their proapoptotic action. Moreover, actioning on the apoptotic machinery using a chemical library of proapoptotic compounds led to the identification of clinical-stage drugs that may be used to fight trastuzumab-TKI resistance.

Topics: Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Line, Tumor; DNA Damage; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Humans; Imidazoles; Lapatinib; Mice; Naphthoquinones; Protein Kinase Inhibitors; Pyridines; Quinolines; Receptor, ErbB-2; Trastuzumab; Xenograft Model Antitumor Assays

Despite recent progress in molecular-targeted therapies, breast cancer remains the primary leading cause of cancer related death among women worldwide. Breast cancer stem cells (BCSCs) are believed to be responsible for therapy resistance and cancer recurrence. We recently demonstrated that human BCSCs (CD24-/CD44+) could survive better than their counterpart non-BCSCs (CD24-/CD44-) when treated with rotenone, possibly due to lower levels of reactive oxygen species (ROS) production, high expression of antioxidant manganese superoxide dismutase (MnSOD), and anti-apoptotic survivin. The aim of this study was to verify the role of survivin on human BCSCs survival under oxidative stress modulation by suppressing its expression using YM155, a survivin inhibitor.. Human BCSCs (ALDH+ cells) were treated with YM155 for 24 h prior to treatment with rotenone for a further 6 h. We determined intracellular superoxide levels were determined using dihydroethidium assay, survivin and MnSOD expression using qRT-PCR, survivin protein level using ELISA, as well as cell viability using trypan blue exclusion and acridine orange/ethidium bromide apoptosis assay.. Suppression of survivin expression using YM155 could reduce the survival of rotenone-treated BCSCs, which may be associated with oxidative stress modulation, as shown by increased ROS levels and decreased MnSOD expression. We confirm that survivin is responsible for maintaining BCSCs survival under oxidative stress modulation. Furthermore, YM155 could modulate oxidative stress in BCSCs by reducing MnSOD expression and increasing ROS levels.. YM155 treatment could be used to overcome BCSCs resistance to oxidative stress-based anticancer therapies.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Insecticides; Naphthoquinones; Neoplastic Stem Cells; Oxidative Stress; Rotenone; Survivin; Tumor Cells, Cultured

Breast cancer is the second in mortality rate malignancy among women. Despite the many advances in breast cancer treatment, there is still a need to improve drug efficacy and reduce non-specific effects. D-alpha-tocopheryl polyethylene glycol succinate (TPGS) is frequently used in the development of drug delivery systems to improve the pharmacokinetics of anti-cancer drugs and reduce multi-drug resistance. We have previously shown that TPGS not only acts as a carrier molecule but also exerts anti-cancer effects. As part of this study, we investigated the effect of TPGS with YM155, a small molecule suppressant of Survivin, in various breast cancer cell lines representing different subtypes of the disease. We aimed to evaluate the presumed synergistic effect of the TPGS-YM155 combination and reveal its mechanism of action. Our results show that the TPGS-YM155 combination acts synergistically to reduce specifically the viability of SKBR3 cells. The combination of these agents reduced activation of the AKT pathway, decreased Survivin and Bcl-2 levels, and induced caspase-dependent and independent apoptosis via the mitochondrial pathway. Importantly, the TPGS-YM155 combination did not significantly affect the viability of MCF-10A normal immortalized cells. In conclusion, the combination of YM155 and TPGS could be a promising approach against SKBR3-type breast cancer.

Topics: Apoptosis; Breast Neoplasms; Drug Delivery Systems; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; MCF-7 Cells; Naphthoquinones; Survivin; Vitamin E

The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains.. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance.. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred.. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns.

Topics: Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drugs, Investigational; Exome; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genomic Instability; High-Throughput Screening Assays; Humans; Imidazoles; MCF-7 Cells; Naphthoquinones; Paclitaxel; Sequence Analysis, DNA; Small Molecule Libraries; Tamoxifen

The aim of this study was to determine the potency and molecular mechanism of action of YM155, a first-in-class survivin inhibitor that is currently under phase I/II clinical investigations, in various drug-resistant breast cancers including the oestrogen receptor positive (ER(+) ) tamoxifen-resistant breast cancer and the caspase-3-deficient breast cancer.. The potency of YM155 in SK-BR-3, MDA-MB-231, MCF7 and its tamoxifen-resistant sublines, TamR6, TamR7, TamR8, TamC3 and TamC6, were determined by MTT assay. Western blot analysis, flow cytometric analysis, reverse transcription-PCR, fluorescent microscopy and comet assay were used to determine the molecular mechanism of action of YM155 in different breast cancer cell lines.. YM155 was equally potent towards the parental ER(+) /caspase-3-deficient MCF7 breast cancer cells and its tamoxifen-resistant sublines in vitro. The ER(-) /HER2(+) SK-BR-3 breast cancer cells and the triple-negative/caspase-3-expressing metastatic aggressive MDA-MB-231 breast cancer cells were also sensitive to YM155 with IC50 values in the low nanomolar range. Targeting survivin by YM155 modulated autophagy, induced autophagy-dependent caspase-7 activation and autophagy-dependent DNA damage in breast cancer cells. Interestingly, YM155 also induced XIAP degradation and the degradation of XIAP might play an important role in YM155-induced autophagy in breast cancer cells.. YM155 is a potent survivin inhibitor that has potential for the management of various breast cancer subtypes regardless of the expression of ER, HER2 and caspase-3. Importantly, this study provides new insights into YM155's molecular mechanism of action and therapeutic potential in the treatment of tamoxifen-resistant breast cancer.

Topics: Antineoplastic Agents; Autophagy; Breast Neoplasms; Caspase 3; Cell Line, Tumor; Cell Survival; DNA Damage; Down-Regulation; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; L-Lactate Dehydrogenase; Microtubule-Associated Proteins; Naphthoquinones; Receptor, ErbB-2; Receptors, Estrogen; RNA, Small Interfering; Survivin; X-Linked Inhibitor of Apoptosis Protein

Specific overexpression in cancer cells and evidence of oncogenic functions make Survivin an attractive target in cancer therapy. The small molecule compound YM155 has been described as the first "Survivin suppressant" but molecular mechanisms involved in its biological activity and its clinical potential remain obscure. We herein show that YM155 exerts single agent toxicity on primary breast cancer cells grown in an ex vivo assay preserving tumor microenvironment. In vitro assays indicate that YM155 more efficiently triggers cell death in breast cancer cells (including these with stem-cell like properties) than in non tumorigenic mammary cells. YM155-induced cell death is critically dependent on autophagy and NF-kB but independent of p53 and it coïncides with DNA damage and a DNA damage response in p53-proficient cells. Our results point out a crosstalk between NF-kB and autophagy controlling YM155-induced death in breast cancer cells and argue for the potential use of YM155 as a genotoxic agent in breast cancer therapy.

Topics: Antineoplastic Agents; Autophagy; Breast Neoplasms; Cell Death; Cell Line, Tumor; Cell Proliferation; DNA Damage; Female; Humans; Imidazoles; MCF-7 Cells; Naphthoquinones; NF-kappa B; Signal Transduction; Transfection; Xenograft Model Antitumor Assays

The molecular determinants of breast cancer resistance to first-line anthracycline-containing chemotherapy are unknown.. We examined the response to doxorubicin of organotypic cultures of primary human breast tumors ex vivo with respect to cell proliferation, DNA damage and modulation of apoptosis. Samples were analyzed for genome-wide modulation of cell death pathways, differential activation of p53, and the role of survivin family molecules in drug resistance. Rational drug combination regimens were explored by high-throughput screening, and validated in model breast cancer cell types.. Doxorubicin treatment segregated organotypic human breast tumors into distinct Responder or Non Responder groups, characterized by differential proliferative index, stabilization of p53, and induction of apoptosis. Conversely, tumor histotype, hormone receptor or human epidermal growth factor receptor-2 (HER2) status did not influence chemotherapy sensitivity. Global analysis of cell death pathways identified survivin and its alternatively spliced form, survivin-ΔEx3 as uniquely overexpressed in Non Responder breast tumors. Forced expression of survivin-ΔEx3 preserved cell viability and prevented doxorubicin-induced apoptosis in breast cancer cell types. High-throughput pharmacologic targeting of survivin family proteins with a small-molecule survivin suppressant currently in the clinic (YM155) selectively potentiated the effect of doxorubicin, but not other chemotherapeutics in breast cancer cell types, and induced tumor cell apoptosis.. Survivin family proteins are novel effectors of doxorubicin resistance in chemotherapy-naive breast cancer. The incorporation of survivin antagonist(s) in anthracycline-containing regimens may have improved clinical activity in these patients.

Topics: Alternative Splicing; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Camptothecin; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Damage; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Female; High-Throughput Screening Assays; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; MCF-7 Cells; Naphthoquinones; Paclitaxel; Receptor, ErbB-2; Survivin; Tumor Suppressor Protein p53

Metastatic triple negative breast cancer [TNBC, with negative expression of estrogen and progesterone receptors and no overexpression of HER2/neu (ErbB-2)] remains a major therapeutic challenge because of its poor overall prognosis and lack of optimal targeted therapies. Survivin has been implicated as an important mediator of breast cancer cell growth and dysfunctions in apoptosis, and its expression correlates with a higher incidence of metastases and patient mortality; thus, survivin is an attractive target for novel anti-cancer agents. In previous studies, we identified YM155 as a small molecule that selectively suppresses survivin expression. YM155 inhibits the growth of a wide range of human cancer cell lines. Tumor regression induced by YM155 is associated with decreased intratumoral survivin expression, increased apoptosis and a decreased mitotic index. In the present study, we evaluated the antitumor efficacy of YM155 both in vitro and in vivo using preclinical TNBC models. We found that YM155 suppressed survivin expression, including that of its splice variants (survivin 2B, δEx3 and 3B), resulting in decreased cellular proliferation and spontaneous apoptosis of human TNBC cells. In a mouse xenograft model, continuous infusion of YM155 led to the complete regression of subcutaneously established tumors. Furthermore, YM155 reduced spontaneous metastases and significantly prolonged the survival of animals bearing established metastatic tumors in the MDA-MB-231-Luc-D3H2-LN orthotopic model. These results suggest that the survivin-suppressing activity of YM155 may offer a novel therapeutic option for patients with metastatic TNBC.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Caspase 3; Cell Line, Tumor; Down-Regulation; Enzyme Activation; Female; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Mice; Mice, SCID; Naphthoquinones; Neoplasm Metastasis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Repressor Proteins; Survivin; Xenograft Model Antitumor Assays