bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C159: Identification of potential cancer drug targets using HT RNAi screening with pooled shRNA libraries.
Authors: Tedesco Donato , Bonneau Kyle , Makhanov Mikhail , Frangou Costas G. , Chenchik Alex
Published: June 2012

Genes modulating proliferation and survival in oncogenic cells have been identified using pooled lentiviral-based libraries expressing many thousands of shRNAs. Viability assays with human isogenic mammary epithelial cells (HMEC) and blood cancer cell lines transduced with these shRNA libraries targeting thousands of genes identified hundreds of essential genes for each panel of cells. Subsequent validation using single shRNA-expressing constructs showed that about 80% of the shRNAs identified in each complex library screen did in fact lead to cell death when transduced in cells. Analysis of the identified essential genes for known biological interactions revealed non-random clusters of interacting proteins that provide some insight into signaling pathways and protein networks specific to these cancers. Also, we have recently adapted the approach to combinatorially screen shRNA sequences targeting hundreds of genes to discover additive and synergistic combinations that generate a synthetic-lethal phenotype. Analysis of the lethal combinations indicates redundant, complementary, and compensatory responses in cancer cells. This presentation will provide an overview of the screening platform, our approach to shRNA library design, and results from the screens for cancer cell-specific lethal and synthetic-lethal genes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C159.
Abstract C164: Preclinical pharmacological characterization of GBR 401, a new monoclonal antibody directed against human CD19.
Authors: Hou Samuel , Blein Stanislas , Skegro Darko , Macoin Julie , Lissilaa Rami , Back Jonathan
Published: June 2012

GBR 401 is a humanized monoclonal antibody directed against domain 2 of human B-lymphocyte antigen CD19 and displays a number of mechanisms which can specifically target and kill B cells. Glenmark is developing this product as a B-cell depleting agent for B cell malignancies.

CD19 is the archetypal B cell marker and is used in the diagnosis of B cell lymphomas/ leukemias by the identification of abnormal B cell numbers and/or populations. Expression of CD19 is found in the majority of B cell lineage malignancies including, but not limited to non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia. Given its role as a signaling molecule, an antibody directed against CD19 might be predicted to affect the progression of lymphomas and leukemias.

GBR 401 is a humanized IgG1 which can specifically kill CD19 bearing cells with very efficient in vitro antibody-dependent cellular cytotoxicity (ADCC) and rapid-onset apoptosis-inducing abilities. It also can inhibit the proliferation of CD19+ tumor cells but has little to no complement dependent cytotoxicity (CDC), at least, in vitro. The in vivo anti-B cell activity of GBR 401 was evaluated using human peripheral blood mononuclear cell (huPBMC) graft models in SCID mice. GBR 401 significantly depleted human B cells in grafted mice at levels down to 0.1mg/kg compared to an isotype control. GBR 401 also produced approximately 50% depletion or EC50 at 0.02mg/kg. These in vitro and in vivo pharmacology data provide a rationale for the clinical testing of GBR 401 in patients with CD19+hematologic malignancies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C164.
Abstract C168: Cancer-selective mitochondrial copper transport by elesclomol results in potent single agent efficacy in multiple tumor types.
Authors: Sang Jim , Nagai Masazumi , Zhang Chaohua , Smith Donald , Sequeira Manuel , Ogawa Luisa Shin , Ye Josephine , Liu Yuan , Inoue Takayo , Zhou Dan , Koya Keizo , Wada Yumiko
Published: June 2012

Elesclomol is a first-in-class investigational drug that exerts potent anticancer activity through the elevation of reactive oxygen species (ROS) levels and is currently under clinical evaluation as a novel anticancer therapeutic. We recently demonstrated that elesclomol preferentially binds extracellular copper (Cu) and selectively transports this metal ion to the mitochondria of tumor cells to promote mitochondrial ROS generation and subsequent apoptosis. Here we report that elesclomol-induced copper transport and apoptosis is tumor selective. Comparative analysis using human PBMCs and the promyelocytic tumor cell line HL-60 demonstrated increased Cu levels in the mitochondrial fraction of HL-60 cells following elesclomol-Cu treatment, but not in donor PBMCs. Further, elesclomol-Cu induces ROS in HL-60-derived mitochondria but not in those isolated from PBMCs. These results suggest that elesclomol-Cu selectively targets cancer cell mitochondria to ultimately produce critical elevations in oxidative stress. To evaluate increased exposure to elesclomol-Cu in vivo, elesclomol was administered continuously to tumor-bearing mice using an Alzet pump at a clinically relevant dose. Upon release, elesclomol immediately chelates copper from the blood to form an elesclomol-Cu complex, achieving 10-fold higher levels of elesclomol-Cu compared to those following bolus injection. Even with this increased formation of elesclomol-Cu in situ, no signs of toxicity have been observed. In five different tumor xenograft models tested, elesclomol consistently demonstrated marked single agent activity with significant tumor growth suppression, indicating that increased elesclomol-Cu levels result in selective and enhanced antitumor efficacy. These findings highlight a unique mechanism of action of elesclomol and support potential single agent activity of this compound in a variety of tumor types.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C168.
Abstract C169: Inhibition of SREBPs by fatostatin reduces glioblastoma cell proliferation and viability.
Authors: Youssef Mary , Reinitz Felicia , Cloughesy Timothy , Mischel Paul , Guo Deliang
Published: June 2012

Glioblastoma (GBM) is the most common type of malignant brain tumor. Due to its aggressive invasion of the surrounding tissue, it is one of the most deadly cancers, with an average patient survival rate of 12–18 months after diagnosis despite surgery, radiation and chemotherapy, underscoring the urgent need to find new molecular targets and effective drugs. Recently, The Cancer Genome Atlas identified that the RTK/PI3K/Akt pathway, which can be initiated by epidermal growth factor receptor (EGFR), is activated in about 88% of GBM; this pathway has been recognized as a major driver in promoting malignant cancer cell growth in several cancers. In accordance with this, our group has demonstrated that aberrant EGFR/PI3K/Akt signaling promotes GBM cell growth through sterol regulatory element-binding protein 1 (SREBP-1) mediated fatty acid synthesis and cholesterol uptake, and identified SREBP-1 as a potential molecular target. The focus of our research is to evaluate inhibitors of lipid synthesis/uptake, and to assess their affect on GBM growth. Previously, the small molecular inhibitor fatostatin was shown to effectively inhibit cleavage and activation of SREBPs, suggesting that it can prevent EGFR induced lipid synthesis and uptake and reduce cancer cell viability. Indeed, GBM cells treated with fatostatin exhibited diminished cell proliferation and increased cell death in a dose-dependant manner. These data suggest that alteration of lipid and cholesterol homeostasis through pharmacological inhibitors can suppress glioblastoma growth, providing a new avenue for treating GBM.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C169.
Abstract C171: TriplatinNC, a nucleolar-targeting platinum agent. Heparan sulfate-mediated cell entry, localization, and apoptosis.
Authors: Peterson Erica , Silva Heveline , Menon Vijay , Benedetti Brad , Kipping Ralph , Farrell Nicholas
Published: June 2012

TriplatinNC, a “non-covalent” derivative of the phase II clinical drug BBR3464, exhibits a distinct mode of DNA binding mediated through “phosphate clamps”, which display structural analogy to the “polyarginine” (arginine fork) DNA/RNA recognition motif. TriplatinNC shows an improved pharmacokinetic profile and increased cellular accumulation compared to BBR3464. Furthering the “polyarginine” analogy, the cellular accumulation of TriplatinNC, unlike cisplatin or oxaliplatin, is dependent upon the presence of cell surface glycosaminoglycans (GAGs), shown through comparison of platinum level accumulation in wild-type Chinese Hamster Ovary (CHO) cell lines to those lacking heparan sulfate (CHO-pgsD-677) or both heparan sulfate and chondroitin sulfate (CHO-pgsA-745). The cellular localization of TriplatinNC and cisplatin was visualized in confocal microscopy experiments utilizing the fluorescently-tagged derivatives, TriplatinNC-NBD or cisplatin-NBD. TriplatinNC, but not cisplatin, shows distinct localization to the nucleolar region of human colon and ovarian carcinoma cell lines, HCT116 and A2780, respectively. It was hypothesized that this pattern of localization, combined with nucleic acid affinity, would allow TriplatinNC to disrupt rRNA synthesis, the primary function within the nucleolus. Using 32P-metabolic labeling to monitor the rate of pre-rRNA transcript formation after cellular treatment, it was observed that both 47S pre-RNA and processed rRNAs, 32S, 28S, and 18S levels decreased dramatically compared to the untreated control in a dose-dependent manner. While the localization and abundance of nucleolar proteins, RNA pol I and UBTF, were unaffected by treatments with TriplatinNC at early timepoints, levels of the clinical relevant proliferative marker Ki-67, decreased markedly within one hour post-treatment. The morphological characteristics of apoptosis, including reduction in cell size, membrane blebbing, and cytosolic vacuolization, become visible 10hrs after drug treatment. This apoptotic process is not dependent on p53, as western blot analysis showed cleavage of procaspases 8, 9, and 3, followed by Parp-1 in HCT116 p53+/+ and p53−/− cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C171.
Abstract C175: JS-K, a nitric oxide-releasing anticancer prodrug with a broad spectrum of action.
Authors: Maciag Anna E. , Saavedra Joseph E. , Nandurdikar Rahul S. , Holland Ryan J. , Shami Paul J. , Anderson Lucy M. , Keefer Larry K.
Published: June 2012

Non-small cell lung cancer (NSCLC) is among the most common and deadly forms of human malignancies. Early detection is unusual and cures are limited to early stage disease. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. O2-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) is a potent anticancer agent that has proven effective in several cancer models in vitro and in vivo, including NSCLC. Here we report mechanistic studies with JS-K and its homopiperazine analogue and structural modification of these into more stable prodrugs. Prodrugs of the JS-K class were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector, activating transcription factor 3 (ATF3). Treatment of the NSCLC cells with JS-K resulted in oxidative/nitrosative stress, which combined with the arylating properties of the compound was reflected in glutathione depletion and alteration in cellular redox potential, mitochondrial membrane permeabilization and cytochrome c release. Inactivation of MnSOD by nitration was associated with increased superoxide and significant DNA damage. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have anti-tumor activity. The data suggest that: 1) diazeniumdiolate-based NO-releasing prodrugs may have application as a therapy for lung cancer; 2) rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C175.
Abstract C176: Activity of novel indolequinone inhibitors of thioredoxin reductase 1 in pancreatic and colon cancers and in melanomas. Signaling mechanisms underlying antiproliferative activity.
Authors: Yan Chao , Inman Martyn , Thompson Christopher , Quackenbush Kevin , Reinemann Jaclyn , Chan Dan , Zhang Zhiyong , Messersmith Wells , Arcaroli John , Siegel David , Moody Christopher J. , Ross David
Published: June 2012

Novel indolequinones (including QG001, 5-methoxy-1-methyl-3-[(2,4,6-trifluorophenoxy)methyl]-1H-indole-4,7-dione and NJ824, 2-(hydroxymethyl)-5-methoxy-1-methyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione) demonstrated marked anti-proliferative activity in MIAPaCa-2 and BxPC-3 pancreatic cancer cells as well as in colon, melanoma and renal cell lines as indicated by testing in the NCI-60 cell line screen. In studies using MIAPaCa-2 and BxPC-3 cell lines we examined the mechanism of action of lead IQs and results demonstrated inhibition of the selenoprotein thioredoxin reductase 1 (TR1) and induction of apoptosis in pancreatic cell lines at doses approximating their IC50 values obtained from MTT growth inhibition assays. Other selenoproteins such as glutathione peroxidase were not inhibited and the depletion of cellular thiols was not observed following treatment with lead IQs indicating target selectivity. The mechanisms underlying IQ-induced apoptosis were investigated and lead IQs were found to induce oxidation of cellular thioredoxin subsequent to inhibition of thioredoxin reductase 1 and downstream activation of p38 and JNK leading to apoptosis. IQ-induced apoptosis could be inhibited by the use of p38 and JNK inhibitors in MIAPaCa-2 cells confirming the importance of this pathway. The role of ASK1 as an intermediary MAPKKK modulating signaling from oxidation of thioredoxin to activation of p38 and JNK was investigated in MIAPaCa-2 cells overexpressing ASK1 and lead IQs were found to induce ASK1 phosphorylation. Studies were extended to panels of eighteen human colorectal cancers and nineteen pancreatic cancer cell lines and lead IQs were found to exhibit marked growth inhibitory activity with IC50 values ranging from 0.05 to 0.5 micromolar. In vivo studies were performed in xenograft systems and lead IQs demonstrated significant growth inhibitory activity in both pancreatic and melanoma xenografts. These data demonstrate that this class of IQ has marked growth inhibitory activity in pancreatic, colon and melanoma tumors and are worthy of further translational evaluation as potential therapeutics.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C176.
Abstract C178: Synergistic activity of SR16388 with microtubule inhibitors against multiple cancer cell lines.
Authors: Zhou Wei , Calaogan Joy , Sato Barbara , Sambucetti Lidia
Published: June 2012

Synergistic combinations of anti-cancer compounds can provide therapeutic benefits by producing better efficacy at potentially lower doses. SR16388, a novel steroidal compound that inhibits estrogen and estrogen-related receptors, has previously been shown to inhibit the proliferation and viability of diverse human cancer cell lines in vitro and to reduce the growth of several types of human xenograft tumors in mice, including, NSCLC and androgen-independent prostate cancer. We examined the two-drug combination effects of SR16388 in cell culture systems using a panel of approved cancer drugs with different mechanisms-of-action. Sixty cancer cell lines were treated with compounds alone or in combination for three days and CellTiter-Glo® Luminescent Cell Viability Assay (Promega Corp.) was used as the endpoint to measure cell viability. Combinations of SR16388 with anti-mitotic drugs Paclitaxel or Vincristine demonstrated synergistic effects on cell killing in multiple cell lines. These synergistic effects were further evaluated by calculating combination-index values using CalcuSyn software (Biosoft, Cambridge, UK)”. Studies are ongoing to elucidate the mechanisms that may lead the synergistic interaction of SR16388 and these antimitotic drugs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C178.
Abstract C179: Discovery of a series of novel PARP-1 inhibitors with potent in vitro and in vivo activity.
Authors: Cai Sui Xiong , Xu Qingbing , Wu Lizhen , Liu Lijun , Jiang Yangzhen , Bao Qingli , Wang Guoxiang , Zhang Xiuyan , Yin Feng , Gu Chengyun , Hu Xiuhua , Wang Xiaozhu , Kang Sishun , Chen Shengzhi , Tian Ye Edward
Published: June 2012

Poly (ADP-ribose) polymerase (PARP) catalyzes the addition of poly (ADP-ribose) to target proteins that is an important process in DNA repair. PARP-1 inhibitors are expected to increase the therapeutic efficacy of DNA damaging anticancer agents, and are cytotoxic to BRCA1 or BRCA2 deficient cancer cells. Recently, phase II clinical trial data have shown that PARP-1 inhibitor olaparib (AZD2281) was effective in the treatment of advanced breast cancer. Hopefully the discovery and development of novel and potent PARP-1 inhibitors will lead to a new class of anticancer drugs. In this presentation, we will report the discovery of a series of novel and potent PARP-1 inhibitors. We have found more than 40 compounds that are several folds more potent than AZD2281 in multiple in vitro assays. Several of these compounds have excellent oral bioavailability (F values approaching 50%) and low toxicity (well tolerated when dosed orally up to 100 mg/kg once a day for 5 days). Two lead compounds have been tested in animal efficacy animal models and found to be 10–20 folds more efficacious than AZD2281.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C179.
Abstract C183: Inhibition of CSF1 receptor signaling targets tumor associated macrophages in a murine ovarian cancer model.
Authors: Dorigo Oliver , Moughon Diana L. , Masri Wafic El , Lily Wu
Published: June 2012

Rationale: CSF1 receptor (CSF1R) mediated signaling is important for the recruitment of CD11b+F4/80+ tumor-associated macrophages (TAMs). TAMs support tumor growth by several mechanisms including suppressing anti-tumor immune responses via the M2 macrophage subpopulation. Macrophages are found in the ascites and tumor tissue of patients with ovarian cancer and therefore present a suitable target for therapy. This study evaluates the effect of pharmacologic CSF1R inhibition on the profile of intraperitoneal macrophages in a murine model of ovarian cancer. In addition, we assessed the direct effect of CSF1R inhibition on several established human ovarian cancer cell lines.

Methods: To establish an orthotopic ovarian cancer model, we injected murine ID8 epithelial ovarian cancer cells into the ovarian bursa of immuno-competent C57BL6 mice. ID8 cells were labeled with the luciferase gene for bioluminescence. Upon establishment of tumor disease and ascites, mice were treated with daily oral doses of the selective CSF-1R inhibitor GW2580. Ascites and tumor tissue was assessed for the presence of CD11b+Gr-1loLy6Chi mononuclear myeloid-derived suppressor cells (MDSCs) and CD11b+F4/80+ tumor-associated macrophages (TAMs). The human ovarian cancer cell lines OVCAR5, IGROV1 and SKOV3 were treated with CSF1R inhibitors and cell proliferation assessed.

Results: In vivo gene imaging showed ID8 tumor growth initially confined to the ovary with subsequent metastatic spread to the peritoneal cavity closely mimicking the growth pattern of human ovarian cancer. In animals with established metastatic tumor disease and ascites, GW2580 treatment caused a significant reduction in the ascites volume to about 25% of the level in untreated animals. GW2580 induced a drastic reduction in TAMs and MDSCs in ascites and intraperitoneal tumor tissue. Both MHCII+ and MHCII- TAM subpopulations were reduced equally. OVCAR5, IGROV1 and SKOV3 showed a decrease in cell proliferation when treated with CSF1R inhibitors albeit at higher doses (>10 M).

Conclusion: Inhibition of CSF1R signaling in vivo reduces immune-suppressive TAMs and MDSCs in an intraperitoneal murine ovarian cancer model. In addition, CSF1 decreases ovarian cancer cell proliferation. This suggests that CSF1R inhibition might have dual therapeutic effects by modulating the intraperitoneal microenvironment and directly targeting ovarian cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C183.
Abstract C188: RalA phosphorylation as a biomarker in pancreatic ductal adenocarcinoma for Aurora A kinase inhibition in response to the investigational agent MLN8237.
Authors: Neel Nicole F. , Escedy Jeffrey A. , Shinde Vaishali , Der Channing J. , Yeh Jen Jen
Published: June 2012

The frequent mutational activation of KRAS in pancreatic ductal adenocarcinoma (PDAC) (greater than 90%) and critical importance of K-Ras-driven signaling in PDAC progression has led to increased efforts to identify K-Ras-targeted therapies. Activation of RalA downstream of K-Ras is essential for anchorage-independent and in vivo growth of PDAC cell lines. Indeed RalA-GTP levels are significantly higher in patient tumors relative to normal matched and unmatched samples. Phosphorylation of RalA on S194 by Aurora A kinase is critical for RalA-mediated effects on PDAC tumorigenesis. In addition S194 RalA phosphorylation is increased in PDAC cell lines relative to immortalized nestin-positive pancreatic epithelial cells. This evidence suggests that targeting RalA phosphorylation with Aurora A kinase inhibitors may prove to be a viable therapeutic option for the treatment of pancreatic cancer. MLN8237 is a novel and specific Aurora A kinase inhibitor. Therefore, we investigated the effectiveness of the MLN8237 at inhibiting anchorage-independent growth of PDAC cell lines and human tumorgraft growth in vivo. In addition, we investigated whether RalA phosphorylation could serve as a biomarker for MLN8237 responsiveness. MLN8237 decreased anchorage-independent growth of a panel of PDAC cell lines, some modestly and others dramatically, at nanomolar concentrations. In addition, administration of MLN8237 resulted in tumor regression in a subset of patient-derived tumorgrafts. Decreases in RalA phosphorylation were observed upon administration of MLN8237 but did not correlate with responsiveness in cell lines or tumorgrafts. These data suggest that further investigation of MLN8237 in a subset of PDAC patients is warranted, though non-clinical data suggests that activity may be RalA-independent. Furthermore, RalA phosphorylation does not appear to be a predictive biomarker for responsiveness to MLN8237.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C188.
Abstract C193: FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a novel orally bioavailable, selective, and potent FGFR inhibitor.
Authors: Porta Diana Graus , Guagnano Vito , Yao Yao , Kauffmann Audrey , Stamm Christelle , Chen Zhi , Zhang Yun , Bordas Vincent , Douget Mickael Le , Ito Moriko , Li Fang , Monahan John , Gaither Alex , Borawski Jason , Wilson Christopher J. , Venkatesan Kavitha , Bruemmendorf Thomas , Hofmann Francesco , Sellers William R.
Published: June 2012

The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTK) consists of FGFR1, FGFR2, FGFR3 and FGFR4, which are the high affinity receptors for 22 different FGF ligands. These ligand-receptor combinations elicit a broad spectrum of biological activities during development and in adult tissue homeostasis.

In contrast, de-regulated FGF signaling has been linked to diseases, most prominently in the pathogenesis of multiple cancers. Epidemiological and molecular studies have revealed a variety of genetic alterations in components of the FGF/FGFR signaling system which result in aberrant receptor activation and thus, enhanced downstream signaling. Hence, on this basis, targeted inhibition of FGFRs can be exploited for therapeutic intervention. In this report we disclose NVP-BGJ398, a novel orally bioavailable, selective and potent kinase inhibitor of the FGFRs currently in Phase I clinical trials. We further describe the identification of patient stratification biomarkers for NVP-BGJ398 by intersecting genome-wide gene expression data with genomic alterations and cell line sensitivity data across an annotated collection of cancer cell lines termed “Cancer Cell Line Encyclopedia”. We show that genetic alterations for selected FGF/FGFR family members predict for sensitivity to NVP-BGJ398 in specific cancer types, thus providing the rationale for clinical trials in well defined subpopulations of cancer patients based upon the presence of these molecular abnormalities.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C193.
Abstract C196: A novel selective inhibitor of FLT3 kinase as a therapeutics for AML.
Authors: Lee Hee Kyu , Kim Hong Woo , Song Ho-Juhn , Lee Jaekyoo , Lee In Yong , Kim Youngsam , Koh Jong Sung
Published: June 2012

Acute myeloid leukemia (AML) is an aggressive cancer, representing 90% of all adult acute leukemias, with an estimated incidence of 200,000 cases each year worldwide. Noticeably malignant cells, in the majority of AML patients, possess aberrantly expressed FLT3. The corresponding tumor-cell genotyping indicates that 25–30% of the AML blasts carry FLT3 mutations. The molecular characterization of these FLT3 mutations has revealed that they contain either internal tandem duplications (FLT3-ITD) in the juxtamembrane region (17–34%) or point mutations at the kinase domain (7%). Therefore, FLT3 has emerged as a promising target in therapy of AML. The first and second generation of the FLT3 inhibitors such as CEP-701, MLN-518, PKC-412, Sunitinib, Sorafenib, and AC220 are under clinical trial for AML treatment. However, their clinical responses have been below expectation likely due to the influence of plasma inhibitory activity, lack of strong inhibition of downstream effectors involved in aberrant activation of growth pathway, and lack of substantial and sustained inhibition of FLT3 activity, consequently resulting in drug resistance.

To address and overcome the key issues leading to several known drug resistances, we have developed a series of novel and highly selective FLT3 inhibitors possessing extreme potency against clinically known FLT3-mutants. One of our leads, SKI-G-801 (G-801), showed IC50 of 0.3 nM for FLT3 and IC50 of 2.1 nM in MV4–11 cells. Furthermore, it also showed IC50 of 3.1 nM in model cell line BaF3 expressing FLT3 D835Y whereas AC220 and PKC412 showed IC50s of 52.4 nM and 11.4 nM in the BaF3 cells, respectively. The tight binding property and the high potency of our lead candidates led to a strong inhibitory activity in the cell model in the presence of human plasma; FLT3 phosphorylation was inhibited by G-801 with IC50 of 9.9nM, while by PKC412 with IC50 of >1000 nM in the human plasma. In addition, a significant tumor regression of 85–100% was observed in a mouse xenograft model using MV4–11 cells by G-801 via oral administration for 28 days. Moreover, a synergistic effect of our lead compounds with AraC was more significant in RS4–11 cells than the known FLT3 inhibitors with AraC. These desirable characteristics of our lead candidates would ostensibly overcome the documented drug resistance confronted by previous FLT3 targeted inhibitors such as AC220, PKC-412, and CEP701. One of our lead candidates is expected to enter preclinical study soon.

Therefore, we are confident that our lead candidate will be a promising acute myeloid leukemia drug.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C196.
Abstract C211: Dexrazoxane for the targeted prevention of anthracycline-induced cardiotoxicity (ACT) in the age of predictive biomarkers and pharmacogenomics.
Authors: Steiner Rudolf K.
Published: June 2012

Anthracycline-induced cardiotoxicity (ACT) is a life-threatening adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Clinical risk factors combined with specific biomarkers and predictive genetic risk profiling now offer novel avenues for high-risk patients who may benefit from preventive use of the cardioprotective agent dexrazoxane. The recent identifications of high sensitivity troponin assays and genetic variants associated with ACT (Herman et al; Lipshultz et al; Wojnowski et al.; Visscher et al.) accurately predict ACT before the myocardial damage has been done. In view of the published safety profile of dexrazoxane in long-term pediatric and adult prospective randomized trials (Lipshultz et al 2010/11; Cochrane reviews 2011) anthracycline-induced cardiotoxicity prevention with dexrazoxane should now be initiated with the first dose of doxorubicin or its analogues given rather than after the irreversible myocardial damage has already been done at the widely accepted cumulative dose of doxorubicin. A biomarker driven ‘targeted’ use of dexrazoxane in preselected high risk ACT-prone patients may lead to safer treatment options for the cost-effective anthracycline-containing chemotherapy schedules in children and adult cancer patietns with or without compromised hearts. This new preventive strategy should now be tested in randomised prospective clinical trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C211.
Abstract C219: Inhibition of cancer cell growth and migration of podophyllotoxin derivative in cancer cells and its mechanistic study.
Authors: Chen Jia-Yang , Li Wen-Shan , Wang Yi-Ching
Published: June 2012

Although some chemotherapy drugs including tubulin-binding agents had been developed from nature plants, such as podophyllotoxin derivatives, taxanes, and vinca alkaloids, the poor cytotoxic selectivity, serious side-effects and the drug resistances remain the main issues of their therapeutic application. Therefore, we developed a podophyllotoxin derivative named Ching001. Using cell-based studies, we found that Ching001 had cytotoxicity selectivity toward different lung cancer cell lines than to the normal cells. In addition, it prevented lung cancer cell from mitosis by inhibiting the polymerization of microtubule and causing cell cycle arrest at G2/M phase. These events eventually led to apoptosis through activation of the ER-stress signaling. Importantly, Ching001 effectively inhibited the migration ability of lung cancer cell lines through changing microtubule and actin filament dynamics. In the animal tests, 2 mg/kg Ching001 treatment apparently inhibited the tumor growth and the effect was stronger than taxol treatment under same dosage. The hematology and biochemistry tests of blood samples as well as tissue examinations indicated that Ching001 treatment did not show apparent organ toxicities in tested animals. The tumor tissue staining further confirmed that Ching001 induced apoptosis of tumor cells and led to tumor nodule shrinkage. In addition, the result of in vivo experimental metastasis tests showed that 0.2 mg/kg Ching001 treatment decreased the metastasis potential of lung cancer cell. In conclusion, the novel podophyllotoxin derivative, Ching001, could be a potential anti-cancer drug and is valuable to be developed as an anti-metastasis agent as well.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C219.
Abstract C224: Anti-CSF-1R antibodies reduce tumor-associated macrophages and inhibit tumor growth in preclinical models.
Authors: Li Yanxia , Mathew Sneha , Wu Lan , Wang Ying , Kearney Jessica , Persaud Kris , Burtrum Douglas , Balderes Paul , Surguladze David , Tonra James , Haurum John , Ludwig Dale , Doody Jacqueline F.
Published: June 2012

In cancer, increased infiltration of macrophages within and surrounding the tumor mass correlates with increased tumor invasiveness and growth. In addition, presence of tumor-associated macrophages (TAMs) has been shown to correlate with poor prognosis, particularly in breast, prostate, ovarian and cervical cancer. TAM proliferation, differentiation and survival is dependent on CSF-1R activation, a type III integral membrane tyrosine kinase receptor selectively expressed on cells of the mononuclear phagocyte lineage. The ligands CSF-1 and the more recently identified IL-34 are responsible for the binding and activation of CSF-1R on macrophage surfaces. While CSF-1R levels are infrequently increased in tumors compared to analogous normal tissues, increased levels of CSF-1 and IL-34 in sera of cancer patients is more frequently observed and is associated with poor prognosis and severity of disease in multiple cancers, again primarily in breast, prostate and ovarian cancer patients. Given that TAMs enhance tumor growth and that activation of the CSF-1R pathway is required for TAM function, an antibody against mouse CSF-1R was generated for proof-of-principle studies. This study summarizes the in vitro and in vivo characterization of an anti-mouse CSF-1R antibody designated CS7. CS7 was shown to inhibit the binding of both CSF-1 and IL-34 to murine CSF-1R and inhibit CSF-1R activation. More importantly, monocytic to macrophage differentiation in vitro was impeded in the presence of CS7. CS7 was evaluated in several mouse tumor models and shown to have good in vivo efficacy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C224.
Abstract C229: Tumor-associated macrophages induce prostate tumorigenesis via CCL4/STAT3 signals.
Authors: Fang Lei-Ya , Izumi Kouji , Lin Wen-Jye
Published: June 2012

Tumor-associated macrophage (TAM) is a major player in the tumor microenvironment that supports cancer development and progression, but the molecular nature of macrophages in promoting prostate tumor initiation remains poorly defined. Here we report that, in an in vitro co-culture model, macrophages are able to induce prostate tumorigenesis of normal prostate epithelial cells. Functional in vitro analyses concluded that this tumorigenesis process is mediated by CCL4 dependent pathway and linked to increased epithelial cell proliferation and migration, STAT3 activation, p53/PTEN downregulation and an epithelial-to-mesenchymal transition (EMT). In vivo suppression of the macrophage migration resulted in inhibition of prostate tumorigenesis, suggesting a distinct role for macrophages in prostate tumor development. Our data suggest that specifically targeting macrophage can inhibit the protumor function of TAMs, and highlight a new mechanism by which TAMs with inflammatory cytokine CCL4 could be new therapeutic targets to battle infiltrating macrophage-induced prostate tumorigenesis at the PIN developing stage.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C229.
Abstract C25: A phase I study evaluating the proton pump inhibitor pantoprazole (PTP) in combination with doxorubicin (DOX) for advanced cancer patients (pts).
Authors: Richter Suzanne , Tran Ben , Patel Krupa , Ocana Alberto , Wang Lisa , Haines Christine , Recel Melanie , Chen Eric X. , Tannock Ian F. , Siu Lillian L. , Bedard Philippe L.
Published: June 2012

Background: Chemoresistance may occur through acidification of the tumor microenvironment, impaired uptake and the inhibition of autophagy. PTP is a proton pump inhibitor that reduces gastric acidification in peptic ulcer disease. Our preclinical studies demonstrate that high dose intravenous (IV) PTP increases the nuclear localization and anti-tumor activity of DOX in xenografts, suggesting It may represent a novel approach to increasing tumor sensitivity. The primary objective of this phase 1 trial is to evaluate the recommended phase II dose and safety profile of IV PTP in combination with DOX; secondary objectives are to assess the preliminary anti-tumor activity, evaluate pharmacokinetics (PK) and to evaluate the influence of PTP on DOX distribution in tumor tissue.

Methods: Patients are eligible with advanced solid tumors with no further standard treatment options, an ejection fraction 50% and prior exposure of 240 mg/m2 DOX or 300 mg/m2 of epirubicin. Treatment is with DOX 60mg/m2 with PTP at 4 predetermined dose levels on a 3 weekly schedule using a 3+3 design. The dose limiting toxicity (DLT) period is 21 days. A DLT is defined as CTCAE v4 grade (g) 4 thrombocytopenia; g4 neutropenia 7 days; g3 febrile neutropenia; g3 infection with g3 neutropenia 7 days; g3 nonhematologic toxicities; and any toxicity resulting in the inability to administer day 1 of a planned cycle within 14 days. Study assessments include weekly hematology and biochemistry (C1, 2) then q3wkly (C3); clinical assessment q3wkly, CT imaging q9wkly and cardiac function q6wkly. Plasma samples for DOX PK analysis are collected post dose at 0, 1, 2, 4, 8, 24, 48 and 72 hours.

Results: As of August 2011, a total of 9 patients have been treated at 80 (DL1), 160 (DL2) and 240 mg (DL3) PTP dose levels. The median age was 61 years (42–73), ECOG PS 1, median treatment time 3 cycles (1,8). Treatment related g 3 toxicities are shown (Table 1). Partial response by RECIST v1.1 was achieved in 1 pt and stable disease in 4 pts. Preliminary data demonstrated no effect of pantoprazole on DOX PKs. Mean Cmax at 240mg PTP correlated to levels observed to enhance chemotherapy in our mice xenografts.

Conclusions: The combination is well tolerated and adverse events were consistent with toxicity profile for DOX alone. Objective antitumor activity was seen. Dose escalation is ongoing.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C25.
Abstract C32: Gene expression analysis of myeloma cells resistant and sensitive to bortezomib.
Authors: Terui Yasuhito , Mishima Yuji , Tomida Akihiro , Hatake Kiyohiko
Published: June 2012

Purpose: The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM). Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. However, resistance to bortezomib as a single agent develops in the majority of patients, and activity in other malignancies has been less impressive. To elucidate mechanisms of bortezomib resistance and find the way to overcome bortezomib resistance, we compared differential gene expression profiles of bortezomib-resistant IM-9 and bortezomib-sensitive IM-9 multiple myeloma cell lines in response to bortezomib. Methods: The differential gene expression profiles of bortezomib-resistant IM-9 and bortezomib-sensitive IM-9 multiple myeloma cell lines in response to bortezomib was performed using Affymetrix GeneChip. To confirm the results, real-time PCR and Western blot analysis were performed.

Results: At concentrations that effectively inhibited proteasome activity (maximum dose with 100nM), bortezomib induced cell death in bortezomib-sensitive IM-9 cells, but not in bortezomib-resistant IM-9. In comparison of differential gene expression profiles between bortezomib-resistant IM-9 and bortezomib-sensitive IM-9 cells, we showed overexpression of KDM3A and KDM5B, which are associated with chromatin-mediated reversible drug-tolerant state, Moreover, CD200, CD69, and IGF1R, which are associated with cancer stem cells, were overexpressed in bortezomib-resistant IM-9.

Conclusion: Histone lysine-specific demethylase inhibitors as combination with bortezomib may be useful for overcoming bortezomib-resistance. Moreover, cancer stem cell antigen such as CD200, CD69, and IGF1R may also become molecular targets against bortezomib-resistance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C32.
Abstract C34: Synergistic interaction between a novel histone deacetylase inhibitor and the proteasome inhibitor bortezomib in platinum-resistant ovarian carcinoma cells.
Authors: Gatti Laura , Benedetti Valentina , De Cesare Michelandrea , Corna Elisabetta , Cincinelli Raffaella , Zaffaroni Nadia , Zunino Franco , Perego Paola
Published: June 2012

Based on the ability of histone deacetylase inhibitors to modulate the expression of genes relevant for growth regulatory or apoptotic pathways, the purpose of the present study was to explore the interest of novel combination treatments for drug-resistant tumors. Thus, using cellular and biochemical pharmacology approaches, we examined the effect of the combination between the novel histone deacetylase inhibitor ST2782 and the proteasome inhibitor bortezomib in ovarian carcinoma cell lines, including the parental IGROV-1 cell line and two platinum-resistant sublines. The IGROV-1/OHP and IGROV-1/Pt1 cells, selected for resistance to oxaliplatin and cisplatin respectively, are characterized by a mutant p53 gene. Using the combination index method and cell sensitivity assays, we found a synergistic interaction between ST2782 and bortezomib, more evident in the p53-mutant resistant sublines. Such an interaction was associated with increased apoptotic cell death, as shown by TUNEL assays. The treatment with ST2782 resulted in early induction of the pro-apoptotic protein Bax as well as in cleavage of caspase 3 and PARP only in the resistant cell lines, as supported by Western blot analyses. The inhibition of p53-transcriptional transactivation by pifithrin alpha in IGROV-1 cells enhanced the synergism between the two drugs. Conversely, knockdown of endogenous wild-type p53 in IGROV-1 cells following transfection of small interfering RNAs determined a considerable synergism reduction. These opposite effects support the relevance of the transactivation-deficient mutant p53 as a determinant of the synergism. Moreover, in vivo studies in IGROV-1/Pt1 xenografts indicated that tumor growth inhibition tended to be more marked in mice receiving the drug combination with respect to those treated with bortezomib alone. In conclusion, the present study supports the potential effectiveness of this combination in p53-mutant ovarian cancer models resistant to platinum compounds.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C34.
Abstract C35: Response of colorectal cancer cells to combination of EGFR mAbs with oxaliplatin is determined by the sequence of administration.
Authors: Elenius Klaus , Karrila Anna , Gustafsson Emil , Sundvall Maria
Published: June 2012

Monoclonal antibodies (mAb) targeting EGFR (epidermal growth factor receptor), cetuximab (Erbitux) and panitumumab (Vectibix), have been approved for the therapy of metastatic colorectal cancer (mCRC). However, the majority of the patients are primarily resistant to EGFR mAbs or become resistant during the treatment. While activating mutations in KRAS have been reported to confer resistance to EGFR mAbs, some recent randomised controlled trials with EGFR mAbs combined to oxaliplatin-based regimens have failed to demonstrate clinical effect even in patients with KRAS wild-type mCRC. We have addressed the effects of EGFR mAbs on the growth of KRAS wild-type and KRAS mutant CRC cell lines in the absence and presence of oxaliplatin. Our observations indicate that while the KRAS mutant genotype is predictive for resistance to single agent EGFR mAbs, the combination of EGFR mAb plus oxaliplatin is not superior to oxaliplatin alone regardless of the KRAS status. However, sequential administration of oxaliplatin prior to EGFR mAb results in a clear additive effect whereas a sequence of EGFR mAb prior to oxaliplatin antagonizes the effect of oxaliplatin. The opposing effects of the two different sequences seem to be independent on both KRAS and BRAF mutation status.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C35.