bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C44: Targeting neuregulin1-ErbB3 signaling in wild-type BRAF/NRAS melanoma.
Authors: Capparelli Claudia , Gaborit Nadège , Yarden Yosef , Aplin Andrew 
Published: August 2014

Abstract
Melanoma is the deadliest form of skin cancer due to its highly metastatic nature and refractoriness to standard chemotherapies. At present, few therapy options exist for wild-type BRAF/NRAS (WT/WT) melanoma patients. We examined the role of the neuregulin (NRG1)-ErbB3 signaling pathway in WT/WT melanoma cells since it is emerging as an important player in melanocyte homeostasis and melanoma pathogenesis. NRG1 has been shown to promote melanoblast proliferation and survival. ErbB3 is elevated in malignant melanoma specimens and cell lines and its expression correlates with reduced patient survival. The purpose of this study was to determine the role of the NRG1-ErbB3 signaling pathway in WT/WT melanoma cells. We demonstrated that in a subgroup of WT/WT cell lines, expressing high level of ErbB3 and NRG1, neuregulin is able to activate ErbB3 in basal conditions. Knockdown of NRG1 in high NRG1-expressing cells led to reduction of cell viability. This effect was associated with a decrease in the phosphorylation of ErbB3 and ErbB2 receptors as well as downstream AKT and ERK1/2 signaling. All these effects were rescued by exogenous addition of NRG1. We obtained analogous effects targeting ErbB3 with either small interfering RNAs or with clinical grade ErbB3 monoclonal antibodies. In these WT/WT cell lines with high expression of NRG1, inhibition of ErbB2-ErbB3 dimerization with pertuzumab caused a decrease in AKT phosphorylation and cell growth, indicating that ErbB3 signaling is dependent on ErbB2. Synergistic effects on cell growth as well as on AKT and ERK1/2 signaling were observed targeting ErbB2 and ErbB3 combining both antibodies. Our study demonstrates that targeting ErbB3 and ErbB2 signaling in a cohort WT/WT melanoma cell lines leads to tumor growth reduction. We propose that NRG1 activation of ErbB3 signaling promotes progression in these tumors and that these findings may form the basis for the use of agents targeting the NRG1-ErbB3 axis as novel treatment strategies in a subset of malignant melanoma.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C44.
Citation Format: Claudia Capparelli, Nadège Gaborit, Yosef Yarden, Andrew Aplin. Targeting neuregulin1-ErbB3 signaling in wild-type BRAF/NRAS melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C44.
Abstract C53: Fractional response to small-molecule TKIs in single cancer cells: A combination rational to overcome adaptive drug resistance.
Authors: Honarnejad Saman 
Published: August 2014

Abstract
Targeted cancer therapies block the growth and spread of cancer cells by interfering with specific molecules that support tumor growth and progression. Despite the successful application of these drugs in clinical settings, patient-to-patient variability and acquired resistance are still the primary challenges facing development and use of such cancer therapies. Here, we describe a cell cycle dependent mechanism of drug sensitivity and the consequential fractional response in a library of small-molecules. In particular, using high-throughput single-cell imaging methods we show how perturbing specific biochemical nodes in a signaling pathway controlling cellular machinery for metabolism and growth leads to heterogeneity in abundance of response modulating protein complexes with known functional roles in cellular senescence and apoptosis. Furthermore, we provide evidence towards a feedback mechanism coordinating signaling state with cell cycle that leads to adaptive drug resistance and propose a combination therapy rational to overcome this resistance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C53.
Citation Format: Saman Honarnejad. Fractional response to small-molecule TKIs in single cancer cells: A combination rational to overcome adaptive drug resistance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C53.
Abstract C57: The biological evaluation of small molecule inducers of Nrf2 transcriptional activity that inhibit the Keap1-Nrf2 protein-protein interaction.
Authors: Fowkes Adrian , Schaap Marjolein , Bertrand Helene , Thiollier Clarisse , Kaatchi Hiroko , Wells Geoff 
Published: August 2014

Abstract
The transcription factor Nrf2 up-regulates a range of cytoprotective enzymes with antioxidant response elements in their promoter regions and thus can protect cells against oxidative damage. Nrf2 is negatively regulated by the ubiquitination facilitator protein Keap1 that facilitates degradation of Nrf2. A number of natural products, including the isothiocyanate sulforaphane up-regulate Nrf2 by interacting with Keap1 in a covalent manner to stall its activity. Inhibition of the protein-protein interaction (PPI) between Keap1 and Nrf2 with small molecules constitutes an alternative strategy for developing pharmacological tool compounds and potential anti-inflammatory and chemopreventive therapeutic agents. We have applied structure-based drug design methods, including in silico screening, to develop a series of new inhibitors of the Keap1-Nrf2 interaction that mimic Nrf2 peptide motifs that bind to the Keap1 Kelch domain. Initial screening demonstrated that a series of substituted diaryl heterocycles were capable of inhibiting the PPI in vitro and inducing the expression of Nrf2 dependent gene products. The early hit compound HB229 is not cytotoxic (IC50&gt;250 µM), induced the expression of NAD(P)H oxidoreductase-1 (NQO1) and hemeoxygenase-1 (HO1) at low micromolar concentrations and increased the nuclear accumulation of Nrf2 in cell based assays using mouse Hepa1c1c7 hepatoma and human Hela and HEK293 cell lines. HB229 inhibited the PPI with an apparent IC50 of ∼7.1 µM in a fluorescence polarisation assay. Further biological evaluation of HB229, and a derivative of a recently described bis-sulphonamide Keap1-Nrf2 PPI inhibitor, revealed a consistent time and dose dependent Nrf2 induction. Additionally, both compounds appear to be capable of interacting with the aryl hydrocarbon receptor (AhR) pathway to some extent. For instance, both compounds induce nuclear accumulation of the AhR in cells, however this behaviour was not observed with the prototype irreversible Nrf2 inducer sulforaphane. The significance of these findings will be discussed.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C57.
Citation Format: Adrian Fowkes, Marjolein Schaap, Helene Bertrand, Clarisse Thiollier, Hiroko Kaatchi, Geoff Wells. The biological evaluation of small molecule inducers of Nrf2 transcriptional activity that inhibit the Keap1-Nrf2 protein-protein interaction. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C57.
Abstract C59: Use of dietary antioxidant supplement during cancer therapy- pros and cons.
Authors: Ghosh Debjani , Dey Subrata , Saha Chabita 
Published: August 2014

Abstract
Black and green teas are rich in antioxidants and its flavonoids like thearubigins, epicatechins and catechins are known to have higher antioxidant efficacy than vitamin C. Despite significant research investigating the use of tea as dietary antioxidant supplement during conventional chemotherapy, no conclusion has been drawn regarding its mechanism of action and safety. In the present study chemopreventive effects of black tea extract (BTE) were evaluated on normal lymphocytes and compared with cancerous K562 cells. Chemotherapeutic drugs (Adriamycin and Daunomycin) act by generating oxidative stress and inducing apoptosis. The level of reactive oxygen species (ROS), apoptosis and gene expression in untreated and BTE treated cells were followed by different biochemical assays, flow cytometry and reverse transcription PCR. Results evidence that efficient scavenging of intracellular ROS by BTE resulting in reduced apoptotic cell population in normal lymphocytes. Gene expression of p53, bax, bcl2 and nrf2 show variation in untreated and BTE treated cells. Activity of endogenous antioxidant enzymes like SOD, GST and catalase is modified on tea treatment. Similar observations were recorded to a lower extent in K562 cells, suggesting BTE conferred protection to cancerous cells also. It can be summarized here that tea as a dietary supplement during chemotherapy shows interference in chemotherapeutic efficacy of the drugs in vitro. More in vitro, in vivo and clinical trials would shed light on the mechanism of action of the dietary antioxidant supplement during chemotherapy and its application.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C59.
Citation Format: Debjani Ghosh, Subrata Dey, Chabita Saha. Use of dietary antioxidant supplement during cancer therapy- pros and cons. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C59.
Abstract C6: Molecular and cellular signaling of PDGFB in cervical cancer cells.
Authors: Tudoran Oana M. , Soritau Olga , Balacescu Ovidiu , Balacescu Loredana , Lindberg Staffan , Berindan-Neagoe Ioana 
Published: August 2014

Abstract
Cervical cancer was reported to be the second most common female cancer worldwide, being the third cause of female cancer mortality annually. Romania ranks first among European countries in cervical cancer incidence and mortality raising the national awareness. Cervical cancer is one of the most aggressive gynecological diseases, mainly is due to rapid development of a functional tumor vascular network.
In solid tumors, PDGF signalling has been showed to participate in processes such as autocrine stimulation of tumor cell growth, recruitment of tumor stroma and stimulation of angiogenesis. PDGF signaling increases the interstitial fluid pressure, an important drawback in drug administration due to loss of active agents before they reach the tumors. Several studies have showed that targeting PDGF pathways have anti-angiogenic and anti-tumor effects, implying that inhibition of PDGF signaling may improve the efficacy of chemotherapies. However, these studies have been focused on effects on tumor vasculature and mural cells, and less on tumor cells. Moreover, the molecular mechanisms of PDGF signaling in tumor cells have yet to be investigated.
Here we report the molecular and cellular effects of PDGFb inhibition of in cervical tumor cells. We used the RNA interference pathway to trigger PDGFb silencing in two HPV16 positive cervical cancer cell lines (Hela, Caski). We investigated the changes in genes expression induced by PDGFb silencing by means of microarray analysis. Transcriptomic analysis revealed 579 genes to be differentially expressed upon PDGFb silencing. Among the top biological functions regulated by these genes are Cell Death and Survival, Cellular Growth and Proliferation, Cardiovascular System Development and Function, Cellular Movement, etc. Cellular investigations on proliferation, apoptosis, and invasion revealed that PDGFb silencing had no effects on cells ability to proliferate nor induced cell death, which suggest that alternative signaling mechanisms are activated to maintain the balance between cell proliferation and apoptosis. This is probably done throughout HPV16 signaling as some of the identified genes are known to be involved in viral infections. We did however observe that PDGFb silencing reduced the invasiveness of cervical cancer cells. Although preliminary, our results could explain the short-term success of antiangiogenic therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C6.
Citation Format: Oana M. Tudoran, Olga Soritau, Ovidiu Balacescu, Loredana Balacescu, Staffan Lindberg, Ioana Berindan-Neagoe. Molecular and cellular signaling of PDGFB in cervical cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C6.
Abstract C76: FoxM1 inhibition sensitized BRCA-proficient triple-negative breast cancer to PARP inhibition.
Authors: Lee Jun Woo , Lee Kyung-Min , Han Wonshik 
Published: August 2014

Abstract
Breast cancer cells with mutations in breast cancer-associated 1 (BRCA1) or BRCA2 have defects in the homologous recombination (HR) DNA repair pathway and this confers sensitivity to inhibitors of poly (ADP) ribose polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. The transcription factor Forkhead box M1 (FoxM1) is a key regulator of cell proliferation and is overexpressed in many forms of primary cancers, leading to uncontrolled cell division and genomic instability. FoxM1 is implicated in genotoxic drug resistance but its role and mechanism of action remain unclear. Our results revealed that triple-negative breast cancer (TNBC) cell lines depleted in FoxM1 levels by small interfering RNA transfection display increase DNA damage, as evidence by activation of checkpoint kinase 2 (Chk2) and phosphorylation of histone H2AX. These results shows a role for FoxM1 in the transcriptional response during DNA damage/checkpoint signaling and we hypothesized that FoxM1 inhibition would result in HR impairment and subsequent sensitization to PARP inhibitor. We found that knockdown of FoxM1 led to sensitization to AZD2281, PARP inhibitor, in MDA-MB-231 (BRCA-wild-type) and MDA-MB-436 (BRCA-mutated) TNBC cells. Combined PARP and FoxM1 inhibition had a synergistic anti-proliferative effect on BRCA1-defective and BRCA-proficient TNBC cell lines in vitro. Furthermore, the combination treatment of AZD2281 and thiostrepton (FoxM1 inhibitor) increased DNA repair-related gene expression such as H2AX, chk1, chk2 and p53 and downregulated BRCA2 expression in TNBC cell lines. Here, we show that depletion or inhibition of FoxM1 compromises the ability of cells to repair DNA by HR and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine FoxM1 and PARP inhibitors. Therefore, this combination may be effective for treating both BRCA1-defective and BRCA-proficient TNBC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C76.
Citation Format: Jun Woo Lee, Kyung-Min Lee, Wonshik Han. FoxM1 inhibition sensitized BRCA-proficient triple-negative breast cancer to PARP inhibition. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C76.
Abstract C77: A novel BRCA2 targeting antisense oligonucleotide sensitizes human tumor cells to chemotherapy and radiotherapy - the induction of ‘complementary lethality’ by targeting DNA repair.
Authors: Rytelewski Mateusz , Tong Jessica , Buensucesco Adrian , Maleki Vareki Saman , Ferguson Peter J. , Figueredo Rene , Vincent Mark , Shepherd Trevor , Deroo Bonnie J. , Koropatnick James D. 
Published: August 2014

Abstract
BRCA2 is a protein involved in homologous recombination repair of double-stranded DNA breaks in human cells. Inactivating mutations in BRCA2 predispose to early onset cancer of the breast, ovary and other tissues. However, patients with tumors that harbour BRCA2 mutations respond more favourably to cancer therapy. Therefore, inhibiting BRCA2 function in cancer cells capable of homologous recombination repair may sensitize otherwise resistant tumors to distinct types of anti-cancer treatment. We have reported that BRCA2 siRNA sensitizes human tumor cells to specific DNA-damaging agents (e.g., cisplatin), but not anti-folate drugs (e.g., pemetrexed), a phenomenon we termed ‘complementary lethality’. Based on these results, we developed and are testing a second generation antisense oligodeoxynucleotide (BR-1) that specifically targets BRCA2. BR-1 decreased BRCA2 mRNA and protein levels, and also inhibited BRCA2-mediated RAD51 repair focus formation. BR-1 potently sensitized human non-small cell lung cancer (A549) cells to cisplatin, melphalan, and carboplatin as evidenced by reduced overall proliferation. In addition, A549 cells exhibited reduced ability to form colonies after concomitant treatment with BR-1 and cisplatin, melphalan, or ionizing radiation. Furthermore, cisplatin-resistant, patient-derived head and neck squamous cancer cells (HN-5a) were rendered sensitive to cisplatin following BR-1 treatment, and the level of cisplatin sensitivity was comparable to that of the parent population. Interestingly, treatment with BR-1 and cisplatin significantly decreased cellular respiration compared to control oligonucleotide and cisplatin treatment, suggesting that downregulation of BRCA2 in the context of alkylating drug treatment alters cellular metabolism. However, this change in respiration occurred independently of mitochondrial integrity. BR-1 is currently being tested in vivo to determine its ability to downregulate BRCA2 in human xenografts and sensitize solid tumors to chemotherapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C77.
Citation Format: Mateusz Rytelewski, Jessica Tong, Adrian Buensucesco, Saman Maleki Vareki, Peter J. Ferguson, Rene Figueredo, Mark Vincent, Trevor Shepherd, Bonnie J. Deroo, James D. Koropatnick. A novel BRCA2 targeting antisense oligonucleotide sensitizes human tumor cells to chemotherapy and radiotherapy - the induction of ‘complementary lethality’ by targeting DNA repair. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C77.
Abstract C91: Targeting enzalutamide resistance in prostate cancer.
Authors: Ketola Kirsi , Bishop Jennifer , Gleave Martin , Zoubeidi Amina 
Published: August 2014

Abstract
Prostate cancer initially responses to androgen ablation or castration, but progression to incurable castrate-resistant prostate cancer often occurs within three years. Androgen receptor pathway inhibitor Enzalutamide (ENZ) has produced promising survival gains of patients with CRPC. However, resistance to this novel therapy also rapidly occurs and novel treatment strategies are needed. We have recently developed a unique ENZ and castrate-resistant LNCaP xenograft model. To identify key regulators and active pathways in ENZ resistant cells, genome-wide gene expression analysis was performed and analyzed using systems biological approaches. We identified that forkhead box M1 (FOXM1) is one of the key upstream regulators activated in ENZ resistant prostate cancer cells. FOXM1 is overexpressed in several cancers and it is an important regulator of cancer characteristics such as cell cycle, proliferation, invasion, metastases and cancer stem cells. FOXM1 is also a critical regulator of oxidative stress and its depletion sensitises cells to oxidative stress induced apoptosis. Interestingly, we further found out that the antibiotic ionophore and oxidative stress inducer monensin that was previously identified as a cancer-specific prostate cancer inhibitor in high-throughput screening, reduces FOXM1 pathway activity and viability of ENZ resistant cells. Thus, the results suggest that inhibition of FOXM1 is a potent novel mean to impair redox control and target ENZ resistant prostate cancer cells. Taken together, our results indicated that FOMX1 activity is increased in ENZ resistant prostate cancer cells and that targeting FOXM1 is a potential means to overcome ENZ resistance in prostate cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C91.
Citation Format: Kirsi Ketola, Jennifer Bishop, Martin Gleave, Amina Zoubeidi. Targeting enzalutamide resistance in prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C91.
Abstract C94: Heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer are sensitive to concomitant inhibition of EGFR and MEK.
Authors: Misale Sandra , Arena Sabrina , Lamba Simona , Siravegna Giulia , Lallo Alice , Hobor Sebastijan , Russo Mariangela , Buscarino Michela , Sartore-Bianchi Andrea , Bencardino Katia , Amatu Alessio , Siena Salvatore , Di Nicolantonio Federica , Bardelli Alberto 
Published: August 2014

Abstract
Monoclonal antibodies targeting EGFR are used in the clinic to treat KRAS wild type metastatic colorectal cancer (CRC). After an initial response, secondary resistance occurs thereby limiting the clinical benefit of these drugs. Relapsed patients have no further therapeutic options, therefore, elucidating the molecular basis of resistance is a prerequisite for the development of further lines of therapy.
We took advantage from a panel of CRC cell lines sensitive to EGFR inhibition by treating with cetuximab or panitumumab until resistant derivatives emerged. The resistant populations were heterogeneous mixture of cells bearing different alterations in KRAS, NRAS and BRAF genes at various frequencies. An RNA interference (siRNA) genetic screening unveiled that suppression of MEK1/2 together with silencing of EGFR was effective in impairing the growth of the resistant cells. Combinatorial treatment with pimasertib, a selective allosteric MEK inhibitor, together with cetuximab re-sensitizes anti-EGFR resistant derivatives despite the genetic alterations heterogeneity. Combinatorial treatment was effective in vitro and in vivo both in cell derived xenografts and in an acquired resistant patient derived xenograft (xenopatient).
These observations provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with targeted agents. We propose that MEK inhibitors, in combination with cetuximab or panitumumab, should be tested in clinical trials in CRC patients who become refractory to anti-EGFR therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C94.
Citation Format: Sandra Misale, Sabrina Arena, Simona Lamba, Giulia Siravegna, Alice Lallo, Sebastijan Hobor, Mariangela Russo, Michela Buscarino, Andrea Sartore-Bianchi, Katia Bencardino, Alessio Amatu, Salvatore Siena, Federica Di Nicolantonio, Alberto Bardelli. Heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer are sensitive to concomitant inhibition of EGFR and MEK. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C94.