bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CN01-01: Opportunities for systemic treatment using siRNA in nanoparticles.
Authors: McCormick Frank 
Published: August 2014

Abstract
Systemic delivery of siRNA has the potential to revolutionize cancer therapy. This technology is indifferent to the “druggability” of the target, and therefore opens up opportunities to target cancers driven by mutant RAS genes, or by MYC, β-catenin, and so on. Furthermore, elimination of well-established drug targets such as EGF-R could circumvent the problem of drug resistance. Complex mixtures of siRNAs can be loaded into nanoparticles, facilitating knock-down of genes that confer adaptive resistance, as well as potentiating the effects of knocking down driver genes by eliminating passengers.
In addition to these opportunities, systemic delivery of siRNA has another major advantage, which could greatly accelerate the rate of drug development, while decreasing costs and risk of failure. One a system is proven safe and effective to deliver a specific siRNA or cocktail, the same system can be used repeatedly for different payloads. This is in marked contrast with the current approach of developing individual chemical entities, each with its own safety profile and its own ADME characteristics,
Effective delivery requires nanoparticles with certain physical and chemical properties, but these particles need to be internalized into cells through surface receptors. The physical properties and internalizing ligands add selectivity to the particles, in addition to the expected selectivity of the siRNA payload. Together these considerations raise the possibility of a new generation of safe and effective therapies for treating cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN01-01.
Citation Format: Frank McCormick. Opportunities for systemic treatment using siRNA in nanoparticles. [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 CN01-01.
Abstract PL01-04: Mechanisms of acquired resistance to ALK/ROS1 inhibitors.
Authors: Shaw Alice T. 
Published: August 2014

Abstract
Chromosomal rearrangements of ALK and ROS1 define two distinct molecular subsets of non-small cell lung cancer (NSCLC). The multitargeted tyrosine kinase inhibitor crizotinib is highly active in both ALK- and ROS1-rearranged NSCLC, inducing responses in approximately 60% of patients. However, most patients relapse within the first year or two of treatment due to the development of resistance. Multiple distinct mechanisms of crizotinib resistance have been discovered in resistant tumor specimens and subsequently validated in the laboratory. These include acquisition of secondary resistance mutations in the ALK or ROS1 tyrosine kinase domain, amplification of the target gene, and activation of alternative signaling pathways like EGFR. In this talk, we will review the data supporting these established mechanisms of resistance. In addition, we will describe emerging resistance mechanisms, including epithelial to mesenchymal transition and pharmacokinetic failure leading to both systemic and central nervous system relapses. We will also explore the potential basis for both the homogeneity and heterogeneity of resistance that has been observed in patients. Finally, we will delve into therapeutic strategies that are currently being developed based on our understanding of resistance. These include more potent and selective ALK/ROS1 inhibitors (so called next generation inhibitors), as well as a variety of different combination strategies. These strategies are being tested primarily in patients who have already developed resistance, but they may in fact have greater impact in sensitive, treatment-naive patients by thwarting or delaying the emergence of resistance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL01-04.
Citation Format: Alice T. Shaw. Mechanisms of acquired resistance to ALK/ROS1 inhibitors. [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 PL01-04.
Abstract PL05-03: Phylogenetic quantification of intra-tumor heterogeneity predicts time to relapse in high-grade serous ovarian cancer.
Authors: Markowetz Florian M. 
Published: August 2014

Abstract
Intra-tumor genetic heterogeneity is the result of ongoing evolutionary change within each cancer. The expansion of genetically distinct sub-clonal populations may explain the emergence of drug resistance and if so would have prognostic and predictive utility. However, methods for objectively quantifying tumor heterogeneity have been missing and are particularly difficult to establish in cancers where predominant copy number variation prevents accurate phylogenetic reconstruction because of horizontal dependencies caused by long and cascading genomic rearrangements. To address these challenges we have developed MEDICC, a method for phylogenetic reconstruction and heterogeneity quantification, which determines optimal phasing of major and minor alleles, computes evolutionary distances between samples, and reconstructs ancestral genomes. Rigorous simulations and an extensive clinical study show the power of our method, which outperforms state-of-the-art competitors in reconstruction accuracy and additionally allows unbiased numerical quantification of tumor heterogeneity. Using MEDICC we investigated the relationship between tumor heterogeneity and patient outcome in high-grade serous ovarian cancer. We found that tumor heterogeneity in this cancer is driven by ongoing clonal evolution with fully branched evolutionary trajectories that do not have clock-like evolutionary rates. Quantitative measures of clonal expansion and temporal heterogeneity were the strongest predictors of progression-free survival. We show in 2 patients that clonal expansion of a minor subclone that was present prior to chemotherapy led to clinical relapse.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL05-03.
Citation Format: Florian M. Markowetz. Phylogenetic quantification of intra-tumor heterogeneity predicts time to relapse in high-grade serous ovarian 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 PL05-03.
Abstract 1753: Comparison between early versus delayed treatment of breast cancer induced osteolytic bone metastasis by TGFβ inhibitors in a murine model
Authors: Bandyopadhyay Abhik , Agyin Joseph , Lopez-Casillas Fernando , Wang Long , Biswas Tanuka , Sun Lu-Zhe 
Published: August 2014

Abstract
In breast cancer patients the preferential metastasis to bone often causes considerable morbidity and mortality. Timely intervention is needed for the prevention and treatment of breast cancer-induced bone metastasis and osteolysis. Increased TGFβ signaling has been implicated to promote cancer cell invasion to bone and cause osteolysis. In this study we have evaluated the efficacy of the early and delayed start of treatment by TGFβ antagonists, TGFβ R1 kinase inhibitor (TβRI) and soluble TGFβ type III receptor (sRIII), in a murine bone metastasis model utilizing human breast cancer cells. The female athymic nude mice injected intracardiacally with human breast cancer MDA-MB-231 cells were divided into five groups (n=10). In the two early treatment groups, the i.p. treatment started on the same day of tumor cell inoculation and in the two delayed treatment groups, treatment started on the 8th day after tumor cell inoculation with TβRI (20 µg/mice) and sRIII (100 µg/mice) respectively and continued every alternate day. Control group of animals were injected with phosphate buffered saline. The experiment was terminated after 25 days. The incidence of osteolytic metastasis determined by Faxitron X-Ray of the legs and tumor burden by the histology of tibia was remarkably reduced in the early treatment group in comparison to the control group. On the other hand, the delayed start of the treatment showed little effect on the reduction of tumor burden and bone loss indicating better efficacy of early treatment by TGFβ inhibitors in preventing homing of the tumor cells into the bone. As a potential mechanism, we have investigated the role of TGFβ inhibitors in vitro on the bone marrow mesenchymal stem cell (BM-MSC) induced cancer cell invasion which has been implicated to facilitate early entry of breast cancer cell into bone marrow. We have observed that the medium conditioned by BM-MSCs stimulated the invasion of MDA-MB-231 cells, which was significantly inhibited by TGFβ antagonists. Our results point to the possible therapeutic utility of TGFβ inhibitors to prevent primarily the initiation of breast cancer-induced bone metastasis by the inhibition of homing of the tumor cells into the bone. The mechanism may involve the modulation of the bone marrow mesenchymal stem cell microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1753. doi:10.1158/1538-7445.AM2011-1753
Abstract 1758: Influence of stromal microenvironment on rGel/BLyS-induced cytotoxicity in diffuse large B-cell lymphoma cells
Authors: Lyu Mi-Ae , Cheung Lawrence H. , Marks John W. , Rosenblum Michael G. 
Published: August 2014

Abstract
Diffuse large B cell lymphoma (DLBCL) is an aggressive sub-type accounting for 30-40% of non-Hodgkin's lymphoma. Despite recent advances in the understanding of the molecular and cellular basis for their pathogenesis, these tumors are still associated with poor response to treatment and a fatal outcome. The interactions of marrow stromal cells (MSCs) with tumor cells appear to be important in the development of tumor drug resistance through complex cytokine and adhesion-mediated mechanisms. We previously generated a highly cytotoxic growth factor fusion toxin designated rGel/BLyS for receptor-mediated delivery of the rGel toxin to malignant B cells. This fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA. In this study, we examined the impact of marrow stromal cells (MSCs) on rGel/BLyS-induced cytotoxicity in DLBCL cells. Treatment of tumor cell lines with dexamethasone and doxorubicine in the presence of MSCs was found to suppress the cytotoxic effect. In contrast, in vitro treatment with rGel/BLyS showed specific cytotoxic effects to DLBCL cell lines (IC50 ∼ 1-10 nM) in absence of MSCs or in presence of MSCs. At these doses, we found no cytotoxicity to MSCs. Treatment with rGel/BLyS induced down-regulation of Mcl-1, c-Myc, Bcl-xL, X-IAP, and Bcl-2 in DLBCL cells in absence of MSCs or in presence of MSCs. We also found that rGel/BLyS induced down-regulation of interleukin-6 receptor in DLBCL cells in absence of MSCs or in presence of MSCs. In addition, treatment of cells with rGel/BLyS induced apoptosis through caspase-9 activation, caspase-3 activation, and PARP cleavage. Our results demonstrate that rGel/BLyS can overcome stromal cell-mediated drug resistance which is a factor reducing the effectiveness of other conventionally-used agents for the treatment of this disease. This suggests that rGel/BLyS may be an excellent candidate for the treatment of DLBCLs which are resistant to conventional chemotherapeutic regimens. This research was conducted, in part, by the Clayton Foundation for Research and by Translational Research Award (LLS 6234-07) from the Leukemia and Lymphoma Society.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1758. doi:10.1158/1538-7445.AM2011-1758
Abstract 1761: Anti-tumor activity of trastuzumab-DM1 in combination with pertuzumab in a gastric cancer model
Authors: Yamashita-Kashima Yoriko , Fujimoto-Ouchi Kaori 
Published: August 2014

Abstract
Objective: Anti-HER2 therapy is considered to be important for gastric cancer as well as breast cancer. In a previous study, we showed the combinational efficacy of trastuzumab and pertuzumab (an anti-HER2 antibody which binds a different HER2 domain from trastuzumab) in HER2-positive gastric cancer models (AACR, 2010). In the present study, we investigated the usefulness of a HER2 antibody-cytotoxic drug conjugate, trastuzumab-DM1 (T-DM1) as monotherapy and in combination with pertuzumab for HER2-positive gastric cancer as a novel therapy.
Methods: A HER2 over-expressing human gastric cancer, NCI-N87 mouse xenograft model was used for examining the efficacy. T-DM1 was administered intravenously once every 3 weeks. Pertuzumab was administered intra-peritoneally once a week. Tumor growth inhibition (TGI) after 6 weeks of treatment was determined from tumor volume measurements. Apoptosis activity was measured with the activity of caspase 3/7. To measure ADCC activity, a real-time cell analyzer was used.
Results: T-DM1 (1.25, 2.5, 5, 10, 20, 40 or 80 mg/kg) as monotherapy showed tumor growth inhibition dose-dependently in the NCI-N87 model. The maximum effective dose was 10 mg/kg and TGI on day 42 after treatment started was 113%. T-DM1 (5 mg/kg) in combination with pertuzumab (40 mg/kg) in the NCI-N87 model showed significantly potent anti-tumor activity with a TGI of 113%. Both T-DM1 and pertuzumab as monotherapies showed significant anti-tumor activity, their TGI were 79% and 47%, respectively. To examine the mechanism of action of the combination of T-DM1 and pertuzumab, we analyzed apoptosis of NCI-N87 cells after treatment with T-DM1, pertuzumab or both under stimulation of EGF or heregulin. 24 h after treatment, the combination group had significantly enhanced caspase 3/7 activity compared with the monotherapy groups. We also examined ADCC activity of these agents. Both T-DM1 and pertuzumab showed ADCC activity and that activity was enhanced by the combination.
Conclusion: In this study, we showed that T-DM1 as monotherapy has significant anti-tumor activity in a mice model of HER2-positive gastric cancer. Furthermore, combining T-DM1 with pertuzumab significantly enhanced the anti-tumor activity compared with the efficacy of each agent used in monotherapy. The mechanism of this combination might be the potentiation of apoptosis induction and ADCC activity. The present study suggests that T-DM1 as monotherapy and in combination with pertuzumab would provide benefit for patients with HER2-positive gastric cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1761. doi:10.1158/1538-7445.AM2011-1761
Abstract 1763: The discovery of novel non-RGD-containing αvβ3 ligands for molecular imaging
Authors: Cho Choi-Fong , Amadei Giulio , Breadner Daniel , Luyt Leonard , Lewis John 
Published: August 2014

Abstract
Metastasis is the cause of 90% of cancer deaths. The detection of neoplasms before they metastasize using non-invasive molecular imaging approaches can have a significant impact on patient survival. For many years it has been known that αvβ3 integrin, which is over-expressed on angiogenic endothelium and many tumours, associates with the extracellular matrix through an RGD tripeptide motif. RGD-mediated targeting has been utilized for a wide variety of peptide and nanoparticle molecular imaging agents that are in various stages of development and in clinical trials. As RGD peptide decreases cell adhesion, concerns regarding its utilization as a molecular imaging agent have been raised (Kiessling et. al., 2009 Radiology). RGD peptides exert an anti-angiogenic effect through their inhibition of αvβ3 integrin, raising the concern given recent studies (Ebos et. al., 2009 Cancer Cell v15; Paez-Ribes et. al., 2009 Cancer Cell v15) that this anti-angiogenic activity may result in increased tumour invasion and metastasis. We sought, therefore, to discover novel αvβ3 integrin-targeted peptides that do not contain RGD for the development of new molecular imaging agents. Using a recently developed “beads on a bead” approach, we screened a linear octapeptide one bead one compound library using purified αvβ3 integrin. Over one hundred peptides were isolated and sequenced “on bead” using a novel MALDI-TOF/MS technique and a number of non-RGD containing peptides were identified. Two of these peptides had a higher binding affinity for purified αvβ3 integrin than the linear RGD peptide (LCE62, KD = 4.7 nM and LCE64, KD = 16.3 nM) as determined by surface plasmon resonance. In contrast to peptides containing RGD, these peptides did not impact the morphology and adhesion of αvβ3 integrin-expressing MDA-435 cells, nor did they inhibit angiogenesis. The uptake of both fluorescein-labeled LCE62 and LCE64 by αvβ3 integrin-expressing breast cancer cells were significantly higher compared with a control AGD peptide. We have also demonstrated that this uptake was effectively blocked by an excess of free unlabeled peptide. These novel αvβ3 integrin-binding peptides could provide a basis for a new and potentially safer generation of molecular imaging agents for the early diagnosis of cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1763. doi:10.1158/1538-7445.AM2011-1763
Abstract 1765: Inhibition of Notch signaling by a Notch1 monoclonal antibody induces robust anti-tumor efficacy in T-cell acute lymphoblastic leukemia and breast cancer
Authors: Wei Ping , Qiu Ming , Peng Qinghai , Lippincott John , Zachwieja Joseph , Kraynov Eugenia , Wu Aidong , Han Bora , Stone Donna , Zhai Wenwu , Rymer Isha , Yang Jennifer , Gajiwala Ketan , Yu Xiu , Gao Yijie , Tchistiakov Lioudmila , Ma Wenxue , Jamieson Catriona H. M. , Los Gerrit , Greenberg Norman , Li Kang 
Published: August 2014

Abstract
Notch signaling is deregulated in T-cell acute lymphoblastic leukemia (T-ALL) and advanced solid tumors, making it an attractive target for oncology drug development.
In this present report, we describe a novel mouse monoclonal antibody, Notch1 mAb, that specifically binds to the negative regulatory region (NRR) of human Notch1 receptor. Using a T-ALL cell line, HPB-ALL, that harbors mutations in Notch1 heterodimerization and PEST domains, we demonstrated that Notch1 mAb blocked Notch signaling by reduction of Notch1 intracellular domain (NICD) and down-regulation of Notch target genes, Hes-1 and cMyc. Notch1 mAb caused cell growth inhibition of HPB-ALL and several other T-ALL cell lines, via induction of cell cycle arrest and apoptosis. Notch1 mAb treatment resulted in robust NICD reduction and marked antitumor efficacy in HBP-ALL xenograft model. Additional mechanism-of-action studies revealed inhibition of tumor cell proliferation and induction of apoptosis in HPB-ALL tumors, suggesting that the anti-tumor activity of Notch1 mAb may be mediated by its direct effects on tumor cell growth or survival. Furthermore, this antibody led to a significant reduction in leukemia progenitor cells (LPCs) baring NOTCH1 mutation in bioluminescent humanized T-ALL LPC mouse models. In addition to its inhibitory effect on mutant Notch1, Notch1 mAb also displayed robust neutralization activity on wild type Notch1 and caused tumor growth inhibition in breast cancer models MDA-MB-231 and MX-1 by targeting the wild type receptor in these tumor types. Interestingly, using a gamma secretase inhibitor PF-03084014, we showed that Notch1 mAb and PF-03084014 elicited similar degree of biology responses in HPB-ALL cells. Our results indicate that antibodies that bind to NRR can act as potent inhibitors of Notch1 signaling and provide opportunities for development of novel cancer therapeutics for T-ALL and solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1765. doi:10.1158/1538-7445.AM2011-1765
Abstract 177: Disruption of the MDM2-p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin resistant human testicular carcinoma cells via the Fas/FasL pathway
Authors: de Jong Steven , Koster Roelof , Timmer-Bosscha Hetty , Bischoff Rainer , Gietema Jourik 
Published: August 2014

Abstract
A major role for p53 in the response and execution of apoptosis after chemotherapy has been described for many cancers. Although testicular cancer (TC) often express high levels of p53 and almost no TP53 mutations are found, resistance to chemotherapy is still observed in a subgroup of TC patients. Therefore, the involvement of wild-type p53 in cisplatin sensitivity and resistance of human TC is not clear. In the present study, we demonstrate that in resistant human TC cells (Tera2-CP, Scha, 2102EP) p53 resides in a complex with murine double minute 2 (MDM2) even at higher cisplatin concentrations compared to cisplatin sensitive human TC cells (Tera2). Hyper-activation of the p53 pathway using the MDM2 antagonist Nutlin-3 in TC cells leads to nuclear localization of p53 and effective apoptosis induction as single agent. Targeting MDM2 with short interfering RNA extremely sensitizes TC cells in a similar way. The observed effects are dependent on the presence of wild-type p53, since mutant p53 expressing TC cells (NCCIT) or wild-type p53 suppressed TC cells are resistant to Nutlin-3. Specifically, we show that the Fas death receptor pathway, i.e. enhanced Fas expression (3-fold) and the induction of Fas/FasL interactions, plays an important role in MDM2 antagonist-induced apoptosis in TC cells as demonstrated by using FasL blocking antibodies and FasL small interfering RNA. Importantly, we have identified a similar mechanism in Hodgkin lymphoma cells (KM-H2 and L540) and acute myeloid leukaemia cells (MOLM-13), suggesting a common profile for Nutlin-3-induced apoptosis, which involves the Fas death receptor pathway. Finally, we combined nutlin-3 with cisplatin, which strongly sensitized TC cells, including cisplatin-resistant TC cells, to apoptosis via Fas pathway activation and reduced cell survival more than 8-fold. These results indicate that targeting the p53/MDM2 axis, in combination with standard treatment, appears to be a powerful strategy to pursue in cisplatin-resistant or -refractory testicular cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 177. doi:10.1158/1538-7445.AM2011-177