bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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 (&gt;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

Abstract
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

Abstract
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

Abstract
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 &gt;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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.