bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3386: Mechanisms of resistance to enzalutamide in LNCaP models.
Authors: Loriot Yohann , Wyatt Alexander , Al Nakouzi Nader , Beraldi Eliana , Toren Paul , Nip Ka Mun , Gleave Martin , Zoubeidi Amina 
Published: August 2014

Abstract
Background
MDV3100 is a potent androgen receptor (AR) antagonist with activity in castration resistant prostate cancer (CRPC); however, progression to MDV3100-resistant (MDV-R) CRPC frequently occurs with rising serum PSA levels suggesting reactivation of AR pathway. We sought to identify AR-based mechanisms of resistance.
Methods
We treated human CRPC LNCAP-derived xenografts with MDV3100 and assessed androgen receptor (AR) levels and localization as well as genomic alterations versus controls. We also generated by selection MDV3100-R LNCaP-derived sub-lines to study mechanisms of resistance to MDV3100.
Results
Serum and tumoral PSA levels were consistently increased in resistant xenogratfs as compared with sensitive xenografts along with AR nuclear localization. MDV3100 did not induce any new mutation in the DNA binding domain and any AR DNA gene amplification. AR full-length (ARfl) and AR-V7 splicing variant were both highly expressed in RNA sequencing compared to CRPC LNCaP xenografts. However, it was no enrichment of AR-V7 versus ARfl in LNCaP MDV-R xenografts. Interestingly, AR was found in the nucleus and constitutively binding to DNA on androgen response element on PSA enhancer as measured by Chromatin immunoprecipitation in MDV-R cell lines compared to CRPC cell lines. These data were translated by increase of AR responsive genes at both mRNA and protein levels.
Conclusions
MDV-R LNCaP cells exhibited AR overexpression without any significant genomic alterations. While MDV3100 induces both ARfl and AR-V7 levels, no enrichment of AR-V7 was detected. Immunofluorescence, CHIP and qPCR studies suggest that ARfl overexpression remains a significant mechanism of resistance to MDV3100 similar to resistance from chronic androgen depletion.
Citation Format: Yohann Loriot, Alexander Wyatt, Nader Al Nakouzi, Eliana Beraldi, Paul Toren, Ka Mun Nip, Martin Gleave, Amina Zoubeidi. Mechanisms of resistance to enzalutamide in LNCaP models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3386. doi:10.1158/1538-7445.AM2013-3386
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 340: Squamous cell carcinoma in the mouse: A novel, rapidly growing, syngeneic orthotopic lung tumor model .
Authors: Giladi Moshe , Schneiderman Rosa S. , Porat Yaara , Munster Mijal , Itzhaki Aviran , Mordechovich Daniel , Cahal Shay , Kirson Eilon D. , Palti Yoram 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer death and accounts for 28% of all cancer death in the United States. About 80% of lung cancers are non-small cell lung carcinoma (NSCLC) of which over 20% are Squamous Cells Carcinoma (SCC). The currently available therapies, for NSCLC, are less effective against squamous cells carcinoma. While there are several established in-vivo models for lung adenoma and adenocarcinomas, there are no rapidly growing, syngeneic, orthotopic tumor models for lung SCC. The goal of the present study was to develop such a model in order to facilitate research of new treatments against SCC.
Murine SCC (KLN205) cells were mixed with matrigel and injected directly into the lungs of C57BL/6 and DBA-2 mice using the same methodology applied during the induction of Lewis Lung Carcinoma orthotopic tumors. Injection of KLN205 resulted in development of highly variable tumors with an average size of 24mm3 in DBA-2 mice after 3 weeks from inoculation. No sustainable tumors were seen in C57BL/6 mice. Cells derived from DBA/2 lung tumors (referred to as KLN205-T1) were subcultured for over 10 generations and their cytological characteristics were determined. A second round of orthotopic tumor injections using KLN205-T1 cells resulted in the formation of reproducible, solitary and localized tumors in the lungs of over 85% of the DBA/2 mice but not in C57BL/6 mice. The tumors increased in average size from 20 to 40 to 80 mm3 between days 10, 13 and 16. Comparable results were obtained while imaging tumor progression using MRI. Metastases were observed only in thoracic lymph nodes which were probably a result of cells escaping the lung during tumor injection. Immunostaining of KLN205-T1 tumors with p63 and cytokeratin 5/6 demonstrated similar characteristics as described for human SCC.
Cisplatin and paclitaxel were tested in this KLN205-T1 tumor model demonstrating its potential use for testing treatment options for SCC lung cancer. The effect of Tumor Treating Fields (TTFields) therapy with and without paclitaxel or cisplatin is currently being tested in this novel tumor model.
Citation Format: Moshe Giladi, Rosa S. Schneiderman, Yaara Porat, Mijal Munster, Aviran Itzhaki, Daniel Mordechovich, Shay Cahal, Eilon D. Kirson, Yoram Palti. Squamous cell carcinoma in the mouse: A novel, rapidly growing, syngeneic orthotopic lung tumor model . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 340. doi:10.1158/1538-7445.AM2013-340
Abstract 3417: Increased anticancer effect of combining Wee1 (MK1775) and Chk1 (AZD7762) inhibitors in malignant melanoma cell lines.
Authors: Magnussen Gry I. , Florenes Vivi A. , Engesæter Birgit , Emilsen Elisabeth 
Published: August 2014

Abstract
Malignant melanoma is one of the most increasing forms of cancer worldwide, in addition to being notoriously resistant to therapy. Despite recent advances, there are no curative treatments once the cancer has spread (stage IV); there is thus a precarious need to find new and better treatment alternatives. Unlike normal cells, the majority of cancer cells have a defective G1/S DNA-damage checkpoint and are therefore more dependent on the G2/M checkpoint when DNA damages arise. Central in regulating the latter checkpoint is Wee1, a kinase which may stop the cell cycle by adding a negative phosphorylation on CDK1. Wee1 is regulated by Chk1 which upon DNA damage can also inhibit the complimentary counterpart of Wee1; CDC25. In recent studies, Wee1 and Chk1 have additionally been indicated as key players in regulating DNA replication in S-phase. We have previously reported that increased Wee1 protein expression was associated with malignancy in melanoma tumour samples, and that siWee1 transfection led to reduced viability in melanoma cell lines. In the present study we have combined inhibitors of Wee1 (MK1775) and Chk1 (AZD7762) in a panel consisting of both metastatic melanoma- and normal cells, including a Plexxikon resistant melanoma cell line (MelJR post3.3). We found that the combination synergistically reduced the amount of viable cells in the melanoma cell lines (∼50-80% reduction), whilst only having very moderate effect (∼10% reduction) in the normal cells. Interestingly, the reduction in number of viable cells was found in both p53WT and p53Mut cell lines, indicating that the p53 status do not predict the response to such treatment. Furthermore, combinational treatment with the inhibitors caused increased cleavage of PARP and caspases, indicative of apoptosis, as compared to MK1775 or AZD7762 treatment alone. The combination also caused a marked increase in DNA double-strand breaks, as demonstrated by augmented levels of γ-H2AX (predominantly found in S-phase cells). In line with this, preliminary results from melanoma cells grown as spheroids, revealed the same tendency, with approximately 50% reduction in spheroid volume when combining the inhibitors. In vivo experiments using melanoma cells grown in SCID mice are currently ongoing. In conclusion, our results indicate a potential new role for inhibitors of Wee1 and Chk1 in treatment of malignant melanoma.
Citation Format: Gry I. Magnussen, Vivi A. Florenes, Birgit Engesæter, Elisabeth Emilsen. Increased anticancer effect of combining Wee1 (MK1775) and Chk1 (AZD7762) inhibitors in malignant melanoma cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3417. doi:10.1158/1538-7445.AM2013-3417
Abstract 343: Transgenic C57/BL6 x Balb/c F1 mice expressing mitochondrial targeted catalase have less spontaneous lung cancer.
Authors: Pettan-Brewer Christina , Morton John , Treuting Piper , Ladiges Warren 
Published: August 2014

Abstract
Human lung cancer is a major cause of morbidity and among the most frequent and deadly malignancies throughout the world. Discrepancies in classification and characterization approaches have resulted in confusions and difficulties in the comparative pathology of mouse and human lung tumors. Currently, there are very few mouse models of spontaneous lung cancer that are available to validate human lung carcinogenesis. Male C57/BL6 x Balb/c F1 (CB6 F1) mice have a high incidence of pulmonary adenocarcinoma that increases with increasing age. For example, 28 month old males have a 52 per cent incidence, while 32 month old males have close to 80 per cent incidence. In order to determine if these tumors were driven by mitochondrial reactive oxygen species (ROS), we crossed wild type Balb/c females with transgenic males on the C57/BL6 background expressing human catalase targeted to mitochondria (mCAT). The offspring were followed through the end of their lifespan when tissues were collected for histological evaluation. Of 65 males examined, we found that those expressing mCAT had a 29 per cent incidence of lung tumors, while wild type littermates had an incidence of 71 per cent (p ≤ 0.01). The presence of mCAT had a similar effect on the incidence of lung tumors in females although the overall incidence was less than in males. Histologically, lung tumors in wild type mice had higher grade malignancy than lung tumors in mice expressing mCAT suggesting that ROS generated by mitochondria might be playing a role in driving this type of cancer in mice. We conclude that spontaneous lung adenocarcinoma in old CB6 F1 mice could be a useful model to study the anti-tumor effect of mitochondrial-targeted anti-oxidants for intervention of human lung cancer.
Citation Format: Christina Pettan-Brewer, John Morton, Piper Treuting, Warren Ladiges. Transgenic C57/BL6 x Balb/c F1 mice expressing mitochondrial targeted catalase have less spontaneous lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 343. doi:10.1158/1538-7445.AM2013-343
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3443: Novel small molecule CRM1 inhibitors induce nuclear accumulation of p53, phosphorylated ERK and apoptosis in human melanoma cells.
Authors: Yang Jennifer , Bill Matthew A. , Young Gregory S. , Landesman Yosef , Shacham Sharon , Kauffman Michael , Senapedis William , Kashyap Trinayan , Saint-Martin Jean-Richard , Lesinski Gregory 
Published: August 2014

Abstract
Inhibition of nuclear export can promote re-activation of tumor suppressor proteins (TSPs) by restoring them to the nucleus. CRM1 (chromosome region maintenance 1, XPO1) is the exclusive exporter of many TSPs. We hypothesized that CRM1 inhibition can be used as a therapeutic target in melanoma. The growth inhibitory and pro-apoptotic effects of KPT-185, KPT-276 and KPT-330, potent, small molecule, selective inhibitors of nuclear export (SINEs) were evaluated in a panel of human metastatic melanoma cell lines using an MTS assay and Annexin V/PI staining, respectively. The weak CRM1 inhibitor, KPT-185 trans-isomer, and DMSO vehicle were controls in all assays. CRM1 protein was expressed in melanoma cell lines regardless of molecular profile (BRAF, NRAS, TP53) as determined by immunoblot. SINEs inhibited cell growth in a concentration-dependent manner and induced apoptosis at nanomolar concentrations (range=139.7nM - 2.41μM). Both BRAF wild type (WT) and BRAF V600E mutant lines were sensitive to apoptosis by SINE, but BRAF V600E lines had an 8.8-fold lower IC50s as compared to BRAF (WT) lines (p=0.018). The cytostatic and pro-apoptotic effects of CRM1 inhibition were associated with nuclear accumulation of p53, and p21 induction in A375 and CHL-1 melanoma cell lines with functional p53 at time points prior to apoptosis, while pERK accumulated in melanoma cells regardless of p53 status. In pharmacokinetic studies in mice, KPT-276 and KPT-330 showed &gt;50% oral bioavailability with Cmax &gt;5μM. Mice bearing either A375 (BRAF V600E) or CHL-1 (BRAF WT) melanoma xenografts were given KPT-276 or KPT-330 SINE by oral gavage. A375 xenografts (p&lt;0.0001 for both drugs) and CHL-1 xenografts (p=0.0087 and 0.0002 respectively) showed significant growth inhibition as compared to vehicle-treated controls with good tolerability. KPT-330 is currently in Phase 1 clinical trials in patients with advanced cancers including melanoma as the first orally bioavailable, SINE CRM1 antagonist.
Citation Format: Jennifer Yang, Matthew A. Bill, Gregory S. Young, Yosef Landesman, Sharon Shacham, Michael Kauffman, William Senapedis, Trinayan Kashyap, Jean-Richard Saint-Martin, Gregory Lesinski. Novel small molecule CRM1 inhibitors induce nuclear accumulation of p53, phosphorylated ERK and apoptosis in human melanoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3443. doi:10.1158/1538-7445.AM2013-3443
Abstract 3456: Macrophages as independent prognostic factors in small T1 breast cancers.
Authors: Carrio Roberto , Koru-Sengul Tulay , Miao Feng , Gluck Stefan , Lopez Omar , Selman Yamil , Alvarez Consuelo , Milikowski Clara , Gomez Carmen , Jorda Merce , Nadji Mehrad , Torroella-Kouri Marta 
Published: August 2014

Abstract
Breast cancer is the second leading cause of death by cancer in women in the United States. The occurrence of high numbers of macrophages in the tumor stroma has been associated with tumor progression and poor prognosis in breast and other solid malignances. However, macrophage numbers in tumors have not been validated as a prognostic factor in clinical practice. The present analysis was designed as a pilot study aimed at determining whether the presence of CD68+ macrophages is an independent prognostic factor in small T1 ER+ breast cancers across three different ethnic groups, i.e. African American, Latinas and Caucasian women. A retrospective pilot analysis of 30 T1 breast cancers cases encompassing these three ethnic groups was carried out. African
American and Latina women present with less incidence but more aggressive breast cancer disease and therefore proportionally higher death rates. Using immunohistochemistry, we sought to find out whether there was any association between the presence and density of CD68+ macrophages and standard prognostic markers with overall survival in these groups. Our data showed that overall survival did not differ significantly for the occurrence or density of CD68+ macrophages in T1 ER+ tumors. There were also no significant differences in overall survival for the occurrence of CD68+ macrophages across ethnicities, although macrophage numbers were significantly higher in tumors from African American and Latinas than in Caucasian patients. Interestingly but not surprisingly, the absence of PR associated very strongly with decreased overall survival. This pilot project shows that CD68+ macrophages are not pivotal in determining tumor prognosis in early T1 breast cancers. New studies are presently being conducted to assess the value of different macrophage markers and macrophage activation profiles as prognostic factors in breast cancers of different clinical stages, using a larger number of patients among these three different ethnicities.
Citation Format: Roberto Carrio, Tulay Koru-Sengul, Feng Miao, Stefan Gluck, Omar Lopez, Yamil Selman, Consuelo Alvarez, Clara Milikowski, Carmen Gomez, Merce Jorda, Mehrad Nadji, Marta Torroella-Kouri. Macrophages as independent prognostic factors in small T1 breast cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3456. doi:10.1158/1538-7445.AM2013-3456
Abstract 3484: CTC enumeration and molecular characterization in a Phase 1 study of IGF-1 and IGF-2 inhibition by MEDI-573.
Authors: Chen Xiaoru , Shi Xiaoqing (Sarah) , Bao Haifeng , LaVallee Theresa M. , Mendel Dirk B. , Burke Patricia A. 
Published: August 2014

Abstract
MEDI-573 selectively binds to human insulin-like growth factor (IGF)-1 and IGF-2 and inhibits ligand-mediated signal transduction via the insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor A isoform (IR-A) pathways, without perturbing glucose homeostasis. As IGF-1, IGF-2, and IGF-1R are overexpressed in bladder cancer, a Phase 1 expansion study including 20 bladder cancer subjects along with 6 additional subjects with other types of cancers from the dose escalation study were included for circulating tumor cell (CTC) analysis as part of a larger 42-subject study (MI-CP184) evaluating PK, safety, and biomarkers. Our objective for the results reported here was to evaluate CTC numbers as a prognostic indicator and as a biomarker of response to MEDI-573 therapy, and to evaluate the expression of IGF-1R on CTC and any correlation with treatment. Subjects in the expansion study were treated with MEDI-573 at 5 mg/Kg weekly (QW) (n=10), 15 mg/Kg QW (n=10), whereas subjects evaluated for CTC in the dose escalation study were treated at 30 or 45 mg/Kg every 3 weeks (Q3W) (n=3 each). CTC collected at screening and pre-dosing each cycle were enumerated and evaluated for IGF-1R expression by CellSearch®. 92% of subjects had at least one CTC at any time during the study and 62.5% had at least one CTC at screening. As has been demonstrated with other tumor types, subjects with ≤3 CTC at screening stayed on study longer than subjects with &gt;3 CTC (2.3 vs. 1.2 months, P=0.0125 [no censoring]). Mean overall survival (OS) was also longer for subjects with ≤3 CTC compared to subjects with &gt;3 CTC (6.37 vs. 2.83 months (P=0.0218, t test), although Kaplan-Myer curves were not different (P=0.0854)). Subjects with decreased numbers of CTC or no change in CTC with treatment stayed on study longer (not significant, P=0.0512, t test) than subjects with increased CTC with treatment (2.95 vs. 1.70 months). 73.3% (11/15) of subjects with positive CTC at screening had at least 1 CTC positive for IGF-1R. In conclusion, our results provide evidence for the utility of CTC as prognostic indicators in a Phase 1 study.
Citation Format: Xiaoru Chen, Xiaoqing (Sarah) Shi, Haifeng Bao, Theresa M. LaVallee, Dirk B. Mendel, Patricia A. Burke. CTC enumeration and molecular characterization in a Phase 1 study of IGF-1 and IGF-2 inhibition by MEDI-573. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3484. doi:10.1158/1538-7445.AM2013-3484
Abstract 3516: AZD1208 PIM kinase inhibitor - Preliminary evidence of target pathway inhibition in Phase I clinical trials of AML.
Authors: McEachern Kristen A. , Cao Yichen , DuPont Rachel , Pablo Lourdes , McCoon Patricia , Cortes Jorge E. , DeAngelo Daniel J. , Minden Mark D. , Hewes Becker , Brown Jeffrey L. , Barrett Carl 
Published: August 2014

Abstract
PIM kinases have been shown to play a key role as downstream effectors of growth factor signalling pathways including Flt3 and the Jak-STAT signalling pathways in AML, NHL and other solid tumors. AZD1208 is a novel, orally bioavailable, highly selective PIM kinase inhibitor with single nanomolar potency against all three PIM kinases and is currently undergoing Phase I testing and dose escalation studies in AML. Here we describe a multiplexed biomarker strategy measuring pBAD, p4EBP1 and p-p70S6K as downstream pharmacodynamic biomarkers for PIM kinase inhibition in clinical trials. Patient bone marrow aspirates and peripheral blood samples were collected pre- and post-AZD1208 treatment in AML patients during the Phase I dose escalation and expansions. Primary patient samples were analyzed for quantitative changes in pBAD, p4EBP1 by NanoPro and MesoScale assay platforms as well as a qualitative evaluation of p-p70S6K and other exploratory endpoints. Preclinical PK-PD modeling data with AZD1208 had suggested that greater than a 50% decrease in the levels of one of these phosphorlyated substrates would be indicative of efficacy and PIM pathway inhibition. Following a single dose of AZD1208 at 120mg, the first dose level, approximately 60-70% inhibition of pBAD, S112 was seen in the bone marrow and peripheral blasts. Taken together, the data presented here provide evidence for single agent AZD1208 activity in AML patients based on quantitative reduction in these biomarkers. Correlations of these biomarker endpoints with Phase I pharmacokinetic data underscore the therapeutic potential of Pim kinase inhibition by AZD1208 for the treatment of AML, and strongly support further investigation of this agent in other indications where PIM signaling may play a role in tumorigenesis and survival.
Citation Format: Kristen A. McEachern, Yichen Cao, Rachel DuPont, Lourdes Pablo, Patricia McCoon, Jorge E. Cortes, Daniel J. DeAngelo, Mark D. Minden, Becker Hewes, Jeffrey L. Brown, Carl Barrett. AZD1208 PIM kinase inhibitor - Preliminary evidence of target pathway inhibition in Phase I clinical trials of AML. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3516. doi:10.1158/1538-7445.AM2013-3516