bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1194: IDH1 mutant inhibitor induces cellular differentiation and offers a combination benefit with Ara-C in a primary human Idh1 mutant AML xenograft model
Authors: Ellwood-Yen Kate , Chen Yue , Wang Fang , Lemieux Rene , Popovici-Muller Janeta , Yang Hua , Straley Kimberly , Choe Sung , Dorsch Marion , Agresta Sam , Schenkein David , Biller Scott , Su Michael 
Published: May 2015

Abstract
Somatic point mutations in isocitrate dehydrogenase 1/2 have a gain-of-function neomorphic activity that converts alpha-ketoglutarate to the oncometabolite, R (-)-2-hydroxyglutarate (2HG). Prospective studies of AML patients carrying IDH mutations have shown that intracellular concentrations of 2HG can range from 3-10 mM. This abnormal level of 2HG results in dysregulation of alpha-ketoglutarate dependent enzymes leading to alterations in the epigenetic state of hematopoietic progenitor/stem cells and functionally blocks their ability to fully differentiate.
We have developed a potent and selective, orally available IDH1 mutant inhibitor AGI-14100, that is able to reduce intracellular 2HG concentrations to baseline levels found in wildtype cells.
We next treated a primary human IDH1 (R132H)/FLT3-ITD mutant xenograft model with AGI-14100 either alone or in combination with Ara-c. In these studies, AGI-14100 alone significantly decreased tumor burden in the peripheral blood after 1 month of continuous BID treatment. In combination with a short-term, low-dose course of Ara-C, we also observed a decrease in the bone marrow tumor burden that was better than either treatment alone. Furthermore, this response was sustainable for &gt;3 weeks even after dosing of both drugs had been terminated. Taken together, these data suggest that inhibition of mutant IDH1with AGI-14100 and low dose Ara-c could provide a combination benefit for patients with AML.
Citation Format: Kate Ellwood-Yen, Yue Chen, Fang Wang, Rene Lemieux, Janeta Popovici-Muller, Hua Yang, Kimberly Straley, Sung Choe, Marion Dorsch, Sam Agresta, David Schenkein, Scott Biller, Michael Su. IDH1 mutant inhibitor induces cellular differentiation and offers a combination benefit with Ara-C in a primary human Idh1 mutant AML xenograft model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1194. doi:10.1158/1538-7445.AM2014-1194
Abstract 1199: Isolation and characterization of human breast epithelial cells
Authors: Hoynowski Steven 
Published: May 2015

Abstract
Breast cancer is one of the most common cancers among women in the United States and it is the second leading cause of cancer deaths in this population. Roughly 232,000 women in the U.S. were diagnosed with malignant breast cancer in 2013 and approximately 40,000 of these patients will die. The majority of breast cancers originate in the lobular or ductal cells of the milk-producing glands. In these structures, there are two main cell types: the inner luminal cells, which are surrounded by basal myoepithelium. These cells are structurally distinct and are the precursors to variable forms of breast cancer. As such, it is important to study them not only separately but also together. Current methods for culturing human mammary epithelial cells select for those of a basal phenotype. Isolation of pure basal and luminal cell populations was accomplished by using antibody-linked magnetic beads to isolate essentially pure populations of both basal (CALLA/CD10) and luminal mammary (MUC-1/CD227) epithelial cells from organoid explant cultures. Organoids were isolated and plated on collagen I coated flasks in either DFCI (basal) or MBCM (luminal) media and cultured at 37°C in 5% CO2 to induce cell migration. The media was replenished every 2 - 3 days until the cells reached confluence. Cultured cells were harvested and immunopurified using a CALLA/CD10 or MUC-1/CD227 antibody and magnetic beads. Positively selected cells were seeded in tissue culture treated flasks and propagated with medium exchange every 2 - 3 days. Each cell population was analyzed using flow cytometry to determine their purity. The DFCI/CD10 cells were over 98% CD10 positive with very little MUC1 reactivity, suggesting that they are an essentially pure basal epithelial cell population. The cells isolated using MBCM/MUC1 appear to be a mixed population with 86% MUC1 positive luminal cells and the remainder being CD10 positive basal cells. A second round of immunopurification resulted in an isolated cell population that was greater than 95% MUC1 positive, suggesting a pure luminal epithelial cell population. This procedure has been used on several organoid preparations and has generated high cell yields in addition to high cell purity. These isolated cell types can now be tested individually for drug sensitivity.
Citation Format: Steven Hoynowski. Isolation and characterization of human breast epithelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1199. doi:10.1158/1538-7445.AM2014-1199
Abstract 1217: Development of a spontaneous in vivo cachexia model using the Champions TumorGraft™ platform
Authors: Anderson Nathan , Khor Tin , Feldhaus Andrew , Gatling Andreya , Olson Katie , Latham John , Sidransky David , Bruckheimer Elizabeth M. 
Published: May 2015

Abstract
Cachexia is present in the majority of patients with advanced cancer progression and is not reversible through nutritional supplementation, leading to loss of skeletal muscle and adipose tissue. There are a lack of quality pre-clinical models for cachexia research. Previously, Champions Oncology reported a mouse cachexia model derived from a primary human renal cell carcinoma tumor implanted in immunocompromised mice. This model, CTG-0804, was developed using the innovative Champions TumorGraft™ platform, which preserves the biological properties of the original human tumor. The Champions TumorGraft platform demonstrated dramatic weight loss in these mice as the tumor grew. Plasma from these mice also showed elevated levels of human IL-6. We have now further characterized this TumorGraft model by evaluating standard of care (SOC) agents for renal cell carcinoma and anti-IL-6 compounds to determine the mechanism of cachexia. The SOC evaluation revealed that sorafenib, sunitinib, temsirolimus and bevacizumab as single agents provided a survival advantage by inhibiting tumor growth and preventing weight loss in these mice. Blockade of human IL-6 with tocilizumab or ALD518 did not inhibit tumor growth and weight loss still occurred, demonstrating the possibility of other pathways involved in the cachexia mechanism. In addition, the SOC data for sunitinib showed significant tumor growth inhibition, but no regression at the study end point. This correlated with the clinical profile, where sunitinib could not prevent metastasis and the patient eventually progressed. The TumorGraft model was molecularly characterized and mutation analysis revealed a KIT V530I mutation. This mutation has been reported in extra-abdominal aggressive fibromatosis (desmoid tumor) and acute myeloid leukemia patients that have responded to c-kit targeting therapies, such as imatanib and dasatinib. Further characterization of this TumorGraft is ongoing to include additional bioinformatics using gene expression and mutation pathway analyses. In summary, we have continued development of this cachexia model using the Champions TumorGraft platform, along with molecular evaluation, to produce a robust and well-characterized approach for cachexia investigation which can also be applied to other areas of drug development and cancer research.
Citation Format: Nathan Anderson, Tin Khor, Andrew Feldhaus, Andreya Gatling, Katie Olson, John Latham, David Sidransky, Elizabeth M. Bruckheimer. Development of a spontaneous in vivo cachexia model using the Champions TumorGraft™ platform. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1217. doi:10.1158/1538-7445.AM2014-1217
Abstract 122: 15-lipoxygenase-1 regulation of HIF-1a and angiogenesis
Authors: Wu Yuanqing , Mao Fei , Zuo Xiangsheng , Moussalli Micheline J. , Elias Elias , Shureiqi Imad 
Published: May 2015

Abstract
Expression of 15-lipoxygenase-1(15-LOX-1) is down-regulated in colon and other major human cancer cells. 15-LOX-1 re-expression in cancer cells suppresses colonic tumorigenesis. We recently reported that targeted transgenic 15-LOX-1 expression in murine intestine suppresses colonic tumorigenesis. Nevertheless, the role of 15-LOX-1 loss of expression in cancer epithelial cells in metastases continues to be debated. Hypoxia-inducible factor 1-alpha (HIF-1a) is a transcriptional master regulator that enhances cancer cell survival under hypoxia and the development of various metastatic mechanisms (e.g. upregulation of VEGF to promote angiogenesis). We therefore examined the effects of 15-LOX-1 expression restoration in colon cancer cells on cell survival, migration and invasion, angiogenesis, and HIF-1a expression and stability under hypoxia.
We found that 15-LOX-1 re-expression in colon cancer cells inhibited colon cancer cell survival, migration and invasion, VEGF expression, HUVEC cell tubular formation, and HIF-1a protein stability under hypoxia. These findings demonstrate that the loss of 15-LOX-1 significantly contribute to the ability of colon cancer cells to acquire metastasis promoting abilities by increasing a HIF-1 protein stability to up-regulate VEGF production of cancer cells and subsequently angiogenesis. Thus, therapeutic targeting 15-LOX-1 ubiquitous loss in cancer cells has the potential to be used to suppress tumor metastases.
Citation Format: Yuanqing Wu, Fei Mao, Xiangsheng Zuo, Micheline J. Moussalli, Elias Elias, Imad Shureiqi. 15-lipoxygenase-1 regulation of HIF-1a and angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 122. doi:10.1158/1538-7445.AM2014-122
Abstract 1226: Breast and ovarian cancer PDXs show excellent conservation of original features but are genetically plastic
Authors: Theillet Charles G. , Manoir Stanislas du , Orsetti Beatrice 
Published: May 2015

Abstract
Patient derived xenografts (PDXs) are increasingly appreciated models in cancer research and preclinical testing. We have established a collection of 20 breast and 20 ovarian cancer PDXs and investigated their biological and clinical characteristics, as well as their genetic stability. Take rates were distinctly lower with breast (16%) compared to ovarian cancers (85%). The majority of our breast PDX originated from triple negative (14/20), grade 3 tumors (18/20) and breast cancers with reduced recurrence free survival. Interestingly, we stabilized 1 ER-/HER2+ and 5 ER+ PDX. Overall we showed that breast tumors that gave rise to a PDX (take) showed significantly different expression profiles compared to tumors which did not take. Ovarian PDX originated all from high grade cancers, but comprised all major ovarian cancer histotypes (mucinous, clear cell, carcinosarcoma and serous carcinoma).
Breast and ovarian PDXs faithfully recapitulated the histological features of their tumors of origin. The excellent conservation of original transcriptome characteristics was a further proof of the phenotypic stability shown by our PDX models. Noticeably, all grafts from ER+ cancers expressed ER at the RNA and protein levels. Array-CGH analysis revealed that PDXs presented a high degree of conservation of the Copy Number Change (CNC) profiles of the tumors they stemmed from and profiles from PDXs established from the same original tumor were highly overlapping. We determined that CNC representing up to 6% of the genome corresponded to oligoclonal events present in the tumor of origin that got gradually lost in the PDXs along passages. Furthermore, we noted that a minority of the PDXs presented a fraction of de novo occurring events representing up to 10% of the genome, suggesting limited levels of ongoing genetic instability.
In conclusion, our data show that breast and ovarian cancer PDX are excellent reproductions of the tumors of origin but remain genetically dynamic elements susceptible to drift during sequential passages.
Citation Format: Charles G. Theillet, Stanislas du Manoir, Beatrice Orsetti. Breast and ovarian cancer PDXs show excellent conservation of original features but are genetically plastic. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1226. doi:10.1158/1538-7445.AM2014-1226
Abstract 1231: In vitro anticancer activity of imidazo-acridinone (HKH40A) in panels of human patient-derived tumor xenografts (PDXs) and human leukemia and lymphoma cell lines
Authors: Fiebig Heinz H. , Maier Armin , Kelter Gerhard , Vuaroqueaux Vincent , Hariprakasha Humcha K. , Michejda Christopher 
Published: May 2015

Abstract
HKH40A is a synthetic, DNA-intercalating (Kosakowska-Cholody et al., 2009) anticancer agent consisting of an imidazo-acridinone linked to a 1,8-naphthalimide moiety via a 1,4-dipropylpiperazine linker. It displayed strong inhibitory activity in the NCI-60 tumor cell line panel in vitro with an IC50 of about 1 nM in selected tumor cell lines (Hariprakasha et al. 2007). In addition, anticancer activity was observed in hepatoma models both in vitro and in vivo. We have investigated the in vitro anticancer activity of HKH40A in 3D cultures, using panels of 206 PDXs and 11 human leukemia and lymphoma cell lines. The 3D clonogenic assay was performed in a 96 well format using a metabolic readout as an equivalent for colony formation. PDXs and hematologic cell lines were propagated in immunedeficient mice.
HKH40A proved to be very potent with a mean IC50 of 6 nM and a mean IC70 of 12 nM. Overall, the hematological cell lines were more sensitive than the solid tumor models. Selective activity (definition: IC50 &lt; 1/3 of mean IC50) was seen in 4 out of 6 acute myeloid leukaemias (AMLs), in 1 out of 1 chronic lymphocytic leukemia (CLL) and in 1 out of 3 non-Hodgkin lymphomas (NHLs). Among the solid tumors, pleural mesotheliomas were most sensitive followed by soft tissue sarcomas and anal cancer. Selective activity was observed in a subset of 8 out of 30 colon cancer models, which presented IC50 values &lt; 1/3 of the mean IC50 of all tumors. The drug sensitivity data will be correlated to mutational and transcriptomic (Whole Exome Sequencing and Affymetrix HG-U133 plus 2.0 array profiles) characteristics of the PDXs to identify predictive biomarkers of drug response and resistance.
Overall, HKH40A is a novel imidazo-acridinone with high in vitro activity mainly in AMLs and NHLs as well as in pleural mesotheliomas, soft tissue sarcomas and in a subset of colon cancer models. The identification of predictive biomarkers is ongoing.
*Deceased during an NCI retreat
Citation Format: Heinz H. Fiebig, Armin Maier, Gerhard Kelter, Vincent Vuaroqueaux, Humcha K. Hariprakasha, Christopher Michejda. In vitro anticancer activity of imidazo-acridinone (HKH40A) in panels of human patient-derived tumor xenografts (PDXs) and human leukemia and lymphoma cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1231. doi:10.1158/1538-7445.AM2014-1231
Abstract 1232: Antiproliferative, antioxidant and antiapoptotic effect of rhamnetin in human prostate cancer cells
Authors: Oak Christine , Bhaskaran Natarajan , Gupta Sanjay , Shukla Sanjeev 
Published: May 2015

Abstract
Persistent oxidative stress due to generation of reactive oxygen species (ROS) has been associated with malignancy and cancer progression. Using a panel of human prostate cancer cells, we observed increased production of intracellular ROS, compared to normal human prostate epithelial cells, accompanied by elevated expression of antioxidant enzymes viz. superoxide dismutase, catalase, peroxiredoxin-1 and thioredoxin that may be a likely mechanism to endure increased oxidative stress. There is a need for novel antioxidant agent that can effectively suppress the generation of increased ROS in cancer cells. Rhamnetin (3,5,3,4-tetrahydroxy-7-methoxyflavone), remains highest on oxygen radical absorbance capacity scale, however its anti-proliferative activities has not been assessed. Rhamnetin is an O-methylated flavonol, abundantly present in cloves, sweet annie, annual wormwood, green vegetables and orchard grass. Previous studies (Shukla et al. Proc. Amer. Assoc. Cancer Res. 102: 5576, 2011) using androgen-responsive human prostate cancer LNCaP and androgen-refractory PC-3 cells, we have demonstrated that rhamnetin possess anticancer activity, induces apoptosis, and inhibits cancer cell growth. In the present study we assessed the antioxidant and anti-proliferative ability of rhmanetin in prostate cancer. Treatment of LNCaP and PC-3 cells with 100μM paraquat, an oxidative stress-inducing agent, induced cellular proliferation in both these cells. Treatment of cells with 5-80μM rhamnetin significantly decreased paraquat-induced ROS production and inhibited cell proliferation in dose-dependent manner. Similar effects were noted with the addition of recombinant Klotho protein to these cells, which is known to offer resistance to oxidative stress at the cellular level. Rhamnetin treatment also increased Klotho protein levels in both cell lines, along with increase in the expression of p53 and p21/waf1. Furthermore, rhamnetin treatment resulted in the increased expression of caspase-3, caspase-9 causing induction of apoptosis, which may be one of the protective mechanism(s) to decrease cell proliferation and enhance resistance to oxidative stress in cancer cells. Taken together, these results demonstrate that rhamnetin acts as a potent antioxidant agent, reduces intracellular ROS levels, increases Klotho protein expression, induces apoptosis in prostate cancer cells, which may have a significant role in the inhibition of prostate cancer progression.
Citation Format: Christine Oak, Natarajan Bhaskaran, Sanjay Gupta, Sanjeev Shukla. Antiproliferative, antioxidant and antiapoptotic effect of rhamnetin in human prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1232. doi:10.1158/1538-7445.AM2014-1232
Abstract 1238: Apigenin suppresses inhibitor of apoptosis family protein expression and disrupts Ku70-bax interaction in prostate cancer cells in culture and in vivo
Authors: Shukla Sanjeev , Fu Pingfu , Gupta Sanjay 
Published: May 2015

Abstract
Apigenin (4′,5,7-trihydroxyflavone), an anticancer agent, selective toxic to cancer cells induces cell cycle arrest and apoptosis. The molecular mechanism(s) of this effect has not been fully elucidated. It is well known that dysfunction of the apoptotic pathway confers apoptosis resistance through inhibitor of apoptosis family protein (IAP) and deregulation of Bax/Bcl2 pathway in prostate cancer cells. In the present study we provide evidence for the mechanisms of apoptosis induction by apigenin. Treatment of androgen-refractory human prostate cancer PC-3 and DU145 cells with 5-40µM apigenin resulted in dose-dependent suppression of XIAP, c-IAP1, c-IAP2 and survivin protein levels. Apigenin treatment (20µM) resulted in significant decrease in cell viability and apoptosis induction with the release of cytochrome C in time-dependent manner. These effects of apigenin were accompanied by decrease in Bcl-xL and Bcl-2 and increase in the active form of Bax protein. The apigenin-mediated increase in Bax was due to dissociation of Bax from Ku70 which is essential for apoptotic activity of Bax. Apigenin treatment resulted in the inhibition of class I histone deacetylases and HDAC1 protein expression, thereby increasing the acetylation of Ku70 and the dissociation of Bax resulting in apoptosis of cancer cells. Furthermore, apigenin significantly reduced HDAC1 occupancy at the XIAP promoter, suggesting that histone deacetylation might be critical for XIAP downregulation. In in vivo studies, per-oral intake of apigenin at doses of 20 and 50µg/mouse/day, two weeks after PC-3 cell implantation, continued for 8 weeks resulted in significant inhibition of tumor volume by 32.5% and 51.3% (P&lt;0.001) and decrease in wet weight tumor by 33.3% and 55.1% (P&lt;0.001), respectively. The animals did not exhibit any signs of toxicity or reduced food consumption. Compared to vehicle-treated controls, induction of apoptosis was significantly increased in tumor xenografts in apigenin fed mice (P&lt;0.001) along with marked reduction in the protein expression of XIAP and survivin in PC-3 tumor xenografts. A dose-dependent decrease in HDAC1 expression, increase in Bax and PARP cleavage was observed in apigenin-treated mice. Taken together, these results suggest that apigenin targets IAP proteins and Ku70-Bax interaction in the induction of apoptosis in prostate cancer cells and in athymic nude mouse xenograft model endorsing its in vivo efficacy.
Citation Format: Sanjeev Shukla, Pingfu Fu, Sanjay Gupta. Apigenin suppresses inhibitor of apoptosis family protein expression and disrupts Ku70-bax interaction in prostate cancer cells in culture and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1238. doi:10.1158/1538-7445.AM2014-1238