bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4204: The cellular hierarchy of intestinal tumors
Authors: Yao Ryoji , Noda Tetsuo 
Published: August 2015

Abstract
Activation of the Wnt signaling is the initiating event in the majority of human colorectal cancers. In mouse models, disruption of the tumor suppressor gene, Apc, induces the adenomatous lesion. However, the analyses of initial events in animal models are hampered by difficulties to control the timing and the efficiency of introducing mutations. To overcome this problem, we used three dimensional organoid culture, which contain all epitherial components of intestinal cells with the defined organization of the crypt- and villus-like domains. In vitro 4-hydroxy-tamoxifen (4OHT) treatment of mouse organoids carrying Apc conditional mutation and CreERT2 allele led to the rapid and efficient gene aberration. Gene expression analysis revealed that the change in response to Apc inactivation was strikingly similar to those observed in the animal model. These observations demonstrated that the oragnoid culture is a useful tool to investigate the early cellular and molecular invents upon Apc inactivation.
Recent analyses identified stem cells in normal intestine as well as cancer stem cells of human colorectal cancer. We found that Apc inactivation in the intestinal organoids led to the alteration in their expression profiles in a strikingly similar manner with those in animal models. The expression levels of tested stem cell markers were increased, except Aldh1. Immunofluorescence analysis demonstrated that their elevated epressions were caused by the increase of the stem cell population. Paneth cells, which provide the stem cell niche, consistently resided with the stem cells, indicating the accelerated growth of stem cells was accompanied by the differentiation process of the normal intestine. Notably, Aldh1 was exclusively expressed in the villus-like domains, which were decreased after 4OHT treatment. In the mouse intestine, it was expressed in the villi of normal intestine, and was not detected in the adenomatous lesion. These observations demonstrated that Apc inactivation led to the expansion of crypt-like domains by altering the proliferation and differentiation program of stem cells.
Since the organoids share the features of the early response upon Apc inactivation with mouse models, they allowed detailed investigation of tumorigenesis. We have used the organoid culture system to elucidate the roles of oncogenic mutations as well as to evaluate the potential therapeutic targets.
Citation Format: Ryoji Yao, Tetsuo Noda. The cellular hierarchy of intestinal tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4204. doi:10.1158/1538-7445.AM2015-4204
Abstract 4209: Development of patient-derived xenograft (PDX) models for small cell lung cancer (SCLC) as a preclinical platform for drug development
Authors: Mullins Chelsea , Ricono Jill , Nair Praveen , Mirsaidi Cyrus , Broudy Thomas 
Published: August 2015

Abstract
Small cell lung cancer comprises 15-20% of all lung cancer cases, is very invasive with a high mortality rate. Although SCLC patients respond to chemotherapy, there is a high rate of recurrence with treated patients and those in advanced stage of the disease often have a refractory response to treatment. As such, the need for new treatment modalities is critical. In this work, we describe the development and characterization including histopathology, IHC and mutational analysis of 8 SCLC PDX models established from a collection of &gt;300 small cell lung cancer specimens, many of which come from prior-treated and metastatic patients. We have also evaluated functional response of these models with in vivo pharmacology studies. Our data demonstrates the potential to use these unique PDX models in drug development for treatment of SCLC.
Citation Format: Chelsea Mullins, Jill Ricono, Praveen Nair, Cyrus Mirsaidi, Thomas Broudy. Development of patient-derived xenograft (PDX) models for small cell lung cancer (SCLC) as a preclinical platform for drug development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4209. doi:10.1158/1538-7445.AM2015-4209
Abstract 4210: Patient-derived models of human acute myeloid and lymphoid leukemia in immunocompromised mice for preclinical drug development
Authors: Oswald Eva , Klingner Kerstin , Hammerich Benedikt , Greve Gabriele , Lenhard Dorothee , Pantic Milena , Fiebig Heinz-Herbert , Luebbert Michael , Schüler Julia B. 
Published: August 2015

Abstract
The generation of functional and reproducible in vivo models is a prerequisite for a better understanding of hematological malignancies and for the development of improved therapeutic strategies. Here, we report the establishment of transplantable PDX models of acute myeloid and lymphoid leukemia (AML, ALL) growing subcutaneously (s.c.) as well as in a disseminated fashion in immunocompromised mice.
Bone marrow (BM) and peripheral blood (PB) cells from 25 AML/ALL patients were injected intratibially into NSG or NOG mice (n = 1-9/patient) and in later passages also s.c. in nude mice (n = 1-3/model). Tumor growth was monitored via determination of overall survival, flow cytometry (verification of patient-derived leukemic clones by hCD34, hCD33, hCD38, hHLA-ABC, hCD3, hCD45, mCD45), and, where applicable, by caliper measurement. Engraftment is defined as ≥5% hCD45+ cells in the BM and/or ≥1% hCD45+ cells in PB. Transplantable models (higher or equal passage 2) were tested with the respective standard of care drugs (SoC) mainly Cytarabine and Dexamethasone.
Bone marrow engraftment in passage 1 was observed for 11 out of 25 leukemia models. Four of them could be established as disseminated models in serial passage. No engraftment was detected for nine models during the observation period of at least 95 days while observation for five models is still ongoing. The four established models were further characterized by fluorescence-in-situ-hybridization (FISH) to confirm patient origin. Treatment of mice bearing the models with the SoC drugs cytarabine and dexamethasone significantly prolonged overall survival. Antitumoral activity was consistent with clinical response of the donor patient. One T-ALL and two AMLs were additionally successfully propagated following s.c. injection in nude mice. They showed stable growth behavior and displayed a similar chemo-sensitivity pattern as their disseminated growing counterparts.
In conclusion, we have established a panel of transplantable PDX models of ALL and AML displaying stable and reproducible growth patterns suitable for in vivo efficacy studies. Our results confirm that PDX models of hematological malignancies replicate important clinical characteristics of the disease and are valuable tools for preclinical drug testing.
Citation Format: Eva Oswald, Kerstin Klingner, Benedikt Hammerich, Gabriele Greve, Dorothee Lenhard, Milena Pantic, Heinz-Herbert Fiebig, Michael Luebbert, Julia B. Schüler. Patient-derived models of human acute myeloid and lymphoid leukemia in immunocompromised mice for preclinical drug development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4210. doi:10.1158/1538-7445.AM2015-4210
Abstract 4224: CD133 knockdown sensitizes melanoma to kinase inhibitors
Authors: AbdusSamad Maryam , Gaur Anirudh , Zhou Hengbo , Zapas John L. , Simbulan-Rosenthal Cynthia M. , McCarron Edward C. , Rosenthal Dean S. 
Published: August 2015

Abstract
Melanoma is an aggressive and lethal form of cancer, responsible for 9,710 deaths in the US every year, as indicated by the Surveillance Epidemiology and End Results (SEER) program. Although early stages are surgically treatable, the advanced or metastatic stages are the most fatal, presumably due to resistance to chemotherapy, radiation or other therapies. Refractoriness of metastatic melanoma is due to self-renewal properties of a subpopulation of resistant cells, which may be the same as what have been termed “melanoma initiating cells” (MIC), many of which have been associated with the expression CD133. CD133 (PROM-1) is a 5-transmembrane-glycoprotein that is a cell surface marker for different cancers including late-stage cutaneous melanoma. By magnetic activated cell sorting, we isolated a CD133-positive population derived from a patient harboring a difficult-to-treat NRASQ61R/BRAFWT profile. The MIC were transfected with CD133-specific small-interfering RNA (siRNAs) to deplete CD133 protein levels in cells. Our results show that knocking down CD133 in NRASQ61R/BRAFWT mutant melanoma renders cells more sensitive to clinically employed-MEK/BRAF inhibitors. Thus, specific gene knockdown or small molecule targeting, along with the multikinase inhibitors, may be a high potency therapeutic of late-stage and recurrent melanoma. Analyses of patient-derived melanomas harboring different mutation signatures are currently in progress to determine if CD133 and MIC play broader roles in melanoma chemoresistance.
Citation Format: Maryam AbdusSamad, Anirudh Gaur, Hengbo Zhou, John L. Zapas, Cynthia M. Simbulan-Rosenthal, Edward C. McCarron, Dean S. Rosenthal. CD133 knockdown sensitizes melanoma to kinase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4224. doi:10.1158/1538-7445.AM2015-4224
Abstract 4229: ATP-binding cassette transporter ABCG2/BCRP inhibition sensitizes CD133+ cells to MEK/BRAF inhibitors
Authors: Mohamad Pauzi Abrar 
Published: August 2015

Abstract
Melanoma is a highly aggressive type of skin cancer. Melanoma-initiating cells (MIC) have self-renewal capacity, are highly tumorigenic and have been identified using CD133, a cell surface marker consisting of a 5-transmembrane protein. After magnetic sorting with anti-CD133 beads, we determined that CD133+ populations were more resistant than CD133- cells to MEK/BRAF inhibitors, the latter of which are targeted therapies for melanoma currently in clinical trials. In a microarray study, we found that the ABCG2 transporter is upregulated in the CD133+ MIC subpopulations. ABCG2, also known as breast cancer resistant protein (BCRP), is an ATP-binding cassette (ABC) transporter that facilitates the efflux of xenobiotics at the plasma membrane and is responsible for multidrug resistance in cancer cells. This study therefore aimed to block the ABCG2 transporter using the dual ABCG2/ABCB1 inhibitor elacridar to sensitize the CD133+ subpopulation to MEK/BRAF inhibitors. Three metastatic primary human melanoma cell lines were used to investigate the effects of inhibiting ABCG2 in drug-resistant CD133+ subpopulations. Elacridar was used for in vitro inhibition of ABCG2 prior to addition of single and combination treatments with trametinib (a MEK inhibitor), dabrafenib (a BRAF inhibitor), and mebendazole (an anthelmintic and possibly anticarcinogenic drug). Elacridar sensitized all treatment groups to drug treatment. Combination treatment using both ABCG2 and MEK/BRAF inhibitors at the lowest effective dose could be a potential therapeutic to eliminate the highly aggressive drug-resistant CD133+ MIC subpopulations.
Citation Format: Abrar Mohamad Pauzi. ATP-binding cassette transporter ABCG2/BCRP inhibition sensitizes CD133+ cells to MEK/BRAF inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4229. doi:10.1158/1538-7445.AM2015-4229
Abstract 4230: Targeting lung cancer stem cells through fatty acid metabolism
Authors: Noto Alessia , Pisanu Maria Elena , De Vitis Claudia , Malpicci Debora , Fattore Luigi , Lobello Nadia , Bonacci Barbara , Ciliberto Gennaro , Mancini Rita 
Published: August 2015

Abstract
Distinctive features of CSC are capacity of self renewal, increased resistance to chemotherapy and the ability to form three dimensional non adherent spheroids in appropriate conditions. We have recently demonstrated that cell cultures derived from malignant pleural effusion (MPE’s) of patients with adenocarcinoma of the lung efficiently form spheroids in non-adherent conditions supplemented with growth factors. By expression profiling, we identified 18 genes whose expression is significantly upregulated in lung tumor spheroids versus adherent cultures. Among the upregulated genes we found five genes involved in lipid metabolism. SCD1, the enzyme involved in the conversion of saturated into monounsaturated fatty acids, was one of those strongly upregulated. We demonstrated that SCD1 inhibition leads to lung cancer spheroid collapse and to the selective apoptosis of ALDH+ cells, a marker enriched in cells with stem like properties. In line with these results we demonstrated by cell sorting that ALDH positive cells were more sensitive to SCD1 inhibition than ALDH negative cells and that treatment with an SCD1 inhibitor strongly enhanced sensitivity of spheroids cells to Cisplatin. Furthermore, we observed that SCD1 inhibited spheroids were strongly impaired in their in vivo tumorigenicity. Using public datasets from lung cancer we conducted a bioinformatics analysis demonstrating that the survival rate of patients expressing SCD1-high levels was significantly lower than that of the patients expressing low level in lung adenocarcinoma. Moreover, we found that the correlation of SCD1 and stemness markers (nanog, CD44, CD24) selects the patients with bad prognosis. These results overall, indicate that SCD1 could be considered a prognostic markers for lung adenocarcinoma and a potential target for therapeutic intervention. Our studies are currently directed to dissect the mechanism pathways leading to SCD1 upregulation in lung cancer stem cells.
Citation Format: Alessia Noto, Maria Elena Pisanu, Claudia De Vitis, Debora Malpicci, Luigi Fattore, Nadia Lobello, Barbara Bonacci, Gennaro Ciliberto, Rita Mancini. Targeting lung cancer stem cells through fatty acid metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4230. doi:10.1158/1538-7445.AM2015-4230
Abstract 4247: BRCAness by MLPA is clinically useful for tailored treatment in triple-negative breast cancer
Authors: Ishikawa Takashi , Narui Kazutaka , Yamada Akimitsu , Sugae Sadatishi , Ichikawa Yasushi , Oba Mari S. , Teraoka Saeko , Kida Kumiko , Shima Hidetaka , Endo Itaru 
Published: August 2015

Abstract
BACKGROUBD: Cytotoxic anticancer drugs are the only clinically available agents for treating triple-negative breast cancer (TNBC). Recent gene expression analysis revealed that TNBC shows considerable overlap with basal-like tumors characterized by a potential loss of BRCA1 function. Further subdivision of TNBC represents an important clinical topic for treatments. We therefore subdivided TNBC into basal-like (BL) and non-BL subtypes defined by EGFR and/or CK5/6 positive in our previous neoadjuvant chemotherapy (NAC) study (KBOG1101 study). We reported that BL subtype were resistant to taxane regimen at AACR2013.
AIM: To examine impaired BRCA1 function “BRCAness” is beneficial for tailored chemotherapy in TNBC.
METHODS: Sixty-six TNBC cases from a randomized phase II trial comparing Docetaxel and cyclophosphamide x 6 (TC6) with 5-fluorouracil, epirubucin and cyclophosphamide followed by docetaxel (FEC-D) as NAC for hormone receptor-negative breast cancer (Kanagawa Breast Oncology Group 1101 Study). TNBC was subdivided by 1) Immunohistochemistry (IHC) of CK 5/6 and EGFR into BL and non-BL subtypes, and 2) Multiplex Ligation-dependent Probe Amplification (MLPA) of BRCAness into BRCAness and non-BRCAness subtypes. The pCR rates were examined according to each regimen and subtype. 3) The association of grade 3 pCR was examined with Ki-67, p53, aldehyde dehydrogenase (ALDH) 1 and topoisomerase 2A (topoIIα) by IHC and TOP2A by FISH for each regimen.
RESULTS: 1) The pCR rates of FEC-D and TC were 37% vs 18.5% in BL(n = 54), while 40.4% and 16.7% in non-BL (n = 11), respectively. FEC-D was superior in both subtypes without statistical significance. 2) In BRCAness (n = 34), FEC-D was significantly superior to TC6 (FEC-D vs TC: 56.3% vs 16.7%, p = 0.030), while not different in non-BRCAness (20.0% vs 16.7%). 3) No factors were associated with pCR.
DISCUSSION: TC6 was less effective than FEC-D in TNBC with BRCAness, showing that taxane cannot exert their anticancer role in tumors with BRCA1 dysfunction. Although BL may contain more BRCA1-defective tumors than non-BL, MLPA of BRCAness was better to identify subtype resistant to taxane than BL defined by IHC. BRCAness by MLPA method is practically useful for treatment selection in TNBC.
Citation Format: Takashi Ishikawa, Kazutaka Narui, Akimitsu Yamada, Sadatishi Sugae, Yasushi Ichikawa, Mari S. Oba, Saeko Teraoka, Kumiko Kida, Hidetaka Shima, Itaru Endo. BRCAness by MLPA is clinically useful for tailored treatment in triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4247. doi:10.1158/1538-7445.AM2015-4247
Abstract 4265: Identification of new NTRK1 gene fusion as oncogene target in colon cancer
Authors: Creancier Laurent , Dejean Caroline , Vandenberghe Isabelle , Blanchet Jean-Christophe , Aussagues Yannick , Annereau Jean Philippe , Selves Janick , Kruczynski Anna 
Published: August 2015

Abstract
In an effort to better characterize the activity of a multi-kinase inhibitors, antiproliferative activity was evaluated against a panel of human tumor cell lines. Among the different cell lines tested we have been able to highlight that the KM12 human colorectal carcinoma present hypersensitivity to inhibition. By intersecting the results of activity of the compound and the bibliographic data, we could confirm that the activity of the compound was mediated by the inhibition of phosphorylation of the receptor NTRK1.
The NTRK1 gene encodes Tropomyosin-related kinase A (TRKA), the hight-affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a human colon carcinoma as a transforming oncogene activated by a somatic rearrangement that fused TPM3 (non-muscle tropomyosin) gene to kinase domain of a novel tyrosine-kinase receptor. The KM12 human CRC cell line expresses the chimeric TPM3-TRKA protein and is hypersensitive to TRKA kinase inhibition.
Using differential quantitative reverse transcriptase PCR and optimised immunohistochemistry we could confirm the existence of low frequency (0.5%) NTRK1 re-arranged / activated forms in colorectal carcinoma. A same colorectal tumor sample could contain different fusion transcripts, highlighting the molecular heterogeneity of this type of tumor Furthermore we detect a novel NTRK1 fusion in colorectal carcinoma clinical samples corresponding to oncogenic rearrangement TRK-T2 identified in papillary thyroid carcinoma.
These results confirm the potential interest of the target NTRK1 in the panel of targeted therapies against colorectal cancer.
Citation Format: Laurent Creancier, Caroline Dejean, Isabelle Vandenberghe, Jean-Christophe Blanchet, Yannick Aussagues, Jean Philippe Annereau, Janick Selves, Anna Kruczynski. Identification of new NTRK1 gene fusion as oncogene target in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4265. doi:10.1158/1538-7445.AM2015-4265
Abstract 429: Novel role of CXCL12/CXCR4 signaling axis in obesity-induced prostate cancer progression in HiMyc mice
Authors: Saha Achinto , Blando Jorge , DiGiovanni John 
Published: August 2015

Abstract
Obesity has been shown to increase prostate cancer (PCa) progression and disease severity in men. In previous studies, we showed that diet-induced obesity (DIO, 60 kcal% fat) increased the incidence and severity of invasive adenocarcinomas in HiMyc transgenic mice compared to mice on a control diet (10 kcal% fat) whereas calorie restriction (30% CR) completely prevented the formation of adenocarcinomas. Increased tumor progression was associated with changes in expression of a large number of cytokines, chemokines and growth factors suggesting that altered growth factor and inflammatory signaling pathways in the tumor microenvironment may be key targets for preventing and controlling PCa progression and especially obesity-related PCa progression. Therefore, in this study we investigated the role of white adipose tissue (WAT)-derived factors on obesity-driven PCa progression in HiMyc mice. We first isolated RNA from the stromal vascular fraction (SVF) of the periprostatic WAT from HiMyc mice maintained on DIO and control diet. qPCR analyses showed a dramatic increase in expression of various chemokines, cytokines, growth and angiogenesis factors in the SVF of obese HiMyc mice. Among them, both CXCL12 and its receptors CXCR4 and CXCR7, were significantly upregulated in SVF from obese HiMyc mice. Recently, we developed a PCa cell line from the ventral prostate of HiMyc mice (HMVP2 cells) and a normal cell line from FVB/N mice (NMVP cells). Two additional cell lines (HMVP2A1 and HMVP2A2) were isolated from the original HMVP2 cells after subsequent tumor formation in FVB/N mice and growth in culture. HMVP2 and the derivative cell lines have characteristics of cancer stem cells and produce tumors in syngeneic mice. Western blot analyses showed expression of both CXCR4 and CXCR7 in the following order HMVP2A2 &gt;HMVP2A1&gt; HMVP2&gt;NMVP cells, which followed their ability to produce tumors in vivo. Furthermore, CXCL12 treatment stimulated migration and invasion of HMVP2 cells (but not NMVP cells), which was inhibited by the CXCR4 antagonist, AMD3100. CXCL12 treatment also led to rapid activation of Akt, Stat3 and NFκB signaling in HMVP2 but not in NMVP cells. These data suggest that CXCL12 has differential effects on PCa cells from HiMyc mice compared to normal prostate cells that may play a role in driving tumor progression. In addition, these data suggest that targeting the CXCL12/CXCR4/CXCR7 axis could lead to novel approaches for offset the effects of obesity on PCa progression, thereby reducing PCa mortality.
Citation Format: Achinto Saha, Jorge Blando, John DiGiovanni. Novel role of CXCL12/CXCR4 signaling axis in obesity-induced prostate cancer progression in HiMyc mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 429. doi:10.1158/1538-7445.AM2015-429