bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3022: Dissecting rapamycin resistance in a Tsc2-null rat leiomyoma cell line developed in a murine xenograft
Authors: Filippidou Natalia , Valianou Mathildi , Johnson Daniel L. , Bissler John J. , Astrinidis Aristotelis 
Published: August 2019

Abstract
Despite the identification of mTOR hyperactivation as the main biochemical defect downstream of TSC1/TSC2 inactivation in Lymphangioleiomyomatosis (LAM) and Tuberous Sclerosis Complex (TSC), and the approval of rapamycin and rapalogs for the treatment of the related lesions, these drugs are cytostatic and continued treatment is required for clinical benefit. The latter raises the possibility of acquired drug resistance over long-term use. To explore the mechanisms leading to rapamycin resistance in LAM/TSC, we xenografted SCID mice with ELT3 cells (Tsc2-null derived from an Eker rat uterine leiomyoma), explanted a tumor that was not responsive to rapamycin, and generated cell line ELT3-245. The cell growth of ELT3-245 is not inhibited by rapamycin in vitro. SCID mice inoculated with ELT3-245 form palpable tumors significantly faster, compared to ELT3 cells, respond very poorly to rapamycin at the initial stages of treatment, but soon become non-responsive. In addition, these cells form macroscopically visible metastases to the lungs of ELT3-245 tumor-bearing mice. We performed global gene expression profiling, comparing ELT3-245 to ELT3 cells, and found that the rapamycin-resistant cells have decreased expression of genes associated with epithelial cells and increased expression of genes associated with mesenchymal-like characteristics. Relative gene expression of Myc, Egfr, Akt2, Jun, and Ocln were assessed by RT-qPCR in ELT3 vs ELT3-245 after 24h of treatment with 20 nM rapamycin or DMSO. Important discrepancies include a 2.8-fold increased expression of Egfr under rapamycin treatment in ELT3 cells but not in ELT3-245; however, ELT3-245 had a 15-fold higher expression of Egfr prior to treatment, compared to ELT3. In addition, ELT3-245 cells strikingly increase expression of Myc when challenged with rapamycin, compared to ELT3. Similarly, Akt2 is increased considerably under rapamycin treatment in ELT3-245 and is already higher prior to treatment compared to ELT3. Finally, Ocln expression was at least 100-fold reduced in ELT3-245, compared to ELT3, both under rapamycin treatment and no-treatment conditions. These results suggest that Myc, Egfr, Akt2, and Ocln are among the genes highly relevant to acquired rapamycin resistance in this Tsc2-null rat leiomyoma cell line and point toward the pathways that need to be interfered with in order to overcome it.
Citation Format: Natalia Filippidou, Mathildi Valianou, Daniel L. Johnson, John J. Bissler, Aristotelis Astrinidis. Dissecting rapamycin resistance in a Tsc2-null rat leiomyoma cell line developed in a murine xenograft [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3022.
Abstract 3028: STAT3 represses miR-145-5p to exacerbate HER3 expression for surviving EGFR-TKIs in lung cancers
Authors: Cheng Chun-Chia , Chiang Ya-Wen , Lim Ken-Hong , Chang Jungshan , Ho Ai-Sheng , Chang Yi-Fang 
Published: August 2019

Abstract
HER3 exerts resistance against epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. Previously, we have demonstrated that EGFR induces HER3 overexpression and that contributes to the formation of cancer stem-like tumorspheres. However, the cellular mechanism of EGFR in regulating HER3 expression was obscure. We hypothesized that EGFR-downstream STAT3 participates in HER3 expression since STAT3 contributes to cancer stemness and surviving EGFR-TKIs. First, RNAseq was used to uncover the potential genes involving in formation of lung cancer HCC827-derived stem-like tumorspheres. EGFR-positive lung cancer cell lines (HCC827, A549, H1975) were individually treated with a panel containing 172 compounds which targeting to stem cell-associated genes in order to searching potential agents against EGFR-positive lung cancers. In addition, gene knockdown and RNAseq were used for investigating the molecular mechanism of STAT3 on regulating tumor progression and survival of lung cancers. We found that BBI608, a STAT3 inhibitor, was a potential therapeutic agent specifically reducing the cell viability of EGFR-positive lung cancers. Interestingly, the inhibitory effects caused by BBI608 were similar with that derived from YM155, an ILF3 inhibitor, both compounds reduced G9a-mediated HER3 expression. We, furthermore, demonstrated that STAT3 upregulated G9a to silence miR-145-5p for exacerbating HER3 expression in this study. In conclusion, this study figured out the potential cellular function of STAT3 in EGFR-positive lung cancers. We also evaluated that BBI608 was potential to eradicate EGFR-positive lung cancers and demonstrated that STAT3 regulated expression of HER3, indicating that STAT3 was a reliable therapeutic target against EGFR-TKI-resistant lung cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Chun-Chia Cheng, Ya-Wen Chiang, Ken-Hong Lim, Jungshan Chang, Ai-Sheng Ho, Yi-Fang Chang. STAT3 represses miR-145-5p to exacerbate HER3 expression for surviving EGFR-TKIs in lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3028.
Abstract 304: Combination therapy of cisplatin with cilastatin enables to increase the dose of cisplatin for enhancing its antitumor effect by suppressing nephrotoxicity
Authors: Arita Masashi , Watanabe Satoshi , Aoki Nobumasa , Takahashi Miho , Shoji Satoshi , Nozaki Koichiro , Ichikawa Kosuke , Kondo Rie , Kuwahara Shoji , Tanaka Junta , Koya Toshiyuki , Saito Akihiko , Kikuchi Toshiaki 
Published: August 2019

Abstract
Cisplatin is an anticancer drug widely used in the treatment of many cancers, including lung cancers. Although cisplatin causes various types of adverse events, the main dose-limiting toxicity of cisplatin is nephrotoxicity. Megalin is an endocytic receptor expressed at the apical membranes of proximal tubules. We previously demonstrated that cisplatin was reabsorbed through megalin and caused kidney injury. Cilastatin, an inhibitor of renal dehydropeptidase-I and used with imipenem, blocked the binding of cisplatin to megalin and reduced the nephrotoxicity induced by cisplatin. In the current study, we precisely evaluated the effect of cilastatin-mediated suppression of cisplatin nephrotoxicity to safely enhance the antitumor activity of cisplatin. BALB/c mice were administrated cisplatin with or without cilastatin. Tubular dilation or atrophy, brush border loss, tubular cell lysis and cast formation were observed in mice treated with cisplatin alone. However, these kidney injuries were decreased or disappeared in mice treated with cisplatin and cilastatin. Cilastatin also decreased the urinary levels of N-acetyl-β-D-glucosaminidase and neutrophil gelatinase-associated lipocalin, proximal tubular injury markers. Next, SCID mice were injected s.c. with A549, a human lung cancer cell line, and treated with cisplatin with or without cilastatin. Cilastatin did not affect the antitumor activity of cilastatin. Notably, A549 did not express megalin. Combined with cilastatin, the mice were successfully treated with 1.5 times dose of cisplatin with enhanced antitumor effects of cisplatin but without nephrotoxicity. In conclusion, cilastatin effectively suppressed nephrotoxicity of cisplatin by blocking the binding of cisplatin to megalin. These findings indicated that we could administer cisplatin into cancer patients without nephrotoxicity if we used cilastatin. Moreover, we might increase the dose of cisplatin and improve the outcome of cancer patients.
Citation Format: Masashi Arita, Satoshi Watanabe, Nobumasa Aoki, Miho Takahashi, Satoshi Shoji, Koichiro Nozaki, Kosuke Ichikawa, Rie Kondo, Shoji Kuwahara, Junta Tanaka, Toshiyuki Koya, Akihiko Saito, Toshiaki Kikuchi. Combination therapy of cisplatin with cilastatin enables to increase the dose of cisplatin for enhancing its antitumor effect by suppressing nephrotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 304.
Abstract 3068: Synergistic effect of BCL-2 inhibitor APG-2575 and CDK9 inhibitor in acute myeloid leukemia and DLBCL preclinical tumor models
Authors: Fang Douglas D. , Tao Ran , Tang Qiuqiong , Gu Shoulai , Zhai Guoqin , Li Jiajun , Wang Qixin , Fang Xu , Li Na , Yang Dajun , Zhai Yifan 
Published: August 2019

Abstract
Effective treatments are urgently needed for elderly acute myeloid leukemia (AML) and relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients as only 10-25% of the population respond to standard therapies and resistance often occurred. Concurrent overexpression of anti-apoptotic BCL-2 gene and proto-oncogene MYC are frequently found in AML and DLBCL and this molecular characteristic is associated with poor prognosis of patients. CDK9 controls non-ribosomal transcription of genes including MYC and MCL-1. Dysregulation in the CDK9 pathway had been reported in AML and DLBCL, making it an attractive target for the combination with BCL-2 inhibitor to achieve more effective therapy.
To test the above hypothesis, in this study, we applied the combination of APG-2575 with a CDK9 inhibitor (alvocidib or dinaciclib) to preclinical tumor models. APG-2575 is a novel, orally bioavailable BH3-mimetic that selectively inhibits BCL-2, but not BCL-xL or MCL-1. After the treatment, synergistic effect of the combination treatment was demonstrated in mice bearing xenograft tumors of human AML or DLBCL. Specifically, in xenograft tumor models derived from human DLBCL cell line U2932, the treatment with APG-2575, alvocidib, or dinaciclib single agent for 22 days exhibited antitumor activity with T/C values of 20-50% (T/C value, average tumor volumes in treatment group vs. the vehicle control group). The combination treatment achieved substantial antitumor activity with T/C value of 5%. All animals in the combination groups showed either partial or complete tumor regression whereas none in the single arms.
Similar synergistic antitumor activity of the combination treatment was consistently observed in the myelodysplastic syndrome SKM-1 and AML OCI-AML-3 xenograft models. Taken together, our data suggest that APG-2575 and CDK9 inhibition combination has a potential therapeutic application in treatment of patients with AML and DLBCL.
Citation Format: Douglas D. Fang, Ran Tao, Qiuqiong Tang, Shoulai Gu, Guoqin Zhai, Jiajun Li, Qixin Wang, Xu Fang, Na Li, Dajun Yang, Yifan Zhai. Synergistic effect of BCL-2 inhibitor APG-2575 and CDK9 inhibitor in acute myeloid leukemia and DLBCL preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3068.
Abstract 3078: Tesetaxel, a novel, oral taxane, crosses intact blood-brain barrier (BBB) at therapeutically relevant concentrations
Authors: James Joyce , Tang Kevin , Wei Thomas 
Published: August 2019

Abstract
Background: Central nervous system (CNS) metastases in cancers such as breast and lung cancer are common and associated with poor outcomes. The taxanes paclitaxel (P) and docetaxel (D) do not significantly cross the BBB (brain to plasma exposure of only 1% and 8%, respectively), making them ineffective in treating CNS metastases. Tesetaxel (T) is a novel, orally administered taxane currently in a Phase 3 study in patients with advanced breast cancer (aBC; NCT03326674). Several properties make it unique, including: oral administration with a low pill burden; a long (~8-day) terminal plasma half-life in humans, allowing infrequent dosing; no history of hypersensitivity reactions; significant activity against chemo-resistant tumors; and, unlike P and D, minimal efflux by the P-glycoprotein pump, a key element of the BBB. The in vivo tissue distribution of tesetaxel was previously investigated in mice treated with 14C-T at 4 mg/kg and sacrificed between 1-168 hours. We now report 2 additional studies in dogs and monkeys. Methods: Dogs and monkeys were dosed at 0.6 mg/kg and 1 mg/kg of 14C-T, respectively, and tissue distribution was assessed at 336 hours. These doses equate to ~44% of the 27 mg/m2 dose in the ongoing Phase 3 study. In vivo radioactivity concentrations in the cerebrum were compared to plasma concentrations and mean tumor GI50 (concentration resulting in 50% tumor growth inhibition) determined by MTT assay in 23 tumor cell lines. Results: The absolute brain concentrations of T in dogs and monkeys far exceeded both the respective plasma concentrations and the tumor GI50 (Table 1). Conclusions: In dogs and monkeys, T brain concentrations far exceed its tumor GI50 for a sustained period when administered at therapeutically relevant concentrations. The inclusion criteria for the ongoing Phase 3 study of T in patients with aBC allows for CNS metastases.
Table 1:Tesetaxel CNS Levels Far Exceed Human GI50a in Dogs and Monkeys14C-T Radioactivity Concentration (ng eq./g or mL) bCerebrum Concentration/ Tumor GI50 cNCerebrum (Mean ± SD)Plasma (Mean ± SD)Cerebrum/ PlasmaDog d310.9 ± 4.00.9 ± 0.112x18xMonkey e36.5 ± 3.80.9 ± 0.27x11xaConcentration of drug required to inhibit growth by 50%b14 days after dosingcMean GI50 for T across 23 tumor cells lines = 0.6 ng/mLdSingle dose of 0.6 mg/kg (equivalent to 44% of a human dose of 27 mg/m2)eSingle dose of 1 mg/kg (equivalent to 44% of a human dose of 27 mg/m2)
Citation Format: Joyce James, Kevin Tang, Thomas Wei. Tesetaxel, a novel, oral taxane, crosses intact blood-brain barrier (BBB) at therapeutically relevant concentrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3078.
Abstract 3091: Effects of melanoma cell-derived exosomes in melanoma patients’ plasma on immune cell functions
Authors: Sharma Priyanka , Diergaarde Brenda , Ferrone Soldano , Kirkwood John M. , Whiteside Theresa L. 
Published: August 2019

Abstract
Background: Exosomes are a subset of small (30-150nm) extracellular vesicles (EVs) of the endocytic origin that mediate intercellular communication in health and disease. Exosomes are actively produced by tumor cells, circulate freely in body fluids and carry messages that alter functions of normal cells in the tumor microenvironment (TME), including immune cell functions. The ability of melanoma exosomes to reprogram immune cell functions might contribute to disease progression.
Methods: To evaluate effects of melanoma cell-derived exosomes (MTEX) on human immune cell subsets, we isolated exosomes from plasma of 12 patients with melanoma and separated MTEX from non-MTEX by immune capture using anti-CSPG4 mAb on beads. These exosome fractions, and exosomes from plasma of 6 normal donors used as controls (NC), were studied by on-bead flow cytometry to quantify their surface protein profiles and in co-incubation assays with immune cell subsets for functional attributes. Phenotypic and functional profiles of MTEX and non-MTEX were compared.
Results & Conclusion: MTEX were enriched (p&lt;0.005)( in FasL and TRAIL, induced apoptosis of CD8+T cells, down-regulated CD69 expression levels on T cells and inhibited their proliferation (all p&lt;0.0005). MTEX also interfered with NK cell functions (p&lt;0.001). Non-MTEX were enriched (P&lt;0.005) in co-stimulatory proteins, CD40L, OX40L, OX40 and, similar
to exosomes of NC, were not immunosuppressive. Thus, MTEX, present in excess in plasma of patients with metastatic melanoma, mediate immune suppression and contribute to immune escape of the tumor.
Citation Format: Priyanka Sharma, Brenda Diergaarde, Soldano Ferrone, John M. Kirkwood, Theresa L. Whiteside. Effects of melanoma cell-derived exosomes in melanoma patients’ plasma on immune cell functions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3091.
Abstract 3098: Maximizing the sensitivity and utility of tissue biopsy by analyzing RNA and incorporating multiple immunotherapy markers
Authors: Kasbek Christopher , Chen Cai , Almalki Nouran , Cortese Jillian , Huang Jun 
Published: August 2019

Abstract
Next-generation sequencing panels are becoming more widely accepted as diagnostics for guiding personalized medicine in oncology. Some weaknesses of current NGS panels include: a lack of prediction of the patient’s response to the recently approved PD-1 checkpoint inhibitors, low sensitivities of fusion variant detection due to the complexity of the translocation events that can occur at the DNA level, and the need for matched normal sample. We are developing a 371-gene panel that uses both DNA and RNA from a single non-matched FFPE sample to guide targeted and immunotherapy decisions. Fusions are identified in RNA, while copy number variation, tumor mutation burden (TMB), microsatellite instability (MSI), HLA typing, single-nucleotide variants, and small insertion/deletion variants are identified in DNA. All exons plus UTR regions of 371 genes are covered at a mean depth of &gt;500X. To validate the TMB test, whole-exome sequencing data from 376 colon adenocarcinoma samples was analyzed with our pipeline using a 4-fold cross-validation design. TMB-high vs. TMB-low was called with 95% accuracy, compared to 90% accuracy of a competitor’s panel. For MSI, the canonical five mononucleotide-repeat sites are interrogated with a limit of detection of 2-5%. RNA samples with Dv200 &gt;10% can be used to identify fusion variants. RNA is converted to cDNA and hybridized with a mixture of probes containing ≈300 well-known fusion junctions and full exon sequences of 37 of the 371 genes which are relevant to fusions. This design leads to improved fusion detection compared to the standard DNA detection, while allowing for the identification of novel fusion junctions. Gender and common SNP’s in DNA and RNA are used to prevent sample misidentification. The accuracy and comprehensiveness of this panel should maximize benefit to the patient.
Note: This abstract was not presented at the meeting.
Citation Format: Christopher Kasbek, Cai Chen, Nouran Almalki, Jillian Cortese, Jun Huang. Maximizing the sensitivity and utility of tissue biopsy by analyzing RNA and incorporating multiple immunotherapy markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3098.
Abstract 3112: Prospective immune phenotyping of neuroblastoma children at diagnosis reveals specific immune defects related to the aggressiveness of the disease
Authors: Susini Sandrine , Rochet Isabelle , Verronèse Estelle , Bardin Christine , Rigal Chantal , Conter Cécile , Marec-Bérard Perrine , Bergeron Christophe , Lardy-Cleaud Audrey , Neymarc Séverine , Metzger Séverine , Stephan Jean-Louis , Plantaz Dominique , Caux Christophe , Ménétrier-Caux Christine , Marabelle Aurelien 
Published: August 2019

Abstract
CONTEXT: Neuroblastoma is the most common extracranial solid tumor in children. Patients with low- and intermediate-risk neuroblastoma (LIRNB) have favorable prognosis and an excellent five-year survival rate of more than 90%. However, in the case of high-risk neuroblastoma (HRNB; ~50% of cases), the prognosis of treatment remains unfavorable and the five-year survival rate remains under 40% despite aggressive multi modal therapy.
QUESTION: We wanted to know if there was a defect in immune surveillance that could explain part of the aggressive phenotype of HRNB.
METHODS: We performed a prospective multi-center study on thirty two new cases of neuroblastoma at all stages. We performed a wide phenotyping of immune cells by flow cytometry in fresh whole blood, and fresh whole bone marrow at diagnosis of children diagnosed for neuroblastoma. Cell counts were performed in order to be able to reason in absolute values (G/L) rather than only percentages. RESULTS: Blood and bone marrow from 20 LIRNB and 12 HRNB were prospectively analyzed. We found that specific subsets of circulating immune cells such as myeloid dendritic cells BDCA-1+, plasmacytoid dendritic cells, Teff/Treg CD4+ T-cells, were decreased in HRNB blood compared to LIRNB groups as opposed to other subsets (e.g iNKT, g9d2 T-cells,⋯). More surprisingly, these differences were not due to defects in cell production as there was no difference found for the same cell populations in the bone marrow between LIRNB and HRNB children.
CONCLUSION: Specific immune cell defects are found in the blood from High risk neuroblastoma children that are not present in the blood of low & intermediate risk neuroblastoma children. These defects are not due to bone marrow production impairment. These results suggest that high risk neuroblastoma disease generates an impairment in the immune homeostasis of children. Gene expression analysis of cytokine/chemokine from these neuroblastoma tumors is underway (NCT01295762).
Citation Format: Sandrine Susini, Isabelle Rochet, Estelle Verronèse, Christine Bardin, Chantal Rigal, Cécile Conter, Perrine Marec-Bérard, Christophe Bergeron, Audrey Lardy-Cleaud, Séverine Neymarc, Séverine Metzger, Jean-Louis Stephan, Dominique Plantaz, Christophe Caux, Christine Ménétrier-Caux, Aurelien Marabelle. Prospective immune phenotyping of neuroblastoma children at diagnosis reveals specific immune defects related to the aggressiveness of the disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3112.