bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4062: A computational driven protocol of metronomic oral vinorelbine in metastatic non small cell lung cancer
Authors: Imbs Diane-Charlotte , Cheikh Raouf El , Ciccolini Joseph , Serre Raphaël , Barlesi Fabrice , Barbolosi Dominique 
Published: July 2017

Abstract
Over the last decade, metronomic chemotherapy (MC) has emerged as an alternative way to administrate chemotherapy. MC can be defined as regular administration of low/less-toxic doses without extended drug-free breaks. Because countless schedules are possible, testing them empirically looks like an unachievable goal. Therefore, mathematical modeling can be an effective tool to determine appropriate metronomic strategies.
A phase Ia/Ib study based on a mathematical model of oral vinorelbine in metastatic NSCLC and malignant pleural mesothelioma was designed to confirm safety and evaluate efficacy of a new metronomic regimen (Elharrar et al. 2016). The optimized schedule providing weekly Day1 (D1), D2 and D4 with respective doses of 60, 30 and 60 mg was suggested by in silico simulations using a Pharmacokinetic-Pharmacodynamic (PKPD) model taking into account vinorelbine PK, PD toxicities and PD efficacy (Faivre et al. 2013). Trial recruitment will be two-staged, as 12 patients have been enrolled to confirm safety and consolidate the calibration of model parameters. An extension phase on 20-extra patients will be conducted to evaluate the efficacy of the optimized protocol. Monolix 4.3.3 was used for population PKPD analysis.
A three-compartment model best described oral vinorelbine PK data. PK analysis revealed a high inter-individual variability on drug exposure (CV=73%). PD toxicity (neutropenia) was adequately described by a modified Friberg model (Friberg et al. 2002), considering continuous administrations of metronomic dosing regimen. On the 12 recruited patients, 3 (25%) presented either a stable disease (SD) or a partial response (PR). No direct link has been established between toxicity (grade 4 neutropenia) and drug exposure. However, responders to treatment were those presenting a higher vinorelbine area under the curve (p=0.02). Tumor assessments were used to adjust efficacy parameters. The model was used to simulate alternative metronomic scenarios targeting higher efficacy with similar toxicity. Simulations showed that the initial proposed schedule was the most appropriate in terms of efficacy/toxicity balance. Its efficacy will be evaluated in the second part of the study.
This trial can be considered as a proof-of-concept study demonstrating the feasibility to run a computational-driven protocol to ensure an optimal efficacy/toxicity balance in cancer patients.
Citation Format: Diane-Charlotte Imbs, Raouf El Cheikh, Joseph Ciccolini, Raphaël Serre, Fabrice Barlesi, Dominique Barbolosi. A computational driven protocol of metronomic oral vinorelbine in metastatic non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4062. doi:10.1158/1538-7445.AM2017-4062
Abstract 4063: Design and synthesis of indole derivatives as ABCG2 mediated resistance reversal agents
Authors: Cai Chao-Yun , Zhai Hong , Lei Zi-Ning , Chen Bao-Li , Du Zhao-Yi , Zhang Yun-Kai , Wang Yi-Jun , Wang Bo , Chen Zhe-Sheng 
Published: July 2017

Abstract
Multidrug resistance is a phenomenon that cancer cells become resistant to anticancer drugs. Multidrug resistance has been shown to be related with the overexpression of ATP-binding (ABC) transporters, including ABCG2. Therefore, ABCG2 is a therapeutic target for the development of multidrug resistance reversal agents. Fumitremorgin C, with an indole group which is an important pharmacophore in many drugs, is a known ABCG2 inhibitor. Inspired by this, we synthesized two series of indole derivatives as ABCG2 mediated resistance reversal agents. With MTT assay, we found that two compounds from the two series of indole derivatives respectively exhibited good reversal activity against ABCG2. The two compounds did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines and they stimulated the basal ATP hydrolysis of ABCG2.
Citation Format: Chao-Yun Cai, Hong Zhai, Zi-Ning Lei, Bao-Li Chen, Zhao-Yi Du, Yun-Kai Zhang, Yi-Jun Wang, Bo Wang, Zhe-Sheng Chen. Design and synthesis of indole derivatives as ABCG2 mediated resistance reversal agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4063. doi:10.1158/1538-7445.AM2017-4063
Abstract 4067: BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in an in vivo C6 rat glioma model and synergizes with temozolomide
Authors: Gesta Stephane , Nagpal Semma , Dadali Tulin , Merchant Milton , Jan Taichang , Diers Anne R. , Kiebish Michael , Jiminez Joaquin , Vishnudas Vivek K. , Narain Niven R. , Sarangarajan Rangaprasad , Recht Lawrence 
Published: July 2017

Abstract
BPM31510, a parenteral nanodispersion of ubidecarenone that is in clinical testing for solid tumors, effectuates an anti-cancer effect in highly metabolic cancers by eliciting an anti-Warburg effect. Intraperitoneal (i.p.) administration of BPM31510 reverses paraplegia in a rat CNS leukemia model demonstrating the bioavailability of the drug to the central nervous system. The study describes data demonstrating the therapeutic utility of BPM31510 in glioblastoma multiforme (GBM). BPM31510 decreased cell proliferation rates in patient derived GBM cell lines compared to temozolamide (TMZ), pretreatment with BPM31510 followed by TMZ challenge was associated with significant synergy in reducing cell proliferation compared to monotherapy. In a C6 glioma allograft rat model treatment with BPM31510 alone (n=30/group) (i.p., 50mg/kg, b.i.d) increased overall survival compared to untreated control group. BPM31510 in combination with procarbazine (oral, 60mg/kg; d 8, 21) and vincristine (IV, 1.4mg/kg; d 8, 29) significantly improved overall survival compared to BPM31510 alone or chemotherapy. Furthermore, long term survival was achieved in four of twenty rats with C6 gliomas receiving BPM31510 doses between 10 and 50 mg/kg compared with none treated with either vehicle or irradiation (P &lt; 0.02, Fisher exact test). Interestingly, the long term survival persisted for over two months after all treatment was discontinued; MR imaging confirmed the presence of static masses in these long term survivors. Collectively, the data demonstrate that BPM31510 has a robust effect in a preclinical model of GBM. Intravenous BPM31510 is currently in Phase 1/2 clinical trial for TMZ+BEV refractory GBM patients.
Citation Format: Stephane Gesta, Semma Nagpal, Tulin Dadali, Milton Merchant, Taichang Jan, Anne R. Diers, Michael Kiebish, Joaquin Jiminez, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan, Lawrence Recht. BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in an in vivo C6 rat glioma model and synergizes with temozolomide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4067. doi:10.1158/1538-7445.AM2017-4067
Abstract 4068: HH-002, a derivative of Homoharringtonine, show promsing in diverse cancer models in preclinical characterization
Authors: Rui Hank 
Published: July 2017

Abstract
Homoharringtonine (HHT) is an anti-cancer drug used to treat imatinib resistant CML, and a reversible inhibitor of translation acting upon the early steps in polypeptide chain elongation. BS-HH-002.SA is a derivative of HHT. BS-HH-002.SA was shown to decrease the phosphorylation of Janus protein tyrosine kinase 2 (JAK2) as well as downstream targets, such as signal transducers and activators of transcription 3 and 5 (STAT3 and STAT 5), it also reduced Myeloid cell leukemia-1 (Mcl-1) protein level significantly and resulted in apoptosis. Evaluation of BS-HH-002.SA efficacy. was test in HEL, an erthroleukemia cell line carrying a JAK2V617F mutation which is seen in 90% of patients with polycythemia vera (PCV) and half of those with essential thrombocythemia or primary myelofibrosis. HH-002.SA showed was highly potent (at low nM concentration) to HEL. Efficacy of BS-HH-002 was tested in a recombinant human erythropoietin injection (rhEpo)-induced murine model of polycythemia Vera, Treatment with BS-HH-002.SA BID for 4 days showed a significant inhibitory effect on rhEpo induced increase in reticulocytes, hematocrit and splenomegaly, as well as in red blood cell, white blood cell and platelet counts. Furthermore, histology evaluations revealed that BS-HH-002.SA exerted an inhibitory effect on rhEpo induced extramedullary hematopoiesis in spleen, and decreased cellularity in bone marrow with more predominant effect on erythroid cells than on myeloid cells. Also, BS-HH-002.SA also show potent in vitro and in vivo efficacy in pancreatic cancer cell line KP-4 and non-small cell lung cancer (NSCLC) NCI-H1975, BS-HH-002.S inhibited STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression Mcl-1 protein levels in both two cancer cell lines.
Note: This abstract was not presented at the meeting.
Citation Format: Hank Rui. HH-002, a derivative of Homoharringtonine, show promsing in diverse cancer models in preclinical characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4068. doi:10.1158/1538-7445.AM2017-4068
Abstract 4070: Salternamide A, a marine natural product, suppresses hypoxia-induced accumulation of HIF-1α and induces apoptosis in human colorectal cancer cells
Authors: Bach Duc-Hiep , Byun Woong Sub , Kim Seong-Hwan , Hong Ji-Young , Park Hyen Joo , Oh Dong-Chan , Lee Sang Kook 
Published: July 2017

Abstract
Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents.
Acknowledgment
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) (MRC No. 2009-0083533)
Citation Format: Duc-Hiep Bach, Woong Sub Byun, Seong-Hwan Kim, Ji-Young Hong, Hyen Joo Park, Dong-Chan Oh, Sang Kook Lee. Salternamide A, a marine natural product, suppresses hypoxia-induced accumulation of HIF-1α and induces apoptosis in human colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4070. doi:10.1158/1538-7445.AM2017-4070
Abstract 409: Genome engineering to generate models of chromosome arm-level aneuploidies in lung carcinoma
Authors: Taylor Alison M. , Ha Gavin , Shih Juliann , Zhang Xiaoyang , Francis Joshua M. , Meyerson Matthew 
Published: July 2017

Abstract
Almost 90% of tumors are aneuploid and have arm- or whole- chromosome level copy number changes. Arm-level copy number alterations cluster by tumor type, suggesting that specific arm-level changes are influenced by cell type. Systematic methods of generating copy number changes on a particular chromosome have not been tested, leaving the effects of specific aneuploidies in cancer unclear. The most frequent genomic alteration in lung squamous cell carcinomas (SCCs) is loss of chromosome 3p. This alteration occurs in 90% of lung SCCs, and covers the entire length of the chromosome arm. Over two-thirds of 3p genes show significantly decreased expression. However, the phenotypic effects of 3p loss in tumorigenesis are not known.
We used the CRISPR-Cas9 system to generate double-strand breaks (DSBs) and produce partial aneuploidies of arm-level loss. We have targeted guide RNAs adjacent to centromeric satellite-repeat sequences on chromosome arm 3p. At this location, we induced homologous recombination with a selection cassette and artificial telomere. We have successfully isolated almost 90 clones of immortalized lung epithelial cells with deletion of the 3p arm, with 8 validated by whole genome sequencing. Consistent with patient data, expression of 3p genes is also decreased upon deletion. Phenotypic characterization revealed that cells with chromosome 3p deletion proliferate more slowly than their siblings. 3p deleted cells show increased G1 arrest, but do not undergo increased apoptosis or cell death. We are currently testing 3p loss in combination with other frequent SCC alterations, such as SOX2 and TP63 gain. We have also identified expression changes in trans, outside of chromosome 3p. These studies provide a robust model that will address a gap in our understanding of aneuploidy in cancer by using targeted endonuclease technology to create models of partial aneuploidies. Future work will include investigation of how different chromosomal changes contribute to cancer formation, which will have implications on our understanding of tumorigenesis.
Citation Format: Alison M. Taylor, Gavin Ha, Juliann Shih, Xiaoyang Zhang, Joshua M. Francis, Matthew Meyerson. Genome engineering to generate models of chromosome arm-level aneuploidies in lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 409. doi:10.1158/1538-7445.AM2017-409
Abstract 4091: AKT can modulate the in vitro response of HNSCC cell to irreversible EGFR inhibitors
Authors: Silva-Oliveira Renato José , Melendez Matias , Martinho Olga , Zanon Maicon Fernando , Viana Luciano de Souza , Carvalho André Lopes , Reis Rui Manuel 
Published: July 2017

Abstract
Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC) tumors. Cetuximab is the first targeted (anti-EGFR) therapy approved for the treatment of patients with locally advanced HNSCC. However, its efficacy is limited due to primary and secondary resistance, and there is no predict biomarkers of response. New generation of EGFR inhibitors with pan HER targeting and irreversible action, such as afatinib and allitinib represents a significant therapeutic promise in HNSCC treatment. In this study, we intend to compare the potential cytotoxicity of two irreversible anti-EGFR inhibitors (afatinib and allitinib) with cetuximab and to identify potential predictive biomarkers of response in a panel of HNSCC cell lines. The mutational analysis in hotspot regions of EGFR, KRAS, NRAS, PIK3CA and PTEN in the eight HNSCC cell lines revealed an EGFR mutation (p.H773Y) and gene amplification in the HN13 cells, and KRAS mutation in the JHU-28 cell line. According to the growth inhibition score (GI), allitinib was the most cytotoxic drug, followed by afatinib and finally cetuximab. The HN13 cell line exhibited a less responsive behavior to all drugs assessed, and interestingly, also displayed the higher levels of AKT phosphorylation. Therefore, we further performed drug combinations and found that with anti-AKT agent (MK2206), afatinib and allitinib, but not cetuximab, sensitivity was restored. Additionally, AKT1gene editing in afatinib and allitinib-treated cell lines showed that AKT1 silencing-induced cell line decreased viability and increased cytotoxicity through caspases 3/7activation.Additionally, in silico analysis of TCGA database showed that AKT1 overexpression was present in 14.7% (41/279) of HNSCC cases, and was associated with perineural invasion in advanced stage. In conclusion, allitinib presented a greater cytotoxic profile when compared to afatinib and cetuximab, and the AKT pathway constitutes a predictive marker of allitinib response. Importantly, in allitinib and afatinib-resistant cases, the pharmacological combination with AKT inhibitors could restore response and increase treatment success.
Citation Format: Renato José Silva-Oliveira, Matias Melendez, Olga Martinho, Maicon Fernando Zanon, Luciano de Souza Viana, André Lopes Carvalho, Rui Manuel Reis. AKT can modulate the in vitro response of HNSCC cell to irreversible EGFR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4091. doi:10.1158/1538-7445.AM2017-4091
Abstract 4093: t-Darpp stimulates protein kinase A activity by interacting with its RI regulatory subunit
Authors: Theile Dirk , Geng Shuhui , Denny Erin , Momand Jamil , Kane Susan E. 
Published: July 2017

Abstract
t-Darpp is the truncated form of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (Darpp-32) and has been demonstrated to confer resistance to trastuzumab, a Her2-targeted anticancer agent, via sustained signaling through the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt pathway. t-Darpp over-expression results in enhanced activity of protein kinase A (PKA), but the mechanism of t-Darpp-mediated PKA activation is poorly understood. In the PKA holoenzyme, when the catalytic subunits are bound to regulatory subunits RI or RII, kinase activity is inhibited. We investigated PKA activity and holoenzyme composition in cell lines that over-express t-Darpp (SK.tDrp) or a T75A phosphorylation mutant (SK.tDrp.T75A), as well as an empty vector control cell line (SK.empty). We also evaluated protein-protein interactions between t-Darpp and PKA catalytic (PKAc) or regulatory subunits RI and RII in those cell lines. Whereas SK.tDrp cells had elevated PKA activity, SK.tDrp.T75A cells did not. In agreement with the effects on activity, a proximity ligation assay showed that SK.tDrp cells, but not SK.tDrp.T75A cells, had diminished association of RI with PKAc. Moreover, t-Darpp was seen to bind directly to RI in co-immunoprecipitation studies. Cells that express both Darpp-32 and t-Darpp had PKA activity levels and RI-PKAc association that were similar to control SK.empty cells. This is consistent with our published findings that Darpp-32 reverses t-Darpp’s effects on trastuzumab resistance and CREB DNA binding activity (downstream of PKA). Taken together, our data suggest that T75 phosphorylation is crucial for t-Darpp-mediated PKA activation and this activation appears to occur through direct binding to RI and release of RI from PKAc. The t-Darpp-RI interaction could be a druggable target to reduce PKA activity in drug-resistant cancer.
Citation Format: Dirk Theile, Shuhui Geng, Erin Denny, Jamil Momand, Susan E. Kane. t-Darpp stimulates protein kinase A activity by interacting with its RI regulatory subunit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4093. doi:10.1158/1538-7445.AM2017-4093
Abstract 4097: Src-met signaling confers apoptosis resistance to the combination of BKM120 and erlotinib in head and neck cancer
Authors: Amin A.R.M. Ruhul , Anisuzzaman Abu , Haque Abedul , Chen Zhuo , Shin Dong 
Published: July 2017

Abstract
Purpose: Molecularly targeted agents will play a major role in the next generation of personalized cancer therapies. However, intrinsic and acquired resistance to targeted agents poses challenges to the success of such treatments. The purpose of the current study was to investigate the intrinsic resistance of head and neck cancer (HNC) cell lines to apoptosis induced by the combination of EGFR inhibitor erlotinib and PI3K inhibitor BKM120.
Methods: In a panel of 10 malignant and 1 premalignant HN cell lines, we evaluated cell growth inhibition (by SRB assay), IC50, combination index, dose reduction index (by CalcuSyn Software), and apoptosis (by Annexin-V staining). Protein expression levels were measured by Western blotting. Small molecule chemical inhibitors and siRNA-mediated knockdown strategies were used to inactivate and shut down the expression of the relevant proteins, respectively.
Results: Single targeting of EGFR with erlotinib or PI3K with BKM120 (pan-PI3K inhibitor) suppressed cellular growth without inducing significant apoptosis. Co-targeting EGFR and PI3K demonstrated in vitro synergy in all except one cell line (based on combination index and dose reduction index) and more effectively inhibited HNC xenograft growth in vivo. The combination of erlotinib and BKM120 induced variable apoptosis: some cell lines were very sensitive (Tu686, 686LN, 93-VU-147T), some moderately (Fadu, SqCCy1, 1483, UMSSC90) and others were resistant (UD-SCC2, MSK-LEUK1, JHU022) to apoptosis induction. JHU022 and 1483 cell lines expressed very high levels of p-cMet. Targeting cMet with the small molecule inhibitor crizotinib or siRNA rendered these cell lines highly sensitive to erlotinib and BKM120 induced apoptosis. Moreover, inhibition of Src family kinases with the small molecule inhibitor dasatinib or with c-Src-specific siRNA inhibited p-cMet. In addition, inhibition of SFK in these cell lines conferred sensitivity to erlotinib and BKM120 induced apoptosis.
Conclusions: Our results strongly suggest that co-targeting of EGFR and PI3K has synergistic activity, is effective in vivo, and induces apoptosis of some HNC cell lines. Two of the resistant cell lines express a high level of p-cMet as a downstream target of SFK, which confers resistance of these cells to the combination of erlotinib and BKM120.
Citation Format: A.R.M. Ruhul Amin, Abu Anisuzzaman, Abedul Haque, Zhuo Chen, Dong Shin. Src-met signaling confers apoptosis resistance to the combination of BKM120 and erlotinib in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4097. doi:10.1158/1538-7445.AM2017-4097