bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2061: DK049, a novel acid-sensitive prodrug of gemcitabine: design, in vitro properties and in vivo efficacy
Authors: Koester David , Garcia Javier , Fuchs Olga , Kratz Felix 
Published: July 2016

Abstract
Gemcitabine (Gemzar®) is an anticancer nucleoside that is widely used to treat solid tumors. Unfortunately, at its recommended dose of ∼1000 mg/m2 approximately 90% are deactivated by cytidine deaminase to the inactive uridine metabolite and excreted in the urine. A further disadvantage resulting in chemo-resistance is the low expression level of the human equilibrative nucleoside transporter 1 (hENT1) on the cell surface of cancer cells thus preventing substantial uptake of gemcitabine. In order to circumvent these disadvantages, we designed an innovative gemcitabine prodrug DK049 that a.) is capped at the amino group of the cytosine moiety with acetyl benzoic acid preventing deamination, and b.) incorporates a proprietary maleimide-bearing LADR™ linker forming a stable, but acid-sensitive hydrazone bond. At its 5′-OH position a phosphate group was introduced rendering water-solubility. Following intravenous administration, DK049 binds rapidly and selectively to circulating albumin and utilizes the advantages of albumin-mediated tumor uptake as well as cellular uptake by endocytosis (1).
After cleavage of the acid-sensitive benzoyl hydrazone bond, we could show that the acetyl benzoic acid is decapped by carboxylesterase 2. In a head-to-head comparison with gemcitabine (4 × 240 mg/kg on a weekly basis) in four subcutaneous human patient-derived tumor xenografts (NSCLC: LXFE397, LXFE937, ovarian cancer: OVXF899, and pancreatic cancer: Panc11159; 8-10 nude mice per group), DK049 (4 × 24 mg/kg gemcitabine equivalents or 8 × 18 mg/kg gemcitabine equivalents over 4 weeks) demonstrated distinctly superior antitumor efficacy versus gemcitabine (p &lt; 0.05). In the LXFE937 and OVXF899 model, DK049 induced long-term significant regressions for several weeks after end of therapy without any loss in body weight or bone marrow toxicity. In summary, these results show a superior long-term antitumor efficacy of DK049 compared to gemcitabine at a significantly reduced dose.
(1) Felix Kratz, Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release 8;132:171-83, 2008.
Citation Format: David Koester, Javier Garcia, Olga Fuchs, Felix Kratz. DK049, a novel acid-sensitive prodrug of gemcitabine: design, in vitro properties and in vivo efficacy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2061.
Abstract 2062: Nanoemulsion formulations for anticancer agent piplartine characterization, toxicological, pharmacokinetics and efficacy studies
Authors: Fofaria Neel , Ranjan Alok , Qhattal Hussaini Syed Sha , Liu Xinli , Srivastava Sanjay K. 
Published: July 2016

Abstract
Piplartine (PL) is an alkaloid found in black-pepper and known for its anticancer activity, however, due to poor solubility and lack of proper formulation, its use for oral
administration is a challenge. The objective of this study was to formulate PL into nanoemulsion drug delivery system for oral delivery and thereafter evaluate toxicity, pharmacokinetics and therapeutic efficacy. Optimized nanoemulsions were formulated by self-emulsification as well as by homogenization-sonication method. Two nanoemulsions enhanced the solubility of PL with low polydispersity index and high stability. Both PL loaded nanoemulsions exhibited enhanced dissolution, cellular permeability and cytotoxic effects as compared to pure PL. Formulation of PL into nanoemulsions did not obstruct its cellular uptake in cancer cells. Blank or PL loaded nanoemulsions did not exhibited toxicity in mice upon daily oral administration for 60 days. Pharmacokinetics of PL followed a two-compartment model after intravenous administration. PL loaded nanoemulsions showed 1.5-fold increase in oral bioavailability as compared to free PL. Finally, PL loaded nanoemulsions showed marked anti-tumor activity at a dose of 10 mg/kg in melanoma tumor bearing mice. In conclusion, for the first time we have developed a stable nanoemulsion delivery system for oral administration of PL, which enhanced its solubility, oral bioavailability and anti-tumor efficacy.
Citation Format: Neel Fofaria, Alok Ranjan, Hussaini Syed Sha Qhattal, Xinli Liu, Sanjay K. Srivastava. Nanoemulsion formulations for anticancer agent piplartine characterization, toxicological, pharmacokinetics and efficacy studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2062.
Abstract 2079: IONP-LPrA2 and PEG-LPrA2 therapies for triple negative breast cancer
Authors: Harmon Tia L. , Harbuzariu Adriana , Rampoldi Antonio , Dill Courtney , Lanier Viola , Daley-Brown Danielle , Lipsey Crystal , Tchio Cynthia , Yang Lily , Gonzalez-Perez Ruben Rene 
Published: July 2016

Abstract
Background: Breast cancer (BC) is an epidemic in the US. It is estimated that there will be over 230,000 new BC diagnoses in 2016. Triple Negative Breast Cancer (TNBC) comprises ∼15% of BC cases and lacks targeted therapeutic options. Obesity and high leptin levels are associated with higher TNBC incidence and poorer patient outcomes. Overexpression of leptin and its receptor, Ob-R, induce BC cell growth and angiogenesis; therefore leptin/Ob-R may serve as a TNBC therapeutic target. We have developed a Leptin Peptide Receptor Antagonist, LPrA2, which effectively inhibits leptin signaling. To increase its efficacy LPrA2
was coupled to iron oxide nanoparticles (IONPs) and polyethylene glycol (PEG), and subsequently tested in vitro and in vivo in obese mice hosting syngeneic TNBC-like mammary tumors.
Methods: The conjugation of LPrA2 to IONPs and PEG was confirmed by immunoblotting analysis. E0771, mouse BC cells, which are progesterone receptor and HER2 negative were made insensitive to estrogen stimuli by long-term treatment with Tamoxifen (TAM). Cell cycle and MTT assays were performed to determine the effectiveness of leptin signaling inhibition by conjugated LPrA2 in vitro. C57BL/6 female mice were fed a 60% fat diet
to induce obesity. The obese mice were injected with E0771-TAM cells in the mammary fat pad and treated with IONP-LPrA2 and PEG-LPrA2 after tumor development. Obese mice treated with IONP-LPrA2 Scramble (Sc) and PEG-LPrA2 Sc served as negative controls.
Results and Conclusion: IONP-LPrA2 and PEG-LPrA2 attenuated leptin signaling in vitro and decreased tumor growth and progression in vivo in comparison to the controls. These findings indicate that conjugated LPrA2
may serve as a targeted therapy for TNBC. IONP-LPrA2 may be especially useful in treating this more aggressive form of BC due to its ability to capture multiple LPrA2 peptides as well as its small and uniform particle size.
Citation Format: Tia L. Harmon, Adriana Harbuzariu, Antonio Rampoldi, Courtney Dill, Viola Lanier, Danielle Daley-Brown, Crystal Lipsey, Cynthia Tchio, Lily Yang, Ruben Rene Gonzalez-Perez. IONP-LPrA2 and PEG-LPrA2 therapies for triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2079.
Abstract 2086: Noscapine chemosensitization enhances docetaxel anticancer activity and tumor stroma disruption against triple negative breast cancer
Authors: Doddapaneni Ravi , Patel Ketan , Chowdhury Nusrat , Sachdeva Mandip 
Published: July 2016

Abstract
Purpose:
The use of Noscapine (Nos) as a chemosensitizer followed by docetaxel (DTX) treatment therapy could be a novel approach for the treatment for breast cancer and possibly reduce the adverse side effects associated with DTX based chemotherapy. The goal of this study was to examine the chemo-sensitizing effect of Nos to DTX and also tumor stromal disruption effect of Nos in mice bearing xenograft TNBC tumors.
Methods:
Effect of Nos chemosensitization on DTX cytotoxicity was evaluated in MDA-MB-231 cells by trypan blue dye method. Apoptosis was measured by AnnexinV/FITC method using flow cytometer. Expression of different proteins like phospho-p38, pJNK, bcl-2, α-tubulin, Akt, pAkt, survivin was evaluated by immunoblot. Alpha-tubulin binding assay was done by fluorescent microscopy. In vivo antifibrotic efficacy of Nos and uptake of coumarin-6 loaded fluorescent liposomes was evaluated by picro-sirius red staining and fluorescent microscopy respectively in xenograft breast tumors.
Results:
MDA-MB-231 TNBC cells were exposed at sub-therapeutic dose of Nos (4 μM) which increased the cytotoxicity of DTX by 3.0-fold. Flow-cytometric analysis showed significant increase (30 percent) of late apoptotic cells in Nos chemosensitized, DTX-treated MDA-MB-231 cells compared with DTX alone treatment. Further, chemosensitization of TNBC cells with Nos at different time intervals (6 h, 12 h and 24 h), the effect on stress transducer p38 stress activator protein kinase was significantly activated (p&lt;0.01). Also, Nos (4 μM) chemosensitized cells followed by DTX treatment showed downregulation of bcl2 (2.3-fold), survivin (1.3-fold) and pAKT (1.9-fold) expression further illustrating the role of Nos in inducing apoptosis. Interestingly, at this dose of Nos (4 μM), there was no impact on alpha-tubulin. Also, in vivo studies with 100 mg/kg Nos given orally to MDA-MB-231 tumor bearing athymic nude mice revealed significant reduction in tumor collagen-1 levels in Nos treated group compared to control as determined by picro-sirius staining. In Nos treated tumors, uptake of coumarin-6 loaded fluorescent liposomes was 7-fold higher compared to controls suggesting antifibrotic role of Nos.
Conclusion:
In conclusion, chemosensitization with sub-therapeutic dose of oral noscapine could be a promising approach to increase anticancer activity of DTX and can further enhance uptake of liposomes suggesting that this approach may have potential in TNBC treatment.
Citation Format: Ravi Doddapaneni, Ketan Patel, Nusrat Chowdhury, Mandip Sachdeva. Noscapine chemosensitization enhances docetaxel anticancer activity and tumor stroma disruption against triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2086.
Abstract 2095: Toxicity of selective allosteric FGFR2 inhibition in preclinical studies
Authors: Lapina Nataliya V. , Melikhova Marina V. , Vakunenkova Olga A. , Kashuro Vadim A. 
Published: July 2016

Abstract
Alofanib (RPT835, Ruspharmtech LLC) is a novel selective allosteric inhibitor binding to the extracellular domain of FGFR2. Alofanib had no direct effect on activation of FGFR1 and FGFR3 in vitro. Selective effect of the compound may reduce toxicity compared to multi-targeted VEGFR/FGFR or pan-FGFR inhibitors. This study characterizes the organ toxicity of alofanib in Sprague-Dawley rats and Chinchilla rabbits, and the reversibility of any treatment-induced effects.
240 rats and 30 rabbits received alofanib (0-40.5 and 0-21.6 mg/kg/day, respectively) intravenously on a consecutive daily dosing schedule for thirteen weeks. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed.
There was no treatment-related mortality, severe toxicity and significant changes in organs in the thirteen-week study. Alofanib was well-tolerated in vivo. Clinical signs of first injection (8.1 mg/kg) included moderate local irritative reaction and decreased activity during hour in rats. Clinical symptoms of toxicity were not observed over study. Animals were active. Body weight remained stable and it was comparable to vehicle groups. Abnormal electrocardiogram findings and blood pressure changes were not detected. It was notable that in the study, none of the hematologic changes was present at the end of the recovery period. Minimal significant decrease in ALT/AST, slight increase in alkaline phosphatase in male rats and mild increase in urea, decrease in chlorine in female rats were found throughout treatment period. Minimal significant decrease in albumin and chlorine was identified in rabbits. Rate of hyperphosphatemia, an on-target side-effect of pan-FGFR inhibitors, will be presented at the AACR Meeting.
We conclude that toxicity of alofanib was mild in the thirteen-week study. Slight decrease of chlorine in blood was most common side effect. The final conclusion will be made after six-month study. This study was supported by a grant from the Skolkovo Foundation.
Citation Format: Nataliya V. Lapina, Marina V. Melikhova, Olga A. Vakunenkova, Vadim A. Kashuro. Toxicity of selective allosteric FGFR2 inhibition in preclinical studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2095.
Abstract 2102A: Simultaneous targeting of EGFR and ALK in EML4-ALK positive lung cancer to inhibit tumor cell proliferation and migration
Authors: Li Chunrong , Kern Joseph G. , Huang Shyhmin , Armstrong Eric A. , Werner Lauryn R. , Harari Paul M. 
Published: July 2016

Abstract
Approximately 4-7% of non-small cell lung cancers (NSCLC) harbor the EML4-ALK chromosomal rearrangement. ALK has been identified as a molecular driver of cancer and ALK inhibitors have been developed for clinical use. We have confirmed high expression of EGFR in EML4-ALK-positive cell lines (H3122 and H2228). Recognizing the capacity of both EGFR and ALK signaling to regulate tumor cell growth, we investigated the effects of co-inhibition of ALK and EGFR on cell proliferation and migration in EML4-ALK-positive cells in vitro. We also examined the anti-tumor effect of ALK and EGFR inhibitors in xenograft mouse models. Cell proliferation was determined by CCK8 and cell migration was examined by wound healing assay and transwell migration assay. ALK inhibitors (crizotinb, ceritifinib and alectinib) and EGFR inhibitors (erlotinib and gefitinib) were utilized to block ALK and EGFR signaling activity.
We confirmed that H3122 and H2228 cells were resistant to EGFR inhibitors in comparison to EML4-ALK negative cell lines H226 and A549. Simultaneous knockdown of ALK and EGFR by siRNA significantly inhibited tumor cell proliferation. Combined inhibition of ALK and EGFR inhibited cell proliferation more potently than single inhibitor treatment alone. In addition, NIH3T3 cells expressing EML4-ALK variants 1, 2 or 3a displayed enhanced ability for cell migration, suggesting a role of EML4-ALK in cell migration. Individual ALK inhibitors and EGFR inhibitors inhibited cell migration. Further, combined ALK and EGFR blockade resulted in a stronger cell migration inhibition than single agent therapy. The combination of ALK inhibitor with EGFR inhibitor was more potent than single target treatment in tumor xenograft growth inhibition. Mechanistic analysis of the co-regulation of cell migration by ALK and EGFR signaling in EML4-ALK positive cells is under investigation.
These results identify enhanced inhibitory effects on tumor cell proliferation and migration with simultaneous blockade of ALK and EGFR signaling suggesting that dual targeting may prove more effective than single agent approaches. These findings indicate the potential for therapeutic benefit of co-targeting ALK and EGFR in patients with EML4-ALK positive NSCLC.
Citation Format: Chunrong Li, Joseph G. Kern, Shyhmin Huang, Eric A. Armstrong, Lauryn R. Werner, Paul M. Harari. Simultaneous targeting of EGFR and ALK in EML4-ALK positive lung cancer to inhibit tumor cell proliferation and migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2102A.
Abstract 2104: ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor in head and neck squamous cell carcinoma
Authors: Yun Mi Ran , Kang Han Na , Cho Byoung Chul 
Published: July 2016

Abstract
Purpose: To investigate resistant mechanisms to NVP-BKM120, a pan-PI3K inhibitor, and potential combination therapies in head and neck squamous cell carcinoma (HNSCC).
Experimental Design: A panel of 10 human HNSCC cell lines including NVP-BKM120-resistant HNSCC patient-derived cell lines were used to evaluate the antitumor activity of NVP-BKM120. Patient-derived tumor xenograft (PDTX) models were established from recurrent/metastatic HNSCC patients treated with and resistant to NVP-BKM120.
Results: Treatment of NVP-BKM120 led to upregulation of interleukin 6 (IL-6) and subsequent activation of either extracellular signal-regulated kinase (ERK) or signal transducers and activators of transcription 3 (STAT3), resulting in a modest antitumor effects on HNSCC cells. In a subset of cell lines, blockade of IL-6 autocrine signaling with IL-6 receptor (IL-6R) siRNA or IL-6R neutralizing antibody completely abolished constitutive or NVP-BKM120-induced activation of ERK and STAT3 as well as expression of oncogenic factors including Bcl2 and cMYC, resulting in the enhanced sensitivity to NVP-BKM120 with a marked reduction of S phase and significant increment of G0/G1 arrest. Interestingly, trametinib, a MEK inhibitor, significantly reduced NVP-BKM120-induced IL-6 and cMYC upregulation, whereas it had no effect on STAT3 inhibition. Moreover, combination of NVP-BKM120 with trametinib yielded more potent anti-tumor effects than combination with a pharmacologic inhibitor of STAT3 or siSTAT3. Furthermore, combination of NVP-BKM120 with trametinib or tocilizumab, a humanised anti-IL-6 receptor antibody, synergistically suppressed the growth of NVP-BKM120-resistant PDTX models as compared with either agent alone, which was confirmed in two PDTX-derived cell lines.
Conclusions: Collectively, these results suggested that IL-6/ERK signaling contributes to intrinsic and adaptive resistance to NVP-BKM120 in HNSCC, providing a rationale for a novel therapeutic strategy to overcome resistance to pan-PI3K inhibitors.
Citation Format: Mi Ran Yun, Han Na Kang, Byoung Chul Cho. ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2104.
Abstract 2115: MEK/ERK and MCL-1 inhibition synergistically reverse apoptosis resistance in colon cancer cells with BRAF(V600E)-mediated MCL-1-upregulation
Authors: Kawakami Hisato , Huang Shengbing , Sinicrope Frank A. 
Published: July 2016

Abstract
Background. Oncogenic BRAFV600E mutations in colorectal cancer (CRC) are associated with poor prognosis and treatment resistance. BRAF mutations activate MAP kinase signaling and may confer apoptosis resistance by upregulating anti-apoptotic BCL-2/BCL-XL/MCL-1 proteins.
Results. Ectopic expression of mutant BRAFV600E was shown to potently activate MEK/ ERK that mediated the phosphorylation (T163) and upregulation of MCL-1, but not BCL-2 or BCL-XL. MEK/ERK-mediated phosphorylation of MCL-1 (T163) increased its protein stability, shown by an MCL-1 phospho-mimic mutant. In human colon cancers, mutant vs wild-type BRAF was associated with increased MCL-1 expression by IHC. MEK/ERK inhibition by cobimetinib induced pro-apoptotic BIM in BRAF mutant CRC cell lines (HT-29, RKO), and suppressed phospho-MCL-1/MCL-1 proteins as did ERK siRNA. Suppression of MCL-1 by shRNA or using a small molecule MCL-1 inhibitor (A-1210477) synergistically enhanced cobimetinib-induced apoptosis (Table) that was associated with BAK/BAX activation. A-1210477 antagonized MCL-1 by disrupting its interaction with BAK and BIM proteins, shown by immunoprecipitation.
Conclusion. BRAF/MEK/ERK induces upregulation of MCL-1 via phosphorylation/stabilization to confer apoptosis resistance that can be overcome by combined ERK and MCL-1 inhibition, suggesting a novel therapeutic strategy against BRAF mutant CRCs. Drug-induced apoptosis (annexin V) in CRC cell linesDrugsHT-29 % apoptosisRKO % apoptosisDMSO16.842.11A-1210477 (2.5 μM)29.5222.88Cobimetinib(5 μM)28.0421.05Combination53.2250.93
Citation Format: Hisato Kawakami, Shengbing Huang, Frank A. Sinicrope. MEK/ERK and MCL-1 inhibition synergistically reverse apoptosis resistance in colon cancer cells with BRAF(V600E)-mediated MCL-1-upregulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2115.
Abstract 2121: Src mediates acquired resistance to ALK inhibitor in ALK-rearranged non-small cell lung cancers
Authors: Yoshida Ryohei , Okumura Shunsuke , Sasaki Takaaki , Osaki Yoshinobu 
Published: July 2016

Abstract
ALK tyrosine kinase inhibitors (TKIs) play a significant role in the treatment of ALK-rearranged non-small cell lung cancer patients.After the significant initial response to ALK-TKIs, the emergence of acquired resistance ultimately occur for all patients.
Understanding the origin of resistance mechanisms within a patient is crucial to guide treatment and developing drugs/combinations to circumvent resistance.
There are reported that some of the tyrosine kinases are involving by bypassing ALK signaling, but comprehensive identification of proteins that are significant for acquired resistance in ALK-TKIs is still required.
Quantitative proteomic analysis provides a powerful approach in screening for alterations in protein levels. An analysis of the differential proteins expression between original cancer cell and acquired resistance cell would be useful for identification of proteins drug resistance.
To investigate the changes of chaperon holding proteins, ALK rearranged-cell line H3122 were used. ALK-TKI Alectinib resistant cell lines were established by exposing increased dose of alectinib to ALK rearranged H3122 cell line (AFR). Luminespib (AUY922, Novartis Pharm.) was used as HSP90 inhibitor and Saracatinib (Selleck Chemicals.) was used as Src inhibitor in this study.
We used iTRAQ (isobaric tags for relative and absolute quantitation) technology using nano-LC-MS/MS analysis, to identify alterations in H3122 protein levels of pre/post HSP90 inhibitor treatment. For further analysis, protein expression was measured by western blot. To assess the cancer cell growth inhibition for ALK and/or Src inhibitors, we used colony formation assay.
Our results revealed that Crk-Src related proteins were overexpressed in ALK TKI resistance cells and had a significant protein expression changes after HSP90 inhibitor treatment. To address the impact of overcoming resistance by blocking Crk-Src pathway, Drugs/combinations with ALK inhibitor and/or Src inhibitors showed that significant treatment effect in vitro and in vivo study using tumor-bearing mouse model.
Conclusion
Src is one of the significant signaling pathways in the ALK-rearranged NSCLCs resistant to ALK-TKIs including alectinib, and inhibiting Src signaling could be a potential target for ALK-rearranged NSCLC after ALK-TKI resistance.
Citation Format: Ryohei Yoshida, Shunsuke Okumura, Takaaki Sasaki, Yoshinobu Osaki. Src mediates acquired resistance to ALK inhibitor in ALK-rearranged non-small cell lung cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2121.