bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C104: TAS-121, a highly potent and mutant-specific EGFR inhibitor, modulates the immune system, resulting in anti-tumor immune responses
Authors: Fukaya Satoshi , Aoyagi Yoshimi , Katoh Masanori , Itoh Kimihiro , Shibutani Toshihiro , Tanaka Nozomu , Haruma Tomonori , Hashimoto Akihiro , Miyadera Kazutaka , Matsuo Kenichi , Iwasawa Yoshikazu , Utsugi Teruhiro , Yonekura Kazuhiko 
Published: May 2016

Abstract
Background:
TAS-121 is one of the 3rd generation EGFR TKI, which specifically inhibits mutant EGFRs, and it leads to high cellular selectivity and potent antitumor activity in various in vivo models. TAS-121 is being investigated in patients with non-small cell lung cancer (NSCLC) harboring not only active mutant EGFR, but also acquired resistance mutation T790M in phase I study. immune-related events observed during treatment with TAS-121 in preclinical and clinical studies suggested that TAS-121 could modulate the immune system and, consequently, might partially contribute to anti-tumor effect. To prove this hypothesis, we examined the immuno-modulating potential of TAS-121 using MLR assay, TCR stimulation assay and in vivo syngeneic tumor models.
Material and methods:
Immune cell proliferation and cytokine production were confirmed by the CFSE dilution using flow cytometry, and ELISA assay, respectively. Anti-tumor immune response was analyzed in syngeneic models bearing with MC38 murine colon carcinoma cell line.
Results:
TAS-121 strongly induced the proliferation of CD4 T cells and CD8 T cells as well as stimulating cytokine production. Other EGFR TKIs, including 1st generation to 3rd generation agents, didn't show these effects. TAS-121 inhibited the growth of syngeneic tumor, MC38 in vivo, while no growth inhibition was observed in vitro. These data demonstrate that TAS-121 can induce anti-tumor immune responses.
Conclusions:
These findings suggest that TAS-121 could specifically modulate the immune system including T cells, leading to the anti-tumor immune responses. Therefore, TAS-121 has a unique profile among the 3rd generation EGFR-TKI. Considering this immune-modulating profile, combination with immune checkpoint blockade agent such as anti-PD1 monoclonal antibody might be beneficial for NSCLC patients harboring mutant EGFR.
Citation Format: Satoshi Fukaya, Yoshimi Aoyagi, Masanori Katoh, Kimihiro Itoh, Toshihiro Shibutani, Nozomu Tanaka, Tomonori Haruma, Akihiro Hashimoto, Kazutaka Miyadera, Kenichi Matsuo, Yoshikazu Iwasawa, Teruhiro Utsugi, Kazuhiko Yonekura. TAS-121, a highly potent and mutant-specific EGFR inhibitor, modulates the immune system, resulting in anti-tumor immune responses. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C104.
Abstract C134: Alternative pathways associated with resistance to tyrosine kinase inhibitors in glioblastoma
Authors: Aljohani Hashim M. , Koncar Robert F. , Zarzour Ahmed , Sun Park Byung , Lee So Ha , Bahassi El Mustapha 
Published: May 2016

Abstract
Glioblastoma (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens. The majority of GBM tumors show a mutated or overexpressed EGFR. However, the kinase domain mutations that usually correlate with response to the tyrosine kinase inhibitors in other cancers are infrequent in glioblastomas and phase II trials of the tyrosine kinase inhibitor (TKI), gefitinib showed no survival benefit in glioblastoma. Furthermore, tumors treated with the TKIs will inevitably recur, highlighting the need to identify signaling pathways involved in GBM resistance to TKIs. We isolated and developed gefitinib-resistant cell lines and subjected those cell lines to RNA sequencing. By evaluating transcriptomic profiles of the resistant cell lines, we were able to identify several upregulated genes, including a number of other tyrosine kinase receptors such as ROS1, DDR1 and PDGFRA that are known to control pathways downstream of EGFR. The upregulation of these genes was confirmed at the protein level by western blot. Treatment with our highly specific pyrazole ROS1 inhibitor in ROS1-overexpressing cell lines led to sensitization to low doses of gefitinib. Combined treatment with gefitinib and ROS1 inhibitor induced massive cell death by apoptosis following a prolonged cell cycle arrest in S phase. Our current study led to the discovery of alternative pathways used by GBM cells to evade cell death following treatment with gefitinib and identifies new therapeutic targets to prevent GBM cell resistance to the drug.
Citation Format: Hashim M. Aljohani, Robert F. Koncar, Ahmed Zarzour, Byung Sun Park, So Ha Lee, El Mustapha Bahassi. Alternative pathways associated with resistance to tyrosine kinase inhibitors in glioblastoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C134.
Abstract C138: Targeting macropinocytosis in pancreatic cancer
Authors: Hunt James , Ng Serina , Whatcott Clifford , Von Hoff Daniel D. , Han Haiyong 
Published: May 2016

Abstract
Pancreatic cancer is the fourth-leading cause of cancer-related deaths in the United States with a 5-year survival rate of &lt;5%. The deadly nature of this disease compounded by a lack of effective treatment options highlights a need for new therapeutics. Past studies have suggested that pancreatic cancer cells acquire the nutrients needed for cell growth through macropinocytosis, an endocytic process by which protrusions from the cell membrane create large vesicles that transport extracellular fluid along with the constituent proteins and lipids into the cell. Additionally, several studies have suggested that macropinocytosis is regulated in part by various genes including p21 protein (Cdc42/Rac)-activated kinase1 (PAK1), ADP-ribosylation factor 6 (ARF6), and sorting nexin 5 (SNX5). In this study, we investigated the effects of knockdown of these three genes on the macropinocytic activity of pancreatic cancer cells. The goal of this study is to assess whether PAK1, ARF6, or SNX5 may serve as potential targets for the suppression of macropinocytosis in pancreatic cancer, which would hamper the cells' uptake of nutrients thus starving the cancer cells and hindering tumor growth. We carried out this study using MIA PaCa-2 pancreatic cancer cells, which are known to exhibit relatively high levels of macropinocytosis. Treatment of cells with siRNA sequences specific to the three genes resulted in a significantly decreased uptake of FITC-labeled dextran as compared to cells treated with non-targeting siRNA and cells that received no treatment, indicating that inhibiting the expression of each of the genes correlates to a reduction in macropinocytic activity. Among the three genes, PAK1 siRNAs exhibited the most significant and consistent inhibitory effect on macropinocytic activity of MIA PaCa-2 cells. We, therefore, further tested the effect of two small-molecule PAK1 inhibitors, namely IPA-3 and PF-03758309, on macropinocytosis. Treatment of cells with the inhibitors resulted in a dose-dependent decrease in the uptake of FITC-labeled dextran and FITC-labeled albumin. The inhibitors also showed potent anti-proliferative activity in pancreatic cancer cell lines. The results of this study indicate that inhibition of PAK1, ARF6, or SNX5 all resulted in reduced macropinocytic activity of pancreatic cancer cells, with PAK1 showing the most promise as a potential therapeutic target for pancreatic cancer.
Citation Format: James Hunt, Serina Ng, Clifford Whatcott, Daniel D. Von Hoff, Haiyong Han. Targeting macropinocytosis in pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C138.
Abstract C143: Utility of growth modulation index and tumor growth rate to evaluate efficacy in metastatic gastric cancer patients
Authors: Beom Seung-Hoon , Jung Minkyu , Kim Hyo Song , Ahn Joong Bae , Rha Sun Young , Chung Hyun Cheol 
Published: May 2016

Abstract
Background
Growth modulation index (GMI) and tumor growth rate (TGR) have been proposed as signs of activity in early phase clinical trials. We explored utility of the efficacy end points in metastatic gastric cancer.
Patients and Methods
We carried out a retrospective study in metastatic gastric cancer patients receiving weekly paclitaxel regimen as second or more line treatment between 2005 and 2013 in Yonsei Cancer Center, and evaluate the association of GMI and TGR with efficacy outcomes respectively. The growth modulation index (GMI) was defined the ratio of time to progression with the nth line (TTPn) of therapy to the TTPn−1 with the n-1th line. TGR was computed during the pretreatment period (reference) and the experimental period. Comparisons used chi-squared and log-rank tests.
Results
A total of 133 patients were enrolled in this study. The median TTPn was 2.7 months, whereas the median TTPn−1 was 5.3 months. Thirty-one patients experienced GMI &gt; 1.2 (23.3%). Median OS was highly correlated with GMI: 6.3 and 7.5 months with GMI ≤ 1.2 and GMI &gt; 1.2 (P = 0.0009). TGR could be evaluated in 52 patients. Among them, 37 patients (71.1%) exhibited a decrease in TGR. The decrease of TGFR was associated with PFS (P = 0.043) and OS (P = 0.045).
Conclusions
GMI and TGR seem to be interesting end points that provides additional information compared with classical criteria. GMI &gt;1.2 and decrease of TGR are associated with significant OS improvement.
Citation Format: Seung-Hoon Beom, Minkyu Jung, Hyo Song Kim, Joong Bae Ahn, Sun Young Rha, Hyun Cheol Chung. Utility of growth modulation index and tumor growth rate to evaluate efficacy in metastatic gastric cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C143.
Abstract C150: High expression of SNAI2 is associated with the emergence of a highly motile fulvestrant-resistant phenotype and is an indicator of poor response to endocrine treatment in estrogen receptor-positive metastatic breast cancer
Authors: Alves Carla L. , Elias Daniel , Lyng Maria , Bak Martin , Lykkesfeldt Anne E. , Ditzel Henrik J. 
Published: May 2016

Abstract
Endocrine resistance is a major clinical problem and is associated with the acquisition of aggressive tumor spread and invasion. To investigate the association between endocrine resistance and tumor cell migration and invasion, we evaluated a panel of MCF7-based cell line models resistant to either tamoxifen, aromatase inhibitors or fulvestrant. Fulvestrant-resistant cell lines showed a significantly higher migration capacity than the parental fulvestrant-sensitive cell line. Gene expression profiling and data analysis using Ingenuity Pathway Analysis (IPA) of these fulvestrant-resistant/fulvestrant-sensitive cell lines identified potential genes involved in the promotion of invasive and aggressive characteristics in the fulvestrant-resistant phenotype, including SNAI2, a transcription repressor that promotes epithelial-mesenchymal transition and tumor metastasis. The higher gene and protein expression levels of SNAI2 in fulvestrant-resistant cells were confirmed by RT-qPCR, Western blotting and immunocytochemistry. Specific gene silencing using small interfering RNA (siRNA) against SNAI2 decreased the migratory capacity of fulvestrant-resistant cells in vitro. Clinical evaluation of SNAI2 expression in estrogen receptor-positive (ER+) metastatic tumor samples from patients treated with endocrine drugs in the advanced setting (N = 86) showed that tumors with higher expression of SNAI2 correlated significantly with shorter progression-free survival (p = 0.001). Our results suggest that upregulation of SNAI2 is associated with the emergence of a highly motile fulvestrant-resistant phenotype in vitro and may be a potential therapeutic target in combination with endocrine therapies in tumors expressing high levels of SNAI2.
Citation Format: Carla L. Alves, Daniel Elias, Maria Lyng, Martin Bak, Anne E. Lykkesfeldt, Henrik J. Ditzel. High expression of SNAI2 is associated with the emergence of a highly motile fulvestrant-resistant phenotype and is an indicator of poor response to endocrine treatment in estrogen receptor-positive metastatic breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C150.
Abstract C163: Understanding the mechanism for synergistic anti-tumor activity of a meosthelin-targeted immunotoxin and taxanes
Authors: Alewine Christine Campo , Kolyvas Emily , Pastan Ira 
Published: May 2016

Abstract
Recombinant immunotoxins (RITs) are antibody-based therapies that carry a bacterial toxin payload. RG7787 is a next generation RIT that targets the cancer antigen mesothelin (MSLN) to deliver a recombinantly engineered variant of Pseudomonas exotoxin A (PE) into the cell cytosol. PE irreversibly modifies elongation factor-2 (EF-2) by catalyzing addition of an ADP-ribose moiety. This causes EF-2 inactivation, inhibition of new protein synthesis, and a drop in the short-lived pro-survival factor mcl-1, triggering apoptosis. Combination of RG7787 with paclitaxel or nab-paclitaxel results in boosted anti-tumor efficacy in several mouse models. In the KLM1 pancreatic cancer xenograft model, either drug alone halts tumor growth while the combination produces complete regressions. Here, we show that enhanced efficacy is also seen using an identically structured RIT that targets the transferrin receptor instead of mesothelin (LMB-74), but is not seen when RIT is combined with gemcitabine, suggesting that the effect is specific to both taxane and PE. Further, we have found that the interaction of RG7787 and taxane can be modeled in vitro. Under these conditions, the interaction is dependent on the dose of RG7787, and cannot be replicated by a chemical inhibitor of protein synthesis. Co-treatment with taxane does not affect the depth, rate of onset or recovery of cells from RG7787-mediated protein synthesis inhibition. Tumor cell killing occurs over a delayed time course and is not associated with an early drop in mcl-1 levels as is seen when using a cytotoxic dose of RG7787 alone. Taken together, these data suggest that PE treatment sensitizes cancer cells to taxane-mediated killing.
Citation Format: Christine Campo Alewine, Emily Kolyvas, Ira Pastan. Understanding the mechanism for synergistic anti-tumor activity of a meosthelin-targeted immunotoxin and taxanes. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C163.
Abstract C169: ER maleate is a novel anticancer agent in oral cancer cells: Implications for cancer therapy
Authors: Fu Guodong 
Published: May 2016

Abstract
ER maleate was investigated as a novel anticancer agent for oral squamous cell carcinoma (OSCC), the most common head and neck squamous cell carcinoma (HNSCC). We identified its putative molecular targets, demonstrated their clinical relevance, and showed its chemosensitization potential for platinum drugs to aid in HNSCC management. Biologic effects of ER maleate were determined on cell proliferation, spheroid/colony formation, caspase activity, cell migration and invasion in vitro and using oral tumor xenografts in vivo. mRNA profiling, real time PCR and western blot suggested ER maleate modulated the expression of polo-like kinase 1 (PLK1) and spleen tyrosine kinase (Syk). Their clinical significance was determined in oral SCC patients by immunohistochemistry and correlated with prognosis by Kaplan-Meier survival analysis. ER maleate induced cell apoptosis, inhibited proliferation, colony formation, migration and invasion in oral cancer cells. Imagestream analysis revealed cell cycle arrest in G2/M phase and increased polyploidy, unravelling deregulation of cell division and cell death. Mechanistically, ER maleate decreased expression of PLK1 and Syk, induced cleavage of PARP, caspase 9 and caspase 3 and increased chemosensitivity to carboplatin; significantly suppressed tumor growth and increased antitumor activity of carboplatin in tumor xenografts. ER maleate treated tumor xenografts showed reduced PLK1 and Syk expression; clinical investigations revealed overexpression of PLK1 and Syk in oral SCC patients that correlated with disease prognosis. In conclusion, our in vitro and in vivo findings provide a strong rationale for pre-clinical efficacy of ER maleate as a novel anti-cancer agent and chemosensitizer of platinum drugs for OSCC.
Citation Format: Guodong Fu, Sr.. ER maleate is a novel anticancer agent in oral cancer cells: Implications for cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C169.
Abstract C174: RAF kinase dimerization mediates clinical acquired resistance to RAF/EGFR inhibition in BRAF V600E colorectal cancer
Authors: Yaeger Rona , Yao Zhan , Hyman David M. , Hechtman Jaclyn F. , Vakiani Efsevia , Cercek Andrea , Baselga Jose , DeStanchina Elisa , Saltz Leonard , Berger Michael F. , Solit David B. , Rosen Neal 
Published: May 2016

Abstract
Background: RAF and EGFR inhibitor combinations have shown promising clinical activity in patients with BRAF V600E colorectal cancer, but resistance invariably develops.
Methods: To define mechanisms of resistance to RAF/EGFR inhibition, we analyzed pre-treatment and disease progression samples from patients with BRAF mutant colorectal cancer using our custom next-generation sequencing platform, MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets). Cell line and patient derived xenograft models were generated to investigate the effects of the genetic alterations identified at disease progression.
Results: We identified alterations predicted to result in RAF dimerization and re-activation of ERK signaling in seven of eight post-progression tumors. These alterations included an intragenic deletion in BRAF encompassing the RAS binding domain, KRAS and NRAS mutations, and KRAS, NRAS, and BRAF amplifications. Notably, these alterations were rapidly enriched in the presence of drug treatment but selected against in the absence of drug exposure. A novel RAF inhibitor, that equipotently inhibits RAF mutant monomers and dimers, effectively suppressed ERK signaling in the RAF/EGFR resistant colorectal tumors at drug doses that did not inhibit ERK signaling in RAS/RAF wild-type cells. Treatment with this novel RAF inhibitor was able to overcome resistance in cell line and patient derived xenograft models.
Conclusions: Our data suggest that alterations that promote RAF dimers, which are resistant to first generation RAF inhibitors, are a unifying mechanism of RAF/EGFR inhibitor resistance in patients with BRAF mutant colorectal cancer. These results support the testing of RAF dimer inhibitors in combination with EGFR inhibitors in patients with BRAF V600E colorectal cancer.
Citation Format: Rona Yaeger, Zhan Yao, David M. Hyman, Jaclyn F. Hechtman, Efsevia Vakiani, Andrea Cercek, Jose Baselga, Elisa DeStanchina, Leonard Saltz, Michael F. Berger, David B. Solit, Neal Rosen. RAF kinase dimerization mediates clinical acquired resistance to RAF/EGFR inhibition in BRAF V600E colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C174.
Abstract C183: Pomhex: a cell-permeable high potency Enolase inhibitor with in vivo anti-neoplastic activity
Authors: Lin Yu-Hsi , Marszalek Joe , Sun Yuting , Hammoudi Naima , Leonard Paul , Maxwell David , Satani Nikunj , Zhang Peng , Link Todd , Lee Gilbert , Di Francesco Maria E. , Czako Barbara , Want Alan Y. , DePinho Ronald A. , Muller Florian L. 
Published: May 2016

Abstract
Glycolysis inhibition is an active area of investigation in cancer. However, few compounds have progressed beyond the cell culture stage. We have recently demonstrated that genomic passenger deletion of the glycolytic enzyme Enolase 1 (ENO1) leaves gliomas harboring such deletions with less than 10% of normal enzymatic activity, rendering them exquisitely sensitive to enolase inhibitors. However, the tool compound that we employed for these in vitro studies, Phosphonoacetohydroxamate (PhAH), has very poor pharmacological properties and was ineffective in vivo. We performed a SAR studies to increase inhibitor specificity towards ENO2 as well as pro-druging to increase cell permeability. The lead compound generated by these efforts, termed POMHEX, is selectively active against ENO1-deleted glioma cells in culture at ∼35nM (versus μM for PhAH). Using an orthotopic intracranial xenografted model where tumor growth and response to therapy are monitored by MRI, we show that POMHEX is capable of eradicating intracranial ENO1-deleted tumors, with mice remaining recurrence-free even after treatment discontinuation. Taken together, these results reinforce that glycolysis is a viable target and provide in vivo proof-of-principal for the concept of using passenger deletions as targetable vulnerabilities in cancer therapy.
Citation Format: Yu-Hsi Lin, Joe Marszalek, Yuting Sun, Naima Hammoudi, Paul Leonard, David Maxwell, Nikunj Satani, Peng Zhang, Todd Link, Gilbert Lee, Maria E. Di Francesco, Barbara Czako, Alan Y. Want, Ronald A. DePinho, Florian L. Muller. Pomhex: a cell-permeable high potency Enolase inhibitor with in vivo anti-neoplastic activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C183.