bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1768: An anti-TGF-β1/2 antibody that spares TGF-β3 retains full anti-tumor efficacy and generates an improved metabolic profile
Authors: Yang Yu-an , Vasu Srividya , Yang Howard , Lee Maxwell P. , Rane Sushil , Mirza Amer M. , Wakefield Lalage M. 
Published: August 2018

Abstract
TGF-β family members are overexpressed in many advanced cancers and correlate with metastasis and poor prognosis. Based on encouraging preclinical data, therapeutics that target the TGF-β pathway are now in early phase clinical trials in oncology. While the three isoforms of TGF-β have essentially identical activities in vitro, there is relatively little known about how they might differ in vivo. Using a panel of twelve mouse allograft models of metastatic breast cancer, we showed that while TGF-β1 protein was consistently up-regulated in mammary tumors compared with normal mammary gland, the opposite was true for TGF-β3. Furthermore, in human breast cancer high TGF-β3 mRNA or protein expression was associated with better outcome, particularly in estrogen-receptor positive breast cancers. Collectively the data suggest that TGF-β1 and TGF-β3 may have opposing effects on breast cancer progression. Using an antibody that selectively neutralizes only TGF-β1 and TGF-β2, we explored the effect of sparing TGF-β3 on therapeutic outcome in the 4T1 and TSAE1 models of metastatic breast cancer. While the TGFβ1,2 antibody and two pan-TGF-β antibodies had similar efficacy against the metastasis endpoint in these very aggressive models, transcriptomic analysis of primary tumors after two weeks of antibody therapy suggested that sparing TGF-β3 might have positive effects on the metabolic profile of treated animals. To address this issue directly, we showed that mice without tumors had a significantly improved glucose tolerance following treatment with anti-TGF-β1/2 antibodies for 2-3 weeks when compared with mice treated with pan-TGF-β antibodies. Addressing potential human relevance, we showed that high expression of transcripts that were selectively upregulated in the primary tumors when TGF-β3 was spared correlated with good outcome in human breast cancer. The data suggest that use of isoform-selective TGF-β antagonists may offer advantages over the use of pan-TGF-β blocking agents for the treatment of breast cancer.
Citation Format: Yu-an Yang, Srividya Vasu, Howard Yang, Maxwell P. Lee, Sushil Rane, Amer M. Mirza, Lalage M. Wakefield. An anti-TGF-β1/2 antibody that spares TGF-β3 retains full anti-tumor efficacy and generates an improved metabolic profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1768.
Abstract 1792: Upregulation of INSR/IGF1Rby C-myc promotes TSCC tumorigenesis and metastasis through the NF-κB pathway
Authors: Wang Anxun , Sun Jingjing , Yu Mei , Lu Zhiyuan , Wang Wei 
Published: August 2018

Abstract
INSR/IGF1R has been detected to be involved in tumorigenesis and metastasis in various malignancies. The aim of our study was to compare the function role and mechanism of INSR/IGF1R in the progression of tongue squamous cell carcinoma (TSCC). We found that INSR had the same up-regulated expression pattern as IGF1R in TSCC tissues. Up-regulation of INSR/IGF1R was correlated each other and associated with lymph node metastasis and poor prognosis. Functional studies established that INSR/IGF1R knockdown dramatically impeded TSCC in vitro cell growth, migration, invasion and in vivo tumorigenesis and tumor metastasis, whereas ectopic overexpression of INSR/IGF1R enhanced these parameters. INSR/IGF1R promoted TSCC tumorigenesis and metastasis by positively modulating the NF-κB pathway. Furthermore, the up-regulation of INSR and IGF1R in TSCC resulted directly from the binding of C-myc to their promoters. Collectively, our current data demonstrate that the INSR/IGF1R axis, directly targeted by C-myc, plays an important role in the development and progression of TSCC, through NF-κB pathway, and that INSR and IGF1R are potential prognostic factors for TSCC.
Citation Format: Anxun Wang, Jingjing Sun, Mei Yu, Zhiyuan Lu, Wei Wang. Upregulation of INSR/IGF1Rby C-myc promotes TSCC tumorigenesis and metastasis through the NF-κB pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1792.
Abstract 1793: Gastrin-releasing peptide causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells
Authors: Moody Terry W. , Alvarez Irene Ramos , Jensen Robert T. 
Published: August 2018

Abstract
Gastrin releasing peptide (GRP) is a 27 amino acid peptide which is present in many lung cancer cell lines (Moody et al., Science 1981; 214: 1246). High expression of the GRP receptor (R) is associated with advanced non-small cell lung cancer (NSCLC) (Mattei et al., Arch Pathol Lab Med 2014; 138: 98). GRP stimulates but the GRPR antagonist PD176252 inhibits the proliferation of NSCLC cells (Moody et al., Eur J Pharmacol 2003; 474: 21). Here the effects of GRP on the transactivation of the EGFR and HER2 were investigated in NSCLC cells. Six of 8 NSCLC tested had GRP-R mRNA whereas all the NSCLC cells had EGFR and HER2 mRNA. Addition of GRP to NCI-H1299 cells elevated cytosolic Ca2+, increased tyrosine phosphorylation of the ERK, EGFR and HER2 and increased colony number. The effects of GRP were blocked by PD176252. The transactivation of the EGFR and HER2 was inhibited by gefitinib (EGFR tyrosine kinase inhibitor (TKI)), lapatinib (EGFR and HER2 TKI), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), N-acetylcysteine (anti-oxidant) and transforming growth factor TGF) α antibody. By ELISA, GRP increased secretion of TGFα from lung cancer cells. PD176252, gefitinib, lapatinib and trastuzumab inhibited NSCLC growth. Activation of the GRPR in NSCLC cells may facilitate the formation of EGFR homodimers and EGFR/HER2 heterodimers.
Citation Format: Terry W. Moody, Irene Ramos Alvarez, Robert T. Jensen. Gastrin-releasing peptide causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1793.
Abstract 1794: The FES-related tyrosine kinase associates with and activates the insulin-like growth factor 1 receptor at sites of cell adhesion
Authors: Stanicka Joanna , Rieger Leonie , Cox Orla T. , O'Shea Sandra , Coleman Michael , O'Flanagan Ciara , Addario Barbara , McCabe Nuala , Kennedy Richard , O'Connor Rosemary 
Published: August 2018

Abstract
Insulin-like Growth Factor-1 signaling has a well-described function in facilitating tumourigenesis and promoting tumour growth. Attempts to suppress IGF signals at the level of the IGF-1 Receptor have been disappointing, with kinase inhibitors and blocking antibodies generally showing poor efficacy in clinical trials. To address the mechanisms for this lack of efficacy we sought to identify proteins that modulate the cytotoxic response to IGF-1R tyrosine kinase inhibition using a functional siRNA screen. We identified the non-receptor tyrosine FES-related (FER) kinase as a mediator of sensitivity to the IGF-1R tyrosine kinase inhibitor in MCF-7 cells. We found that FER and the IGF-1R co-locate and can be co-immunoprecipitated from different cell types. Ectopic expression of FER strongly enhanced IGF-1R expression and phosphorylation on the atuophosphorylation sites at tyrosines 950 and 1131. FER phosphorylated these sites in an IGF-1R kinase-independent manner and also enhanced IGF-1-mediated phosphorylation of SHC, and activation of either the AKT or MAPK signaling pathways in breast cancer cell lines. The IGF-1R, β1 Integrin, FER and its substrate cortactin were all observed to be co-located in cell adhesion complexes, the disruption of which reduced IGF-1R expression and activity. High FER expression correlates with phosphorylation of SHC in breast cancer cell lines and with a poor prognosis in patient cohorts. FER and SHC phosphorylation and IGF-1R expression could be suppressed with a known ALK inhibitor that shows high specificity for FER kinase. Overall, we conclude that FER-enhances IGF-1R expression, phosphorylation and signaling to promote cooperative growth and adhesion signaling that may facilitate cancer progression and resistance to IGF-1R inhibition.
Citation Format: Joanna Stanicka, Leonie Rieger, Orla T. Cox, Sandra O'Shea, Michael Coleman, Ciara O'Flanagan, Barbara Addario, Nuala McCabe, Richard Kennedy, Rosemary O'Connor. The FES-related tyrosine kinase associates with and activates the insulin-like growth factor 1 receptor at sites of cell adhesion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1794.
Abstract 1816: Mechanism of resistance to single treatment with MET inhibitor in EGFR-mutant lung cancer cell secondarily acquiring c-MET amplification
Authors: Lee Youngjoo , Choi Yu-Ra 
Published: August 2018

Abstract
Amplification in c-MET is the second most common mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in lung cancer harboring activated EGFR mutations. An acquired resistance mechanism to single treatment with MET kinase inhibitor remains unknown. In this study, we modeled acquired resistance to experimental type I MET kinase inhibitor PHA66572 in MET-amplified HCC827 lung cancer cell line, which was established under chronic exposure to gefitinib in our lab. We found that reactivation of the EGFR pathway emerges as a resistance mechanism in MET secondarily amplified EGFR-mutant lung cancer cells after prolonged exposure to PHA66572. Any gene alteration influencing sensitivity to the drugs was not observed. Long treatment with only MET inhibitor resulted in partial resensitization to EGFR-TKI in these resistant lung cancer cells. Thus, the combination of gefitinib and PHA66572 could completely suppress the cell growth. Our findings support an intimate relationship between the EGFR and MET signaling pathways in HCC827 lung cancer cell line.
Citation Format: Youngjoo Lee, Yu-Ra Choi. Mechanism of resistance to single treatment with MET inhibitor in EGFR-mutant lung cancer cell secondarily acquiring c-MET amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1816.
Abstract 1820: Overcoming drug resistance in NSCLC with SRC inhibitor
Authors: Mukherjee Soumavo , Suresh Dhananjay , Zambre Ajit P. , Upendran Anandhi , Kannan Raghuraman 
Published: August 2018

Abstract
Lung cancer accounts for about 27 percent of all cancer deaths in the United States. Approximately 85 percent of lung cancers are non-small cell type (NSCLC) and, when treated with both chemotherapy and targeted therapies, have a five-year overall survival rate of approximately 16 percent. These statistics clearly emphasize the need for developing treatment methodologies more effective than the current standard of care. Here, we evaluated the efficacy of combined inhibition of SRC and AXL in NSCLC.Dasatinib, a BCR/abl and src family tyrosine kinase inhibitor (TKI) is a drug that has a potential to be used against both EGFR and KRAS mutated lung cancer patients, alone (phase II clinical trial) and in combination with cetuximab (in phase III clinical trial), osimertinib and erlotinib (both in phase II clinical trials) by exploiting its SRC inhibition capabilities. However, NSCLC patients treated with dasatinib often develop resistance and is the major reason for the low median survival in stage IV patients. Recently, AXL pathway has been shown to be upregulated in Dasatinib resistant cells causing activation of EMT, AKT and survival pathways. It has been suggested that auto-phosphorylation of DDR2 and subsequent activation of SHP2/RAS/AKT pathway as a result of AXL upregulation is one of the major reasons for failure to induce apoptosis in cells during dasatinib resistance. Therefore, we examined whether inhibition of AXL resensitized TKI resistant NSCLC to dasatinib. Our results show that AXL knockdown can resensitize cells to dasatinib. IC50 values decreased significantly following AXL inhibition. We have also demonstrated that nanoparticle-mediated AXL knockdown also produces similar resensitization. The details of the study will be presented.
Citation Format: Soumavo Mukherjee, Dhananjay Suresh, Ajit P. Zambre, Anandhi Upendran, Raghuraman Kannan. Overcoming drug resistance in NSCLC with SRC inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1820.
Abstract 1831: PKCδ as a novel target for HER2-positive, trastuzumab resistant breast cancer
Authors: Wyatt Debra L. , Zlobin Andrei , Ma Emily , Denning Mitchell F. , Osipo Clodia 
Published: August 2018

Abstract
Breast cancer is the most common cancer diagnosis and second leading cause of cancer related deaths among women in the United States. This poor prognosis is in part due to the high rates of resistance. In particular, resistance to anti-HER2-based therapy remains a clinical challenge for women with breast cancer suggesting that better treatment strategies are needed. Results demonstrate that resistance to trastuzumab correlates with lower PKC activity compared to trastuzumab sensitive breast cancer cells, suggesting that downregulation of PKC activity may contribute to trastuzumab resistance. The exact mechanism by which PKCs contribute to trastuzumab resistance is not well understood. Here, we hypothesized that activation of PKCs could prevent trastuzumab resistance and thus inhibit the survival and recurrence of HER2+ breast cancer. Our results show that in two distinct trastuzumab-resistant cell lines (HCC1954 and BT474), activation of PKC by the phorbol ester TPA inhibits both proliferation of bulk cells and survival of cancer stem cells (CSC) as assessed by mammosphere formation. Further, treatment using a pharmacological PKC inhibitor (GF109203X) almost completely rescued the anti-proliferative and anti-CSC survival effects of TPA in two distinct trastuzumab-resistant cell lines. Measurement of PKC isoforms at the transcript and protein levels showed that PKCδ was overexpressed in the resistant cell line compared to the sensitive cell line. PKCδ depletion using a siRNA prevented the anti-proliferative and anti-CSC survival effects of TPA, suggesting that PKCδ was the target of TPA activation in trastuzumab resistant cells. TPA-mediated activation of PKCδ was found to cause G2/M cell cycle arrest, almost complete inhibition of AKT phosphorylation at serine 473, and decreased expression of the CSC marker, ALDH1A1. These results suggest that phorbol ester-mediated activation of PKCδ could be a novel therapeutic strategy for HER2+ breast cancer that is resistant to trastuzumab-based therapy.
Citation Format: Debra L. Wyatt, Andrei Zlobin, Emily Ma, Mitchell F. Denning, Clodia Osipo. PKCδ as a novel target for HER2-positive, trastuzumab resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1831.
Abstract 1837: Overcoming trastuzumab resistance in HER2-overexpressing breast cancer by utilizing PHB2, a tumor suppressor of multiple resistance pathways
Authors: Yoshimaru Tetsuro , Matsushita Yosuke , Sasa Mitsunori , Miyoshi Yasuo , Katagiri Toyomasa 
Published: August 2018

Abstract
Overexpression of the human epidermal growth factor receptor 2 (HER2) is associated with aggressive tumor behavior and poor prognosis in breast cancer. Although anti-HER2 monoclonal antibody, trastuzumab shows considerable efficacy and extends the overall survival of patients with HER2 overexpressing breast cancer, about half of individuals with HER2-overexpressing breast cancer do not respond to trastuzumab-based therapies due to multiple resistance mechanisms. Therefore, acquired and de novo resistance to trastuzumab remains an important issue in the clinical treatment of HER2-overexpressing breast cancer. Our previous studies demonstrated that Brefeldin A-Inhibited Guanine nucleotide-exchange protein 3 (BIG3), which is exclusively overexpressed in the majority of breast cancers, functions as an A-kinase anchoring protein that binds protein kinase A (PKA) and protein phosphatase 1 (PP1Cα), thereby inactivating prohibitin2 (PHB2) suppressive activity through its dephosphorylation on Ser39. We further developed the stapled dominant-negative peptide (stERAP; stapled ERAP), which is designed to specifically inhibit the BIG3-PHB2 interaction and improve duration of their anti-tumor effects. Here we newly report that stERAP has significant suppressive effects on the HER2 signaling network by activating the tumor suppressive ability of PHB2. Intrinsic PHB2 released from BIG3 by stERAP was rapidly serine- and threonine-phosphorylated via PKCα and/or TTK, which are essential for its tumor suppressive activity, and effectively disrupted the HER2-HER3 interaction associated with acquired resistance to trastuzumab, resulting in significant reduction of proliferation of HER2-overexpressing breast cancer cells (IC50 = 54 nM in SK-BR-3 cells). We also confirm that stERAP inhibited HER2 phosphorylation on Thr488, HER2-HER3 interaction, and NF-κB pathway, which are associated with trastuzumab-resistance, respectively, resulting in significant suppression of growth of trastuzumab-resistant breast cancer cells. More importantly, stERAP treatment led to the enhancement of trastuzumab-sensitivity, resulting in a synergistic growth suppression of HER2-overexpressing and trastuzumab-resistant breast cancer cells, respectively. Our findings strongly suggest that stERAP is a novel promising anti-cancer drug to suppress the growth of trastuzumab-resistant breast cancer in clinical use.
Citation Format: Tetsuro Yoshimaru, Yosuke Matsushita, Mitsunori Sasa, Yasuo Miyoshi, Toyomasa Katagiri. Overcoming trastuzumab resistance in HER2-overexpressing breast cancer by utilizing PHB2, a tumor suppressor of multiple resistance pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1837.
Abstract 1844: Centriole amplification sensitizes cells to paclitaxel
Authors: Lasek Amber L. , Britigan Eric M. , Weaver Beth A. 
Published: August 2018

Abstract
Paclitaxel (Taxol) is a widely utilized treatment for primary and metastatic breast cancer. However, only about 50% of patients respond and no predictive biomarker for paclitaxel efficacy is currently available. Identification of a clinically validated predictive biomarker would substantially improve patient outcomes. Aneuploidy, an aberrant chromosome number, was recognized in the late 1800s as a hallmark of tumor cells. This led to the hypothesis that aneuploidy drives tumorigenesis. However, experiments in animal models have shown that the effect of aneuploidy on tumors depends on the rate of ongoing chromosome missegregation, also known as chromosomal instability (CIN). Low rates of CIN are weakly tumor promoting, while high rates of CIN lead to cell death and tumor suppression due to loss of one or more essential chromosomes. Combining two independent insults that each cause low CIN results in high CIN, cell death, and tumor suppression. We have recently shown that, in primary breast cancer patients, paclitaxel does not reach sufficiently high concentrations to cause mitotic arrest, as it does at typically used concentrations in cell culture. Instead, low clinically relevant doses of paclitaxel cause CIN due to multipolar spindles. We hypothesize that a preexisting low rate of chromosomal instability (CIN), which occurs in about 50% of breast tumors, sensitizes cells to paclitaxel treatment, since paclitaxel increases their rate of CIN over a maximally tolerated threshold. Centrosome amplification is common in breast cancer and can cause CIN through induction of multipolar spindles. To test whether CIN induced by centrosome amplification sensitizes cells to low, clinically relevant doses of paclitaxel, we inducibly overexpressed Polo-like kinase 4 (Plk4), the master regulator of centriole duplication, to generate supernumerary centrioles. Plk4 overexpression induced centriole amplification and increased the incidence of multipolar divisions, even in subclinical levels of paclitaxel. Consistent with our hypothesis, CIN induced by supernumerary centrosomes potentiates the decrease in cell viability caused by paclitaxel treatment. Decreased cell viability is accompanied by an increase in mitotic errors, CIN, and cell death and a reduction in the percentage of cycling cells. This data suggests that the subset of patients whose tumors exhibit centrosome amplification prior to treatment may be more likely to benefit from paclitaxel therapy.
Citation Format: Amber L. Lasek, Eric M. Britigan, Beth A. Weaver. Centriole amplification sensitizes cells to paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1844.