bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 654: PG-101 in combination with docetaxel or Herceptin improves breast cancer survival
Authors: Wadehra Madhuri , Kiyohara Meagan , Dillard Christen , Ashki Negin , Qin Christie 
Published: August 2015

Abstract
Background: Breast cancer is a heterogeneous disease with several subtypes which dictate which course of treatment each patient will receive. However, resistance remains a significant challenge. In triple negative breast cancer (TNBC), an aggressive histological subtype with limited treatment options and very poor prognosis, resistance to current standard therapies such as taxanes severely limits the available options for previously treated patients. This problem also occurs with targeted therapies. Trastuzumab is the standard of care for HER2+ tumors. However, de novo or acquired Trastuzumab resistance is a major limitation for its clinical efficacy. Thus, there remains an urgent unmet need for improved targeted agents for this patient population.
Methods: To this end, we define another marker epithelial membrane protein-2 (EMP2) as a novel target for Trastuzumab and taxane resistant tumors. EMP2 expression was determined using standard immunohistochemistry. We have recently developed a novel IgG1 monoclonal antibody to EMP2 termed PG-101. Acquired Trastuzumab and docetaxel resistant tumors were treated with PG-101 using human xenograft models.
Results: EMP2 is an oncogenic protein whose expression has been shown to correlate with tumor progression as well as the formation of breast cancer stem cells. In this study, we present evidence that EMP2 is highly expressed in acquired resistant tumor cells both in culture as well as in patient samples. We also tested the efficacy of PG-101 in combination with docetaxel, and we have evidence that the combination significantly improves tumor-free survival. Moreover, preliminary data also strongly suggests that PG-101 can be used as an adjuvant therapy for docetaxel and Trastuzumab resistant tumors whereby PG-101 reduced both tumor load in both models in vivo.
Conclusions: Given that EMP2 is also overexpressed in endometrial and ovarian cancers, our data collectively suggest that PG-101 therapy has the potential to revolutionize the outcomes for women with cancer.
Citation Format: Madhuri Wadehra, Meagan Kiyohara, Christen Dillard, Negin Ashki, Christie Qin. PG-101 in combination with docetaxel or Herceptin improves breast cancer survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 654. doi:10.1158/1538-7445.AM2015-654
Abstract 655: The next generation of targeted toxins: A novel deimmunized sarcin ribotoxin fused with an EphA2 Abdurin binder
Authors: Gehlsen Kurt R. , Demartis Anna , Jones Tim 
Published: August 2015

Abstract
Abdurins are a novel antibody-like scaffold derived from the engineering of a single CH2 domain (CH2D) of IgG. The prolonged serum half-life of Abdurins, the result of retained FcRn binding, is 10-20 times longer than the serum half-life of any other protein scaffold of comparable molecular weight. Here we present data on the isolation and characterization of high affinity ABDURIN binders to the cancer target EphA2. α-Sarcin is a small (17 kDa) fungal ribonuclease produced by Aspergillus giganteus. Sarcin functions by catalytically cleaving a single phosphodiester bond in the sarcin-ricin loop, a well-defined RNA motif within the rRNA scaffold of the large ribosomal subunit. This cleavage makes the ribosome unrecognizable to elongation factors and hence, blocks protein synthesis. We have deimmunized α-sarcin (Sarcin-DI) and made several variants lacking T cell epitopes while retaining cytotoxic activity. This novel Abdurin EphA2 binder fusion with Sarcin-DI creates a new generation of targeted toxins with a longer half-life, low immunogenicity and potent tumor cell killing.
Citation Format: Kurt R. Gehlsen, Anna Demartis, Tim Jones. The next generation of targeted toxins: A novel deimmunized sarcin ribotoxin fused with an EphA2 Abdurin binder. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 655. doi:10.1158/1538-7445.AM2015-655
Abstract 657: Microtubule stabilizers inhibit the cellular transport and signaling of EGFR in breast cancer cells
Authors: Rohena Cristina Coral , Dybdal-Hargreaves Nicholas F. , Mooberry Susan L. 
Published: August 2015

Abstract
Breast cancer is the second most diagnosed cancer in women and it is estimated that approximately 40,000 women die every year from this disease in this country alone. The overexpression of EGFR in breast cancer is associated with drug resistance and an aggressive nature resulting in an overall poor outcome. The EGFR signaling pathway requires internalization of the receptor, endosomal translocation and in some cases nuclear accumulation of the receptor. These processes are dependent on functional microtubules. Microtubule targeting agents (MTAs) have been used with great success in the treatment of breast cancer alone and in combination with other agents. MTAs impair microtubule dynamics, which results in the inhibition of mitosis. Microtubules are additionally important in cellular signaling events including cellular transport of the EGFR. The effects of the microtubule stabilizer taccalonolide AJ on EGFR transport and activation in breast cancer cells were compared to the effects of paclitaxel. Our results show that microtubule stabilization interrupts the cellular trafficking of EGFR, leading to the retention of the receptor in the cell periphery.. Taccalonolide AJ and paclitaxel impaired the association of EGFR with the early endosome and delayed its association with the lysosome. This disruption in cellular transport also led to decreased phosphorylation of EGFR downstream targets AKT, ERK1/2 and STAT3, with taccalonolide AJ being the more effective inhibitor. Our studies show that microtubule stabilizers also prevent the association of EGFR with the Golgi instead leading to the fragmentation of this organelle. Paclitaxel caused a higher degree of Golgi fragmentation and it was observed in nearly all cells. The inhibition of EGFR localization to the Golgi caused by taccalonolide AJ and paclitaxel suggests that microtubule stabilization interferes with the trafficking of EGFR to the nucleus. This was confirmed by our results showing that microtubule stabilization impairs the nuclear transport of EGFR in breast cancer cells. Not surprisingly, in this case, paclitaxel was much more effective at preventing this nuclear accumulation. These studies highlight the utility and versatility of microtubule stabilizers and suggest the potential for combination treatments with microtubule stabilizers and small molecule inhibitors of EGFR and EGFR dependent pathways in breast cancer.
Citation Format: Cristina Coral Rohena, Nicholas F. Dybdal-Hargreaves, Susan L. Mooberry. Microtubule stabilizers inhibit the cellular transport and signaling of EGFR in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 657. doi:10.1158/1538-7445.AM2015-657
Abstract 658: Phosphorylated HER3 levels associated with trastuzumab resistance in HER2 gene amplified uterine serous carcinoma xenograft tumors
Authors: Hernandez Silvia F. , DiGloria Celeste , Groeneweg Jolijn , Borger Darrell , Foster Rosemary , Rueda Bo , Growdon Whitfield 
Published: August 2015

Abstract
Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. Clinical trial has demonstrated that USC is impervious to trastuzumab therapy, though the mechanism is poorly understood. Since HER3 mediated signaling has been implicated in trastuzumab resistance in breast cancer, we sought to understand the relevance of HER3 activation in USC xenografts derived from the HER2 gene amplified (HER2:Chr 17 &gt; 15) non-immortalized USC cell line ARK2. Cohorts of mice harboring xenografts derived from ARK2 were treated with either vehicle, trastuzumab (10 mg/kg IP BIW), lapatinib (150 mg/kg QD oral gavage) or the combination of trastuzumab and lapatinib for 21 days. Acute and chronic post treatment tumor samples were assessed for downstream signaling alterations. Single agent trastuzumab had no impact on xenograft growth compared to vehicle. Lapatinib alone resulted in significant tumorstatic effects (p &lt; 0.01) and dual therapy with trastuzumab and lapatinib induced synergistic activity that significantly decreased tumor volume compared to all other arms (p &lt; 0.01). Single agent trastuzumab was associated with rapid elevation in pHER3 levels with unchanged pAKT and pERK expression compared to vehicle. These elevated pHER3 levels were similarly elevated after the 21 day treatment. Anti-tumor activity observed in the lapatinib and dual lapatinib/trastuzumab arm was not associated with any alterations in pHER3 levels following 21 day treatment, though acute elevations in pHER3 were noted in the dual HER2 blockade arm at 24 hours after treatment. In conclusion, trastuzumab alone failed to impact USC xenograft growth and this innate resistance was associated with an elevation in pHER3 levels that was still evident in xenografts at the end of the treatment period. Unlike single agent trastuzumab, treatment arms that utilized lapatinib demonstrated significant anti-tumor activity with no increase in pHER3 above vehicle over the course of treatment. These data highlight HER3 activation as a possible trastuzumab resistance mechanism in USC that can be abrogated through the addition of lapatinib.
Citation Format: Silvia F. Hernandez, Celeste DiGloria, Jolijn Groeneweg, Darrell Borger, Rosemary Foster, Bo Rueda, Whitfield Growdon. Phosphorylated HER3 levels associated with trastuzumab resistance in HER2 gene amplified uterine serous carcinoma xenograft tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 658. doi:10.1158/1538-7445.AM2015-658
Abstract 660: Polyisoprenylated cysteinyl amide inhibitors exhibit anti-tumor effects in human breast cancer cell lines
Authors: Salako Olufisayo O. , Poku Rosemary A. , Nkembo Augustine T. , Mazu Typhon , Flores-Rozas Hernan , Lamango Nazarius S. 
Published: August 2015

Abstract
PURPOSE: Triple negative breast cancer (TNBC) is the most aggressive and fatal form of breast cancer. TNBC has no effective therapies since it is not driven by the estrogen (ER), progesterone (PR), and human epidermal growth factor type 2 (Her2/Neu) receptors for which there are targeted drugs. Human epidermal growth factor receptors (EGFR) are overexpressed in 92% of TNBC cases, however, anti-EGFR therapies are ineffective. Monomeric G-proteins that regulate cell proliferation, angiogenesis, migration and apoptosis operate downstream of EGFR and other signal transduction pathways. Polyisoprenylated methylated protein methyl esterase (PMPMEase) metabolizes monomeric G-proteins, allowing them to function properly. PMPMEase is overexpressed in many cancers and may serve as a biomarker and target for cancer therapy. We have synthesized polyisoprenylated cysteinyl amide inhibitors that may inhibit PMPMEase and/or disrupt polyisoprenylated protein function. We hypothesize that the PCAIs will promote anti-tumorigenic effects, inducing apoptosis, while inhibiting cell survival, proliferation, migration, and invasion. The purpose of this study was to test the effectiveness of PCAIs against the biological hallmarks of TNBC.
METHODS: Four TNBC cell lines were treated with the PCAIs and analyzed for their effects on cell survival, viability, F-actin organization, cell migration and apoptosis.
RESULTS: Treatment of TNBC cells with the PCAIs resulted in a concentration-dependent death of the TNBC cells with EC50 values ranging from 2.13 to 2.78 μM for NSL-BA-040 and NSL-BA-055 in media containing 5% FBS. AO/EB staining revealed early apoptosis at 1 μM. NSL-RD-036 inhibited MDA-MB-231 cell migration by 71% (163±10.7 cells in control versus 47±6.9 in treated (±SEM, N = 3). PCAIs induced complete disruption of F-actin filament organization at 2 μM in MDA-MB-468 cells.
CONCLUSION: The PCAIs’ ability to induce apoptosis, and inhibit cell migration by disrupting F-actin filaments suggest that their potential therapeutic value could involve the inhibition of TNBC tumor growth, metastasis, and angiogenesis, which are all essential hallmarks for breast cancer progression. The PCAIs may ultimately fill the targeted therapy void in TNBC therapy.
Citation Format: Olufisayo O. Salako, Rosemary A. Poku, Augustine T. Nkembo, Typhon Mazu, Hernan Flores-Rozas, Nazarius S. Lamango. Polyisoprenylated cysteinyl amide inhibitors exhibit anti-tumor effects in human breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 660. doi:10.1158/1538-7445.AM2015-660
Abstract 662: USP8 modulates ubiquitination of LRIG1 for Met degradation
Authors: Lee Ji Min , Kim Bogyou , Kim Kyung-Ah 
Published: August 2015

Abstract
The Met receptor tyrosine kinase is an attractive target for cancer therapy as it promotes invasive tumor growth. SAIT301 is a novel anti-Met antibody, which induces LRIG1-mediated Met degradation and inhibits tumor growth. However, detailed downstream mechanism by which LRIG1 mediates target protein down-regulation is unknown. In the present study, we discovered that SAIT301 induces ubiquitination of LRIG1, which in turn promotes recruitment of Met and LRIG1 complex to the lysosome through its interaction with Hrs, resulting in concomitant degradation of both LRIG1 and Met. We also identified USP8 as a LRIG1-specific deubiquitinating enzyme, reporting the interaction between USP8 and LRIG1 for the first time. SAIT301 triggers degradation of LRIG1 by inhibiting the interaction of LRIG1 and USP8, which regulates ubiquitin modification and stability of LRIG1. In summary, SAIT301, a Met targeting antibody, employs ubiquitination of LRIG1 for its highly effective Met degradation. This unique feature of SAIT301 enables it to function as a fully antagonistic antibody without Met activation. We found that USP8 is involved in deubiquitination of LRIG1, influencing the efficiency of Met degradation. The relation of Met, LRIG1 and USP8 strongly supports the potential clinical benefit of a combination treatment of a USP8 inhibitor and a Met inhibitor, such as SAIT301.
Citation Format: Ji Min Lee, Bogyou Kim, Kyung-Ah Kim. USP8 modulates ubiquitination of LRIG1 for Met degradation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 662. doi:10.1158/1538-7445.AM2015-662
Abstract 663: Targeting autophagy potentiates the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma
Authors: MITOU Géraldine , FRENTZEL Julie , LAMANT Laurence , MEGGETTO Fabienne , ESPINOS Estelle , CODOGNO Patrice , BROUSSET Pierre , GIURIATO Sylvie 
Published: August 2015

Abstract
ALK (Anaplastic Lymphoma Kinase)-positive Anaplastic Large Cell Lymphoma (ALCL) occurs predominantly in children and young adults. Their chemotherapeutic treatment leads to a 5-year overall survival amounted to 70-80%. The tumor relapses are often very aggressive and lethal and their underlying mechanisms are unknown. Therefore, there is still a need to improve current therapy. Crizotinib is the most advanced ALK tyrosine kinase inhibitor already used in clinics for ALK-associated lung cancers. However, mechanisms of escape to crizotinib have been reported in cell lines and patients submitted to continuous crizotinib treatment. Thus, its use in frontline treatment for ALCL is hampered by the emergence of resistance. As autophagy has been proposed as a cell survival mechanism potentially involved in the acquisition of resistance to tyrosine kinase inhibitor, we investigated here whether autophagy was activated during ALCL treatment. We demonstrated in ALCL that autophagy is induced upon ALK inactivation, as a pro-survival response. We found that different ALK inhibition approaches (crizotinib or ALK-targeting siRNA) combined with autophagy inhibition (chloroquine, 3-methyladenine or ATG7-targeting siRNA) compromised cell survival and cell growth. Altogether, our results suggest that crizotinib and chloroquine (two drugs already used in clinics) co-treatment could be beneficial for ALK-positive ALCL patients.
Citation Format: Géraldine MITOU, Julie FRENTZEL, Laurence LAMANT, Fabienne MEGGETTO, Estelle ESPINOS, Patrice CODOGNO, Pierre BROUSSET, Sylvie GIURIATO. Targeting autophagy potentiates the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 663. doi:10.1158/1538-7445.AM2015-663
Abstract 665: Inhibition of mitochondrial complex I enhances the therapeutic benefit of BRAF inhibition in mutant melanoma cell lines
Authors: Schoeckel Laura , Bitschar Katharina , Héroult Mélanie , Kopitz Charlotte , Hägebarth Andrea 
Published: August 2015

Abstract
Metabolic reprogramming is considered to be one of the major hallmarks of cancer. Selective inhibitors of mutant BRAFV600E, are a widely used targeted therapy for melanoma. Unfortunately, acquired drug resistance, which commonly occurs, represents a major limitation to clinical efficacy. Recent studies have highlighted the role of BRAF inhibition in promoting oxidative phosphorylation (OXPHOS), over glycolysis, in BRAFV600E melanomas, a switch commonly seen in conjunction with development of drug resistance. This metabolic switch occurs at the transcriptional level, indicated by the up-regulation of PGC1α through the lineage-specific transcription factor MITF. Based on these data, we propose that increased OXPHOS is required for melanoma cells to acquire resistance against the BRAF inhibition, which supports our investigation of the therapeutic benefit of combining BRAF and OXPHOS inhibitors. For the latter, respiratory Complex I, an essential enzyme in the mitochondrial respiratory chain, is a logical target for OXPHOS inhibition.
We investigated the molecular, metabolic and bioenergetic effects of a selective mutant BRAF inhibitor (Vemurafenib/PLX4032) and BAY 87-2243, a small molecule inhibiting respiratory Complex I, in vitro using various BRAF-mutant melanoma cell lines. First, our study revealed that BRAF inhibition increased the expression of mitochondrial genes and mitochondrial respiration, which is associated with elevated mitochondrial oxidative stress, independent of the expression of PGC1α. Furthermore, BAY 87-2243 inhibited OXPHOS, down-regulated the expression of mitochondrial genes and increased reactive oxygen species (ROS) production. We also demonstrated that inhibition of BRAF increased the OXPHOS phenotype and therefore enhanced the effect of BAY 87-2243 on mitochondrial metabolism; the combination of both inhibitors showed synergistic effects in vitro.Interestingly, long term BRAF inhibition resulted in BRAFV600E melanoma cells to become resistant to BAY 87-2243. Preliminary studies suggest that melanoma cells pretreated with a BRAF inhibitor, with higher rates of mitochondrial respiration and elevated ROS levels, are prone to cell death when targeted by pro-oxidants. Further studies are currently ongoing to understand this resistance phenotype as well as the underlying mechanism which drives the synergistic drug effect.
Citation Format: Laura Schoeckel, Katharina Bitschar, Mélanie Héroult, Charlotte Kopitz, Andrea Hägebarth. Inhibition of mitochondrial complex I enhances the therapeutic benefit of BRAF inhibition in mutant melanoma cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 665. doi:10.1158/1538-7445.AM2015-665
Abstract 667: Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis
Authors: Chen Dongshi , Wei Liang , Yu Jian , Zhang Lin 
Published: August 2015

Abstract
Regorafenib, a multi-kinase inhibitor targeting the Ras/Raf/MEK/ERK pathway, has recently been approved for the treatment of metastatic colorectal cancer (CRC). However, the mechanisms of action of regorafenib in CRC cells have been unclear. We investigated how regorafenib suppresses CRC cell growth and potentiates effects of other chemotherapeutic drugs. We found that regorafenib treatment induces PUMA in CRC cells irrespective of p53 status through the NF-κB pathway following ERK inhibition and glycogen synthase kinase 3β (GSK3β) activation. Upregulation of PUMA is correlated with apoptosis induction in different CRC cell lines. PUMA is necessary for regorafenib-induced apoptosis in CRC cells. Chemosensitization by regorafenib is mediated by enhanced PUMA induction through different pathways. Furthermore, deficiency in PUMA abrogates the in vivo antitumor, antiangiogenic and chemosensitization effects of regorafenib. Our results demonstrate a key role of PUMA in mediating the anticancer effects of regorafenib in CRC cells. They suggest that PUMA induction can be used as an indicator of regorafenib sensitivity, and also provide a rationale for manipulating the apoptotic machinery to improve the therapeutic efficacy of regorafenib and other targeted drugs.
Citation Format: Dongshi Chen, Liang Wei, Jian Yu, Lin Zhang. Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 667. doi:10.1158/1538-7445.AM2015-667