bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5795: Loss of CDCP1 in patient prostate cancer metastasis leads to uncoupling of beta-1 integrin from its cytoplasmic signaling through FAK
Authors: Pollan Sara G. , Huang Fangjin , Lang Joshua M. , Sperger Jamie M. , Shah Kavita , Knudsen Beatrice S. 
Published: July 2017

Abstract
The Cub-Domain Containing Protein - 1, CDCP1, is a transmembrane glycoprotein, which is able to sequester Src and PKCδ into unique microdomains within the plasma membrane. CDCP1 can either promote or suppress tumor metastasis, dependent on the cancer type and experimental system. How the loss of CDCP1 leads to tumor metastasis is not well understood. We demonstrated for the first time in patients with prostate cancer (PCA), a significant reduction of CDCP1 expression in circulating cancer cells (CTC) and tumor metastasis relative to primary tumors and concordant analytical results. To investigate how the loss of CDCP1 facilitates PCA metastasis, we determined the consequences of CDCP1 loss in non-adherent cancer cells, which provide an experimental model system of CTCs. In this system, CDCP1 silenced cells exhibit 3-fold higher proliferation, 4-fold greater anchorage independent growth with colonies exceeding 5 microns in diameter, and a 2-fold reduction in migration ability. In 10% human plasma, these cells up-regulate p-FAK, p-SRC, p-AKT and p-MAPK expression, and at the same time loose expression of activated β1-integrin. The loss of inside-out activation of β1-integrin occurs through prevention of TALIN phosphorylation. Upon loss of CDCP1, Talin is no longer phosphorylated by CDK5 and this causes the disassembly of the β1 integrin - Talin complex. In addition, β1-integrin dissociates from CDK5 and from the CDK5-regulatory subunit, p35, but remains bound to p-FAK. We determined the pathway by which the loss of CDCP1 arrests CDK5 kinase activity. Upon loss of CDCP1, SRC phosphorylates p35. This generates a binding site for the C2 domain of PKCδ and phosphorylation of CDK5-T77 by PKCδ. The subsequent dissociation of the regulatory subunit abolishes the activity of CDK5. We show that both SRC inhibition and silencing of PKCδ reestablish the inside-out activation of β1-integrin. Altogether we discovered a new mechanism of regulation of CDK5 in prostate cancer cells, which leads to the uncoupling of β1-integrin and FAK. The potential biological and clinical consequences of this mechanism are (1) a switch from cell-matrix to cell-cell adhesion, (2) increased sensitivity of CTCs to FAK inhibitors and (3) improved adaptation and survival of cancer cells in the circulation and at the metastatic sites.
Citation Format: Sara G. Pollan, Fangjin Huang, Joshua M. Lang, Jamie M. Sperger, Kavita Shah, Beatrice S. Knudsen. Loss of CDCP1 in patient prostate cancer metastasis leads to uncoupling of beta-1 integrin from its cytoplasmic signaling through FAK [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 5795. doi:10.1158/1538-7445.AM2017-5795
Abstract 5799: Targeting CX3CR1 impairs the reseeding of cancer cells recirculating from metastatic tumors
Authors: Qian Chen , Worrede-Mahdi Asurayya , Kaur Ramanpreet , Shen Fei , Salvino Joseph , Meucci Olimpia , Fatatis Alessandro 
Published: July 2017

Abstract
Cancer cells re-enter systemic blood from established metastatic tumors. Recent evidence indicates that these recirculating cancer cells further seed and colonize skeleton and soft tissues to expand metastatic dissemination, thus precipitating the clinical progression to terminal disease. We have previously shown that the chemokine receptor CX3CR1 is implicated in the metastatic seeding of breast cancer cells and that novel small-molecule antagonists for this receptor effectively contains the number and size of secondary tumors in animal models. Using the same models, we now report that targeting CX3CR1 also restrains the re-seeding of skeleton and soft-tissue by circulating cancer cells (CTCs) departing from existing metastatic lesions. Notably, we also found that CTCs unable to re-seed are forced to remain in the blood circulation longer, eventually succumbing to apoptotic death. It has been proposed that when either spontaneously or forcibly (re)circulating in the blood, cancer cells from solid tumors are more vulnerable to the effects of both cytotoxic and targeted therapeutics. Given the role of CX3CR1 antagonists in prolonging the time spent by CTCs in the blood, we sought to assess whether these compounds could synergize with docetaxel by extending bioavailability and its cytotoxic effects. Thus, we tested this paradigm on CTCs departing from skeletal and soft-tissue lesions generated by breast and prostate cancer cells in mice. Based on the results obtained from these experiments, it can be concluded that implementing the development of CX3CR1 antagonists and promoting their clinical use will provide novel and effective tools to contain the progression of metastatic disease in cancer patients.
Citation Format: Chen Qian, Asurayya Worrede-Mahdi, Ramanpreet Kaur, Fei Shen, Joseph Salvino, Olimpia Meucci, Alessandro Fatatis. Targeting CX3CR1 impairs the reseeding of cancer cells recirculating from metastatic tumors [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 5799. doi:10.1158/1538-7445.AM2017-5799
Abstract 58: Local intratumoral treatment with anti-mesothelin Immunotoxins overcomes resistance to anti-CTLA-4 therapy
Authors: Leshem Yasmin , Liu Xiu-fen , Bera Tapan , Terabe Masaki , Berzofsky Jay A. , Bossenmaier Birgit , Niederfellner Gerhard , O'Brien James , Reiter Yoram , Pastan Ira 
Published: July 2017

Abstract
Background: SS1P and RG7787 are immunotoxins composed of anti-mesothelin antibody fused to a fragment from pseudomonas exotoxin A. We previously observed delayed tumor responses in patients treated with SS1P leading us to hypothesis that immunotoxins can provoke anti-tumor immunity. We hypothesize that intra-tumoral injection of SS1P or RG7787 will produce immunologic death and convert living tumors to a source of antigens and boost the therapeutic effect of immune check point blockade.
Method: A BALB/c breast cancer cell line was transfected with human mesothelin (66C14-M) and grown in BALB/c mice transgenic for human mesothelin. SS1P or RG7787 was injected directly into established tumors (80-100 mm3) and anti-CTLA-4 administered IP.
Results: We observed total tumor regressions in 23 out of 38 mice (60%) treated with anti-CTLA-4 and either RG7787 or SS1P. No cure was achieved when the drugs were given as a monotherapy supporting the case for synergic anti-tumor activity. Pathologic evaluation of regressing tumors showed a massive inflammation of admixed eosinophils and mononuclear cells located in a collar surrounding the tumors. Tumor regression was associated with increased number of CD8+ cells and was blocked when CD8+ cells were depleted by an antibody. In addition, cured mice were resistant to re-implantation of 66C14 cells not expressing mesothelin indicating that a long-term anti-tumor immunity was formed. To determine if pathogen associated molecular patterns contributed to the response, we combined anti-CTLA-4 with an inactive RG7787 and observed a major reduction in anti-tumor activity (P&lt;0.01) indicating that the effect is not mediated by recognition of a foreign bacterial protein.
Conclusions: We suggest that injecting immunotoxins into tumors is a useful approach to boost the activity of anti-CTLA-4. Based on the synergistic anti-tumor effect demonstrated in this study we believe that there is a strong rational to explore such combination therapies in patients.
Citation Format: Yasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Jay A. Berzofsky, Birgit Bossenmaier, Gerhard Niederfellner, James O'Brien, Yoram Reiter, Ira Pastan. Local intratumoral treatment with anti-mesothelin Immunotoxins overcomes resistance to anti-CTLA-4 therapy [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 58. doi:10.1158/1538-7445.AM2017-58
Abstract 5818: Disrupting the Aurora kinase A interactome in pediatric cancer
Authors: Mukherjee Sucheta , Tu Carolyn , Gustafson Clay 
Published: July 2017

Abstract
Neuroblastoma is the most common extra-cranial solid tumor of childhood. Amplification of the MYCN proto-oncogene occurs in 50% of the high-risk neuroblastoma and indicates an aggressive and lethal form of the disease. As a transcription factor with no apparent small-molecule surfaces, direct inhibition of MYCN has proven challenging. Proteolytic cleavage of MYCN is regulated in part by an activity-independent scaffold function of Aurora Kinase A (AURKA). The dynamic expression and activation of AURKA allows for precise cell cycle regulation of several substrates identified by protein-protein interaction studies that are also viable anti-cancer targets, such as the aforementioned MYCN oncoprotein. Utilizing co-immunopreciptation, flow cytometry, and other pertinent cell biology techniques, we aim to delineate a novel mechanism of targeting the AURKA interactome by conformation disruption of AURKA. We have recently described a neoteric class of confirmation disrupting “amphosteric” inhibitors of AURKA (CD-AURKAi) that orthosterically inhibit the ATP-binding pocket to dramatically disrupt the active conformation of AURKA to dissociate and degrade MYCN, a critical oncogenic driver of the pediatric cancer neuroblastoma. In addition to MYCN, our preliminary results show CD532 will also dissociate other oncogenic proteins that interact with AURKA. We hypothesize that conformation disruption of AURKA and subsequent blockade of an array of protein-protein interactions will delineate the roles of AURKA, MYC, and MYCN in the cell cycle and expand the clinical applications for CD-AURKAi in cancer to include non-MYCN driven diseases.
Citation Format: Sucheta Mukherjee, Carolyn Tu, Clay Gustafson. Disrupting the Aurora kinase A interactome in pediatric 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 5818. doi:10.1158/1538-7445.AM2017-5818
Abstract 5821: Loss of Pin1 suppresses Hedgehog-driven medulloblastoma tumorigenesis
Authors: Rual Jean-Francois M. 
Published: July 2017

Abstract
Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy and chemotherapy) have led to significant improvements, but are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed. Genetic mutations leading to the activation of the Hedgehog pathway drive tumorigenesis in ~30% of medulloblastoma. In a yeast two-hybrid proteomic screen, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hedgehog signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the post-phosphorylation fate of its targets. The GLI1/PIN1 interaction was validated by reciprocal pulldowns using epitope-tagged proteins in HEK293T cells as well as by co-immunoprecipiations of the endogenous proteins in a medulloblastoma cell line. Our results support a molecular model in which PIN1 promotes GLI1 protein abundance, thus contributing to the positive regulation of Hedgehog signals. Most importantly, in vivo functional analyses of Pin1 in the GFAP-tTA;TRE-SmoA1 mouse model of Hedgehog-driven medulloblastoma demonstrate that the loss of Pin1 impairs tumor development and dramatically increases survival. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in Hedgehog-driven medulloblastoma tumorigenesis.
Citation Format: Jean-Francois M. Rual. Loss of Pin1 suppresses Hedgehog-driven medulloblastoma tumorigenesis [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 5821. doi:10.1158/1538-7445.AM2017-5821
Abstract 5823: Modulation of the Hippo pathway protein YAP as a mechanism of resistance to MEK inhibition in MAPK hyperactivated neuroblastoma
Authors: Coggins Grace E. , Hart Lori S. , Elias Jimmy , Maris John M. 
Published: July 2017

Abstract
Background: Current therapies for high-risk neuroblastoma are highly toxic and ineffective, as a majority of patients will face therapy-resistant relapses. Our recent whole genome sequencing analysis revealed that a majority of relapsed tumors had mutations causing RAS-MAPK pathway activation. Recent studies have implicated the Hippo pathway transcriptional coactivator protein YAP in relapsed neuroblastoma as well as resistance to MEK inhibition in other cancer models. Based on these findings, we hypothesized that YAP activity may lead to acquired resistance to MEK inhibition, and that dual inhibition of these two pathways may have synergistic therapeutic efficacy.
Methods: We selected the cell line NLF from a panel of NB cell lines due to its high YAP expression and NF1 loss. NLF cells were treated with MEK inhibitor trametinib (20 nM) over a 72-hour period and whole cell lysates and nuclear lysates were collected for immunoblot. Effects of YAP knockdown via siRNA transfection with and without trametinib co-treatment on survival were assessed by CellTiter-Glo and RT-CES. Cell signaling analyses of tumor lysates from mouse SKNAS (NRAS Q61K) xenografts treated with vehicle, 0.3 mg/kg, 1 mg/kg, or 3 mg/kg for YAP, ERK, and apoptosis pathways were performed via immunoblot.
Results: Immunoblots of 72-hour time course treatments of trametinib in NLF showed decreased pYAP, the cytosolic inactive form of the YAP protein, indicating increased YAP capable of translocating to the nucleus, which was confirmed by analyses of nuclear extracts. siRNA-mediated knockdown of YAP alone in NLF cells had a modest effect on survival, while combinatorial inhibition of MEK and YAP signaling caused a significant reduction in cellular proliferation and survival. Immunoblotting of trametinib-treated SKNAS xenografts indicated decreased pYAP and pERK in response to increasing trametinib dose, while total YAP levels remained constant.
Conclusion: Our results demonstrate that prolonged trametinib exposure causes a marked nuclear enrichment of unphosphorylated YAP and co-inhibition of MEK and YAP in neuroblastoma models effectively reduces proliferation and survival. We are currently investigating the effects of MEK inhibition on the expression of YAP target genes and on cellular proliferation upon modulation of YAP protein expression.
Note: This abstract was not presented at the meeting.
Citation Format: Grace E. Coggins, Lori S. Hart, Jimmy Elias, John M. Maris. Modulation of the Hippo pathway protein YAP as a mechanism of resistance to MEK inhibition in MAPK hyperactivated neuroblastoma [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 5823. doi:10.1158/1538-7445.AM2017-5823
Abstract 5828: Targeting the polyamine-hypusine nexus for the treatment of neuroblastoma
Authors: Bachmann Andre S. , El-Khawaja Raid , Schultz Chad 
Published: July 2017

Abstract
The highly conserved and unique post-translational hypusine modification is essential for the activation of a single cellular protein called eukaryotic initiation factor 5A (eIF5A). Hypusination of eIF5A represents an essential mechanism in the control of cell proliferation and has been linked to cancer. The hypusine modification of eIF5A requires the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) and, importantly, uniquely depends on the polyamine spermidine as a selective substrate. Polyamines including spermidine are frequently dysregulated in neoplastic disease and are critical for cell proliferation. Ornithine decarboxylase (ODC) is the sentinel enzyme in polyamine biosynthesis. We pioneered the repurposing of the irreversible ODC inhibitor alpha-difluoromethylornithine (DFMO) for neuroblastoma (NB), a devastating pediatric cancer of the sympathetic nervous system. Our preclinical work was confirmed by other groups and spurred two consortia (NMTRC and NANT) to test DFMO in independent phase I/II NB clinical trials.
The oncogene MYCN is commonly amplified in high-risk NB patients and predicts poor prognosis. MYCN directly activates ODC (and eIF5A) and drives NB tumor progression, presumably through the activation of polyamines, but the precise molecular mechanisms are not fully understood. Since spermidine is the only molecule that can activate eI5FA through hypusine modification, we hypothesized that the polyamine-hypusine nexus provides a rational target site to identify new drug combinations that trigger synergistic anti-tumor effects.
In this study we found that DFMO combined with DHPS inhibitor GC7 induced synergistic drug reactions in NB at concentrations that are not lethal on their own. While each drug alone at higher concentrations induced p27/Rb-mediated G1/S cell cycle arrest, the combination of both drugs resulted in the induction of programmed cell death (apoptosis). The intracellular free polyamine levels (putrescine, spermidine, and spermine) were quantified by C-18 RP-HPLC and responded directly to drug treatments, suggesting specific drug targeting effects.
This dual-pronged drug combination approach that specifically targets the blockade of the unique polyamine/spermidine-dependent hypusine-eIF5A signaling circuit known to be involved in cell proliferation might lead to more effective DFMO treatment options by reducing high DFMO doses currently needed while achieving better therapeutic outcomes in NB.
Citation Format: Andre S. Bachmann, Raid El-Khawaja, Chad Schultz. Targeting the polyamine-hypusine nexus for the treatment of neuroblastoma [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 5828. doi:10.1158/1538-7445.AM2017-5828
Abstract 5847: SIRT1 protects against radiation-induced lung injury via de-acetylating the Ku70 and P65
Authors: Xue Jianxin , Zhou Lin , Na Feifei , Deng Lei , Lan Jie , Lu Bo , Dicker Adam , Lu You 
Published: July 2017

Abstract
Radiation-induced lung injury (RILI) is a common and serious complication in the radiation therapy of thoracic cancer, which significantly restricts the radiation doses of tumor. The prevention and treatment of RILI have long been clinical challenges. SIRT1 is an NAD+ dependent protein deacetylase and the exact role of SIRT1 in RILI remains unclear. The aim of this study is to investigate the prevention and repairing efficacy of RILI by adenovirus-mediated SIRT1 gene overexpression in a mice model. Our studies confirmed that the protein expression and activity of SIRT1 in lung tissues were decreased in RILI mice models in a time-dependent manner, but the mRNA expression level was not obviously changed. The activity of SIRT1 was elevated by orally given resveratrol, an agonist of SIRT1. The extent of RILI could be evidently alleviated by orally given resveratrol, as assayed by histopathology, malondialdehyde (MDA) and plasma cytokines (IL-1β, TNF-α and active TGF-β1). Overexpressing SIRT1 could obviously mitigate the extent of RILI (H&E staining and CT scan), the concentration of MDA and ROS in lung, IL-1β and active TGF-β1 in plasma; as well as improve the mice survival. Moreover, SIRT1 could inhibit the radiation-induced DNA damage in vivo and in vitro, and decreased the expression of acetylated- Ku70 in the lung. In vitro Co-IP experiment showed that the expression of SIRT1 in irradiated cells was reduced and the acetylated- Ku70 was increased; over-expressing SIRT1 promoted the de-acetylation of Ku70; interference of Ku70 could reverse the effect of SIRT1 in DNA repair. Furthermore, overexpressing SIRT1 could inhibit the acetylation level of NF-κB subunit RELA (P65) in the lung; in vitro report gene experiment showed that SIRT1 suppressed the NF-κB transcriptional activity. In conclusion, our results suggest that SIRT1 could evidently mitigate the RILI, repair the irradiation-induced DNA damage and inflammation via de-acetylating the Ku70 and P65. Our study may provide new avenue for the prevention and treatment of RILI in clinic.
Note: This abstract was not presented at the meeting.
Citation Format: Jianxin Xue, Lin Zhou, Feifei Na, Lei Deng, Jie Lan, Bo Lu, Adam Dicker, You Lu. SIRT1 protects against radiation-induced lung injury via de-acetylating the Ku70 and P65 [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 5847. doi:10.1158/1538-7445.AM2017-5847