bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5195: Modulating the UPR using the impridone ONC201 to change the impact of radiation on prostate cancer cells
Authors: Amoroso Francesca , Pickard Adam , McNaney Alice , Tarapore Rohinton , Allen Joshua E. , Mills Ian G. 
Published: July 2017

Abstract
Prostate cancer is the highest incidence non-cutaneous cancer in men, and a significant cause of cancer mortality. Localized disease is treated with surgery or radiotherapy and whilst androgen deprivation therapy can extend survival in the subset of cases that progress, metastatic disease is incurable. We have found that oncogenic drivers of prostate cancer, as well as therapy, lead to changes in the activation of prostate cancer cell stress signaling pathways and in particular the unfolded protein response (UPR). We have previously reported that the androgen receptor sustains the cytoprotective activity of the IRE1-XBP1 arm of the UPR and represses the activation of the PERK-ATF4 arm. We showed that treating prostate cancer cells with radiation leads to the activation of all three arms of the UPR, culminating in treatment resistance in surviving cells. In this study we assess whether the activation of the UPR in response to radiation mirrors the immunogenic/inflammatory response, which is known to occur in an initially acute apoptotic phase before resolving to a chronic sustainable level. Further we have evaluated the impact of combining radiation with ONC201, a novel anti-cancer small molecule in clinical trials that is an activator of the UPR, on the viability of prostate cancer. We find that ONC201 has a delayed cytotoxic effect as a single agent, with the impact on viability occurring from 72 hours onwards at low microMolar concentrations. However activation of multiple arms of the UPR occurs earlier and is detectable at 24 hours for ATF4, ATF6 and IRE1-XBP1 at the protein/mRNA levels. This time difference creates a window in which to introduce sequential administration of radiation to test ONC201 as a primer for cytotoxic response radiation. We have undertaken this work in a panel of cell-lines (PC3, DU145 and AR-expressing cell-lines) in which we have also knocked down key regulators (PERK, IRE1, CHOP) of separate arms of the UPR. This represents the first in vitro study to characterise the impact of ONC201 on the radiation-responsiveness of prostate cancer cells.
Citation Format: Francesca Amoroso, Adam Pickard, Alice McNaney, Rohinton Tarapore, Joshua E. Allen, Ian G. Mills. Modulating the UPR using the impridone ONC201 to change the impact of radiation on prostate cancer cells [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 5195. doi:10.1158/1538-7445.AM2017-5195
Abstract 5201: PSMA-targeted alpha radioimmunotherapy for prostate cancer with 225Ac-J591
Authors: Batra Jaspreet S. , Liu He , Kim Sae , Navarro Vicente N. , Vallabhajosula Shankar , Tagawa Scott T. , Bander Neil H. 
Published: July 2017

Abstract
Background: Prostate cancer (PC) is a radiosensitive disease. In addition to external beam and brachytherapy, systemic bone-seeking radioisotopes have been utilized clinically for many years, with radium-223 leading to overall survival benefits. However, the available beta and alpha emitting particles in the clinic target tumors / stroma in bone only. Biologically targeted radiopharmaceutical treatment has shown promising results in our earlier multiple clinical trials using beta-emitting anti-PSMA therapy with Leutetium-177 radiolabeled anti-PSMA monoclonal antibody (mAb) J591, with accurate targeting and tumor response, but treatment is limited by myelosuppression. Both beta and alpha-small molecule PSMA ligand directed therapy has been utilized anecdotally outside of the US, but has not been systemically studied. Based upon their biodistribution, targeting of salivary glands and potentially proximal renal tubules may pose longer term toxicity issues. mAb-based targeted alpha-particle delivery may be advantageous with less expected myelosuppression than seen with β-emitters.
Experimental procedures: To optimize labeling of humanized DOTA-J591 mAb, actinium-225 (225Ac) nitrate was obtained from Oak Ridge National Laboratories and was dissolved in HCl solution and then mixed with trimethyl ammonium acetate and L-ascorbic acid. This preparation was incubated with DOTA-J591. The labeling efficiency (LE) was determined by ITLC-SG. If the LE is &gt;60%, 225Ac-DOTA-J591 mAb was purified by gel filtration and sterilized by membrane filtration. In a pilot pre-clinical study, we studied the toxicity in non-tumor bearing BALB/c mice.
Results: The radiochemical purity is &gt;95% and the immunoreactivity was &gt;80%. Twenty-five BALB/c mice received from 2.1 to 6.3 KBq of 225Ac-J591. Treatment was well tolerated, with all mice alive and healthy at Day 26.
Conclusions: A stable alpha emitting-antibody complex has been produced with 225Ac-J591. Initial mouse safety experiments have been successful. A RIT dose escalation study of PSMA-targeted alpha emitter in a LNCaP xenograft model is underway.
Citation Format: Jaspreet S. Batra, He Liu, Sae Kim, Vicente N. Navarro, Shankar Vallabhajosula, Scott T. Tagawa, Neil H. Bander. PSMA-targeted alpha radioimmunotherapy for prostate cancer with 225Ac-J591 [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 5201. doi:10.1158/1538-7445.AM2017-5201
Abstract 5209: Ionizing radiation abrogates pro-tumorigenic effects from cancer-associated fibroblasts in xenografts
Authors: Hellevik Turid , Grinde Maria T. , Vik Jørg , Camilio Ketil A. , Martinez-Zubiaurre Inigo 
Published: July 2017

Abstract
Non-malignant elements of tumors play fundamental roles in both cancer sustainability and responses
to therapies. In the context of clinical radiotherapy (RT), all cells that reside in the tumor mass receive
radiation, but the impact of cancer-associated fibroblasts (CAFs) to treatment outcomes remains largely
unexplored. In this study, we have investigated the effects of radiation on the natural pro-tumorigenic
actions of CAFs in animals. Ionizing radiation (IR) was delivered to CAFs either as a single-high dose
or fractionated medium doses. Tumor development was compared in xenografts after co-implantation
of A549 lung tumor cells with irradiated or non-irradiated human lung CAFs. Quantitative histology
and immunohistochemistry was applied to investigate potential biological mechanisms behind tumor
growth regulations. As expected, CAFs showed resistance to radiation-induced cell death, however, the
enhanced tumorigenic effects observed with admixed non-irradiated CAFs was nullified. Quantitative
determinations of parameters such as desmoplasia, angiogenesis, inflammation, innate immunity or
tumor cell proliferation revealed enhanced blood vessel density in tumors established with irradiated
CAFs. Experiments to ascertain fate of implanted CAFs showed that both irradiated and non-irradiated
CAFs only reside at the implantation site during early stages, suggesting that the regulatory functions of
admixed CAFs may take place during the initial phases of tumor formation. In this study, we show that
CAFs receiving ionizing radiation lose their pro-tumorigenic potential in vivo, affecting angiogenesis
and possibly other mechanisms related to tumor engraftment. This finding represent a previously
unknown advantageous effect induced by radiotherapy, which adds to the well-known direct cytotoxic
effects on transformed epithelial cells.
Note: This abstract was not presented at the meeting.
Citation Format: Turid Hellevik, Maria T. Grinde, Jørg Vik, Ketil A. Camilio, Inigo Martinez-Zubiaurre. Ionizing radiation abrogates pro-tumorigenic effects from cancer-associated fibroblasts in xenografts [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 5209. doi:10.1158/1538-7445.AM2017-5209
Abstract 5211: Hormophysa triquerta polyphenol, an elixir that deters CXCR4- and COX2-dependent dissemination destiny of treatment-resistant pancreatic cancer cells
Authors: Aravindan Sheeja , Ramraj Sathish Kumar , Somasundaram Dinesh Babu , Kandasamy Kathiresan , Thirugnanasambandan Somasundaram S. , Herman Terence , Aravindan Natarajan 
Published: July 2017

Abstract
Therapy resistant pancreatic cancer (PC) cells play a crucial role in tumor relapse, recurrence, and metastasis. Recently, we showed the anti-PC potential of an array of seaweed polyphenols and identified efficient drug deliverables. Herein, we investigated the benefit of one such deliverable, Hormophysa triquerta polyphenol (HT-EA), in regulating the dissemination physiognomy of therapy resistant PC cells in vitro, and residual PC in vivo. Human PC cells exposed to clinical radiation (FIR), with/without HT-EA pretreatment were examined for the alterations in the tumor invasion/metastasis (TIM) transcriptome (93 genes, QPCR-profiling). Utilizing a mouse model of residual PC, we investigated the benefit of HT-EA in the translation regulation of crucial TIM targets (TMA-IHC). Radiation activated 30, 50, 15, and 38 TIM molecules in surviving Panc-1, Panc-3.27, BxPC3, and MiaPaCa-2 cells. Of these, 15, 44, 12, and 26 molecules were suppressed with HT-EA pretreatment. CXCR4 and COX2 exhibited cell line-independent increases after FIR, and was completely suppressed with HT-EA, across all PC cells. HT-EA treatment resulted in translational repression of FIR-induced CXCR4, COX2, β-catenin, MMP9, Ki-67, BAPX, PhPT-1, MEGF10, and GRB10 in residual PC. Muting CXCR4 or COX2 regulated the migration/invasion potential of IR-surviving cells, while forced expression of CXCR4 or COX2 significantly increased migration/invasion capabilities of PC cells. Further, treatment with HT-EA significantly inhibited IR-induced and, CXCR4/COX2 forced expression-induced PC cell migration/invasion. This study (i) documents the TIM blueprint in radiotherapy-resistant PC cells, (ii) defines the role of CXCR4 and COX2 in induced metastatic potential, and (iii) recognizes the potential of HT-EA in deterring the CXCR4/COX2-dependent dissemination destiny of therapy resistant residual PC cells.
Citation Format: Sheeja Aravindan, Sathish Kumar Ramraj, Dinesh Babu Somasundaram, Kathiresan Kandasamy, Somasundaram S. Thirugnanasambandan, Terence Herman, Natarajan Aravindan. Hormophysa triquerta polyphenol, an elixir that deters CXCR4- and COX2-dependent dissemination destiny of treatment-resistant pancreatic cancer cells [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 5211. doi:10.1158/1538-7445.AM2017-5211
Abstract 5214: Activation of WNT/b-catenin signaling results in resistance to PI3K/mTOR dual inhibitor in co-existing KRAS and PIK3CA mutant colorectal cancer cells
Authors: Park Ye-Lim , Kim Hwang-Phill , Cheon Seul-Ki , Kang Jun-Kyu , Lim Yoojoo , Song Sang-Hyun , Han Sae-Won , Kim Tae-you 
Published: July 2017

Abstract
KRAS is a frequently mutated gene in colorectal cancer. In addition, PIK3CA mutations commonly co-exist with KRAS mutations and lead to additive activation of the PI3K/mTOR signaling pathway. Here, we investigated preclinical activity of gedatolisib, a PI3K/mTOR dual inhibitor, to identify mechanism of inhibition of PI3K/mTOR in 28 colorectal cancer (CRC) cells. Cells specifically with PIK3CA mutation were sensitive while those with KRAS mutation were resistant to gedatolisib. 9 out of 28 CRC cells harbor PIK3CA & KRAS co-mutation and 7 out them were shown to be sensitive to gedatolisib. However, HCT15 and LS174T cells were resistant. We identified that resistant cell lines have high activity of GSK3B and TCF7 frameshift mutation (465insertC466;H155fs*), which functions as positive regulator of WNT/b-catenin pathway. The effects of GSK3B-knockdown showed decreased activity of mTOR downstream molecules in gedatolisib-treated resistant cells. Interestingly, these effects also caused a decrease in activity of WNT/b-catenin pathway. In addition, combination treatment of gedatolisib and CHIR-99021, GSK3B inhibitor, resulted in significantly enhanced cytotoxicity against gedatolisib-resistant TCF7 frameshift mutant cells. Taken together, these show that aberrant regulation of WNT/b-catenin pathway and high activity of GSK3B by TCF7 frameshift mutation cause resistance to PI3K/mTOR dual inhibitor. Inhibition of GSK3B activity in colorectal cancer cells with KRAS and PIK3CA co-mutations increases sensitivity to PI3K/mTOR dual inhibitor.
Citation Format: Ye-Lim Park, Hwang-Phill Kim, Seul-Ki Cheon, Jun-Kyu Kang, Yoojoo Lim, Sang-Hyun Song, Sae-Won Han, Tae-you Kim. Activation of WNT/b-catenin signaling results in resistance to PI3K/mTOR dual inhibitor in co-existing KRAS and PIK3CA mutant colorectal cancer cells [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 5214. doi:10.1158/1538-7445.AM2017-5214
Abstract 5218: Breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) transport ibrutinib and may restrict its oral availability and brain accumulation, whereas CYP3A4 limits ibrutinib oral availability
Authors: Hoppe Stephanie van , Rood Gert-Jan , Wagenaar Els , Sparidans Rolf , Beijnen Jos , Schinkel Alfred 
Published: July 2017

Abstract
Introduction: Ibrutinib (Imbruvica, PCI-32765) is an orally administered tyrosine kinase inhibitor (TKI) approved by the FDA in 2014 for treatment of B-cell malignancies. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with promising clinical activity and tolerability in B-cell malignancies. Ibrutinib is converted into several metabolites, primarily by CYP3A4. Its main metabolite, PCI45227, has an inhibitory activity towards BTK approximately 10 times lower than its parent compound. We investigated whether ibrutinib is a substrate for the multidrug efflux transporters ABCG2 and ABCB1 and whether these transporters influence oral availability and brain and other tissue accumulation of ibrutinib.
Materials: We used in vitro transport assays to assess human (h)ABCB1-, hABCG2- or murine (m)Abcg2-mediated transport of ibrutinib. To study the single and
combined roles of Abcg2 and Abcb1a/1b in oral ibrutinib disposition, we used appropriate knockout mouse strains. To assess the role of Cyp3a in the bioavailability of ibrutinib we used knockout strains as well as humanized CYP3A4 strains and measured the ibrutinib and PCI45227 concentrations at various time points.
Results: Ibrutinib was transported reasonably well by hABCB1 and mAbcg2, but not by hABCG2 in vitro. Upon oral administration of ibrutinib, Cyp3a-/-, Abcg2-/-, Abcb1a1b-/-, and Abcg2;Abcb1a1b-/- mice displayed an increase of 9.8-, 1.3-, 1.6- and 1.1 fold in ibrutinib plasma AUC0-20min compared to wild-type mice. At 20 min, preliminary data indicated that the relative brain accumulation of ibrutinib was not significantly altered for the Abcg2;Abcb1a/1b-/- mice compared to wild-type mice.
Conclusion: Abcg2 and Abcb1a/1b possibly restrict oral availability of ibrutinib. Based on our (preliminary) data ibrutinib may not substantially cross the blood-brain barrier. Cyp3a restricts the oral availability of ibrutinib and therefore inhibition of this enzyme may be of clinical importance for patients undergoing ibrutinib therapy.
Citation Format: Stephanie van Hoppe, Gert-Jan Rood, Els Wagenaar, Rolf Sparidans, Jos Beijnen, Alfred Schinkel. Breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) transport ibrutinib and may restrict its oral availability and brain accumulation, whereas CYP3A4 limits ibrutinib oral availability [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 5218. doi:10.1158/1538-7445.AM2017-5218
Abstract 5227: Synthesis of a biotin probe for identification of the ajoene protein targets in cancer cells ajoene protein targets in cancer cells
Authors: Kaschula Catherine H. , Kusza Daniel A. , Schafer Georgia , Katz Arieh A. , Singh Shivendra V. , Hunter Roger 
Published: July 2017

Abstract
Garlic (Allium sativum) is a medicinal plant belonging to the lily family which has been used since ancient times for its beneficial health effects which include protection against infections and cancer. There are a cluster of bioactive compounds found in crushed garlic which contain sulfide or polysulfide functional groups. One of these compounds, ajoene, is able to interfere with biological processes by undergoing thiolysis exchange reactions with biological thiols, for example glutathione and cysteine residues on proteins. Importantly, ajoene is cytotoxic to cancer cells in the low micromolar range. We have previously found that ajoene targets multiple proteins in cancer cells and the aim of this project is to identify the specific protein targets of ajoene. To achieve this aim, we have synthesized a “tagged” ajoene analogue containing a biotin functional group. As biotin may alter the biological properties of ajoene, our strategy was to initially synthesize an azide-containing ajoene analogue (called azide-ajoene) using our 4-step synthetic route to ajoene analogues previously published. Azide-ajoene was found to retain cancer cell cytotoxicity similar to that of the parent ajoene. We then treated cancer cells (MDA-MB-231 breast and WHCO1 oesophageal cancer) with azide-ajoene to allow transfer of an azide label to the protein targets during thiolysis exchange with ajoene. We then collected lysate from the treated cells and performed an in vitro click reaction with a separately synthesized biotin-alkyne partner which was synthesized via a series of substitution and amide coupling reactions. Click chemistry covalently links biotin to the ajoene-tagged protein via a triazole linkage; and the feasibility of this method was validated by western blot. The biotinylated protein targets were purified using immobilised streptavidin beads and identified by MALDI-TOF mass spectrometry. It is anticipated that knowledge of the specific ajoene protein targets will provide valuable insights into the cytotoxic mechanism of action of ajoene in cancer cells.
Citation Format: Catherine H. Kaschula, Daniel A. Kusza, Georgia Schafer, Arieh A. Katz, Shivendra V. Singh, Roger Hunter. Synthesis of a biotin probe for identification of the ajoene protein targets in cancer cells ajoene protein targets in cancer cells [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 5227. doi:10.1158/1538-7445.AM2017-5227
Abstract 523: HGF mediated upregulation of PHLDA2 is associated with apoptosis in gastric cancer
Authors: Koh Sung Ae , Lee Kyung Hee , Kim Jae Ryong , Kim Sang Woon 
Published: July 2017

Abstract
Pleckstrin homology-like domain family A member 2 (PHLDA2), a homolog of the mouse TDAG51 gene, was the first apoptosis-related gene shown to be imprinted and expressed from the maternal allele in normal development. It is located within the tumor suppressor region of 11p15, and its expression was reported to be suppressed in several cases of malignant tumors. But, the apoptotic regulatory mechanism and its role is not fully known in gastric cancer. The purpose of the this study is to identify of function of PHLDA2 associated with apoptosis in gastric cancer.
We used cell culture, western blotting, RT-PCR, MTT assays, PHLDA2 knock-down with short hairpin RNA (shRNA). First, we confirmed that the expression level of PHLDA2 was up-regulated by HGF(hepatocyte growth factor). To identify associated pathway of HGF-induced LCN2, the cells were treated with PI3-kinase inhibitor (LY294002) or MEK inhibitor(PD098059) or p38 inhibitor(SB203580) and then analyzed by Western blotting. The HGF-mediated PHLDA2 protein level was only decreased with LY294002. The role for PHLDA2 with was determined by knock down cell of PHLDA2. PHLDA2-sh RNA cells showed a decreased level of P53 and a increased level of pAKT. We also examined to confirm the role of HGF-mediated PHLDA2. HGF-mediated cell proliferation and in vitro invasion was increased in PHLDA2 knock down cell. Also, HGF-mediated cell apoptosis decreased in PHLDA2 knock down cell.
Our study showed that PHLDA2 upregulated HGF is regulated through PI3K/AKT pathway in gastric cancer, and PHLDA2 have a role in cell apoptosis in gastric cancer, which may be a possible target for developing gastric cancer therapy.
Citation Format: Sung Ae Koh, Kyung Hee Lee, Jae Ryong Kim, Sang Woon Kim. HGF mediated upregulation of PHLDA2 is associated with apoptosis in gastric 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 523. doi:10.1158/1538-7445.AM2017-523
Abstract 5235: Affecting activity of the linear ubiquitin chain assembly complex (LUBAC) with stapled alpha-helical peptides
Authors: Whiting Amanda L. , Aguilar-Alonso Francisco , Mitala Joseph J. , Bernal Federico 
Published: July 2017

Abstract
The linear ubiquitin chain assembly complex (LUBAC) is the only E3 ubiquitin ligase known to generate linear polyubiquitin chains in vitro. LUBAC is composed of three proteins - HOIL-1L, HOIP and SHARPIN - of which the interaction between HOIL-1L and HOIP has been shown to be critical for LUBAC assembly and function. This interaction occurs between the ubiquitin-like (UBL) domain of HOIL-1L and the ubiquitin-associated (UBA) domain of HOIP. One known substrate of LUBAC is the regulatory subunit NEMO (NF kappa B essential modulator), part of the IKK complex, which results in activation of NF-κB. We hypothesize that disruption of the HOIL-1L-HOIP interaction would prevent LUBAC ubiquitylation activity and result in down-regulated activation of NF-κB. We have synthesized a family of small inhibitor peptides designed to mimic aspects of the bent alpha-helical interacting interface of HOIP-UBA. Here we demonstrate how single amino acid substitutions and hydrocarbon stapling can affect overall peptide shape and helicity, and correlate that structural information to peptide binding affinity, ability to affect LUBAC complex formation and resulting effect on LUBAC ubiquitylation activity in vitro. These findings continue to validate inhibition of LUBAC via interference with the HOIL-1L-HOIP interaction as a potential target to affect NF-κB signaling. Compounds which affect LUBAC activity have potential use in LUBAC-dependent NF-κB activation in the activated B cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), the DLBCL subtype that is most resistant to current therapies.
Citation Format: Amanda L. Whiting, Francisco Aguilar-Alonso, Joseph J. Mitala, Federico Bernal. Affecting activity of the linear ubiquitin chain assembly complex (LUBAC) with stapled alpha-helical peptides [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 5235. doi:10.1158/1538-7445.AM2017-5235