bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4354: Dihydroartemisinin inhibits mTORC1 signaling in tumor cells.
Authors: Odaka Yoshinobu , Xu Baoshan , Huang Shile 
Published: August 2014

Abstract
Dihydroartemisinin (DHA) is a derivative of artemisinin, a natural product isolated from the plant, Artemisia annua. DHA is also the active metabolite of first-generation artemisinin derivatives (artemisinin, artesunate, artemether, etc.). Artemisinins have been clinically used to treat malaria for decades. Recent studies have demonstrated that artemisinin and its derivatives possess anticancer activity. This study was set to investigate the anticancer mechanism of DHA. We found that DHA inhibited proliferation in a spectrum of tumor cells, by arresting cells in G1/G0 and G2/M phases, which was linked to downregulation of cyclin D1, CDK4 and CDC25A, as well as CDK1 and CDC25C expression, respectively. We also observed that DHA induced caspase-dependent apoptosis, which was related to downregulation of survivin, Mcl-1 and Bcl2. As the mammalian target of rapamycin (mTOR) is a master kinase that regulates cell proliferation and survival, we further tested whether DHA inhibits mTOR signaling. Interestingly, we observed that DHA inhibited phosphoryaltion of mTOR and its downstream effector molecules, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), in a concentration- and time-dependent manner, but did not obviously affect mTORC2-mediated phosphorylation of Akt, which is in contrast to the conventional mTORC1 inhibitor, rapamycin. The results suggest that DHA may represent a novel class of mTORC1 inhibitor, and may execute its anticancer activity primarily by blocking mTOR-mediated signaling pathways in the tumor cells.
Citation Format: Yoshinobu Odaka, Baoshan Xu, Shile Huang. Dihydroartemisinin inhibits mTORC1 signaling in tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4354. doi:10.1158/1538-7445.AM2013-4354
Abstract 4391: MET is a potential therapeutic target and a candidate for combination therapy with EGFR inhibition in triple-negative/basal-like breast cancer.
Authors: Kim Yu Jin , Choi Jong-Sun , Song Ji-Young , Jung Kyungsoo , Oh Ensel , Shin Young Kee , Choi Yoon-La 
Published: August 2014

Abstract
Triple-negative breast cancer (TNBC)/basal-like breast cancer (BLBC) are known as poor outcome subtypes with deficiency of targeted molecular therapy. Previous studies showed that MET may play a critical role in the development of TNBC and may be a rational therapeutic target. In order to evaluate MET as a potential therapeutic target for TNBC, we investigated genomic aberration and expression status of MET and evaluated efficacy of MET inhibitor, PHA-665752 in TNBC cell lines. MET protein expression was relatively high in TNBC cell lines. The depletion of MET using small interfering RNA (siRNA) led decreased cell proliferation and migration. PHA-665752 treatment resulted in decreased cell viability, and most of these cell lines were found to be moderately sensitive in their response to PHA-665752. The most resistant cell line, MDA-MB-468, showed exclusively high expression of EGFR, and then EGFR depletion using siRNA induced increased sensitivity to PHA-665752. In our cohort, BLBC was the subtype showing the highest relationship with MET expression among 5 subtypes (77/134, 57.5%, P&lt;0.001). MET expression had a poorer OS (P=0.001) and DFS (P=0.010). Interestingly, TNBC patients with co-expression of MET and EGFR worsen the DFS significantly compared with EGFR expression only. Our findings highly suggest that MET can be a potential therapeutic target in TNBC, and the combined inhibition of MET and EGFR may benefit for the treatment of BLBC patients.
Citation Format: Yu Jin Kim, Jong-Sun Choi, Ji-Young Song, Kyungsoo Jung, Ensel Oh, Young Kee Shin, Yoon-La Choi. MET is a potential therapeutic target and a candidate for combination therapy with EGFR inhibition in triple-negative/basal-like breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4391. doi:10.1158/1538-7445.AM2013-4391
Abstract 4420: Generating preclinical models to assess bone marrow toxicity induced by the PARP inhibitor olaparib in combination with chemotherapy.
Authors: O'Connor Mark J. , Mason Helen , Horner Steve , Slater Ian , Lau Alan , Cadogan Elaine , Oplustilova Lenka 
Published: August 2014

Abstract
Inhibitors of the DNA damage response (DDR) provide an exciting opportunity as new anti-cancer therapies. A prominent example is olaparib, an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1), that has shown potential as a monotherapy for tumours bearing BRCA1/2 defects in clinical trials. Apart from monotherapy based on the concept of synthetic lethality, PARP inhibitors also have the potential to provide additional benefit when used in combination with DNA damage-inducing chemotherapies. In the clinic, however, this approach has been challenging due to enhanced bone marrow toxicity.
Our aim is to generate preclinical models to provide a better understanding of the mechanisms for this limiting bone marrow toxicity. We characterized in vitro responses to DNA damage induced by IR and chemotherapy in human hematopoietic multipotent progenitors and mesenchymal stem cells, both components of bone marrow. In parallel, we modelled the effects of a platinum chemotherapy (carboplatin) in combination with olaparib in wild type rats with the aim of reproducing the clinical combination-induced bone marrow toxicity.
We will present data that provide initial insights into the suitability of the rat pre-clinical model to guide combination dose and schedules with olaparib and an assessment of the ability of different bone marrow and peripheral blood cell populations to act as useful biomarkers to guide better tolerated combination schedules.
Citation Format: Mark J. O'Connor, Helen Mason, Steve Horner, Ian Slater, Alan Lau, Elaine Cadogan, Lenka Oplustilova. Generating preclinical models to assess bone marrow toxicity induced by the PARP inhibitor olaparib in combination with chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4420. doi:10.1158/1538-7445.AM2013-4420
Abstract 447: Hypoxia induces tumor cell escape from T cell-mediated immunity via up-regulation of B7-H1.
Authors: Barsoum Ivraym B. , Smallwood Chelsea A. , Siemens D. Robert , Graham Charles H. 
Published: August 2014

Abstract
In the current research we describe a novel mechanism by which hypoxia contributes to tumour cell escape from lysis mediated by cytotoxic T lymphocytes (CTLs). Specifically, we show that when exposed to hypoxia for 24 h, human DU145 prostate and MDA-MB-231 breast cancer cells, as well as mouse B16-OVA melanoma cells, increased their expression of the immune inhibitory ligand B7-H1 at both the mRNA and protein levels in a manner dependent on hypoxia-inducible factor-1α (HIF-1α). Moreover, our findings revealed that the hypoxia-induced up-regulation of B7-H1 expression in tumour cells resulted in increased tumour cell resistance to lysis mediated by primed CTLs. We previously demonstrated that activation of nitric oxide (NO) signalling blocks HIF-1α accumulation in tumour cells exposed to hypoxia. Here we show that the NO mimetic glyceryl trinitrate (GTN; 10 nM) prevented the hypoxia-induced up-regulation of tumour cell B7-H1 expression as well as the increased resistance to CTL-mediated lysis. Furthermore, co-culture studies revealed that the increased expression of B7-H1 following exposure of tumour cells to hypoxia led to the apoptotic death of CTLs as well as Jurkat leukemia cells in a manner that could be prevented by blocking B7-H1, programmed cell death-1 receptor (B7-H1 receptor expressed by T cells) or by incubation with low concentrations of GTN. These results indicate that a potential immunotherapy of cancer could involve interference with B7-H1 function in hypoxic tumour cells via administration of NO mimetics.
Citation Format: Ivraym B. Barsoum, Chelsea A. Smallwood, D. Robert Siemens, Charles H. Graham. Hypoxia induces tumor cell escape from T cell-mediated immunity via up-regulation of B7-H1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 447. doi:10.1158/1538-7445.AM2013-447
Abstract 4470: Mechanisms of acquired resistance to the PI3K inhibitors in colorectal cancer cell lines.
Authors: Edgar Kyle A. , Wagle Marie-Claire , Yan Yibing , Belvin Marcia , Friedman Lori , Wallin Jeffrey 
Published: August 2014

Abstract
Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene or loss of the tumor suppressor PTEN. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K is a promising therapeutic target for cancer. There are multiple PI3K inhibitors in clinical trials and the current study investigates preclinical mechanisms of resistance to two clinical PI3K inhibitors, GDC-0941 and GDC 0032. Acquired resistance to PI3K inhibitors was generated in vitro, in SW48 parental and SW48 knock-in clones harboring hotspot PIK3CA mutations. We found that GDC-0941 resistant clones and GDC-0032 resistant clones demonstrated a marked signaling increase in the PI3K/Akt/mTOR pathway when released from drug inhibition, and different nodes in the pathway were activated. GDC-0941 resistant clones have elevated pAKT levels due to loss of PTEN, and the pAKT is further increased when drug is removed. GDC-0032 resistant clones retained functional PTEN protein, but had increased pS6 levels in the absence of GDC-0032. The result of increased PI3K pathway signaling in cells with acquired resistance to PI3K inhibitors resulted in a decreased sensitivity to inhibitors of the MAPK pathway upon removal of drug. Resistant cells maintained on PI3K inhibitors gained sensitivity to MAPK pathway inhibitors. These preclinical data may provide rationale for combination therapy in the clinic.
Citation Format: Kyle A. Edgar, Marie-Claire Wagle, Yibing Yan, Marcia Belvin, Lori Friedman, Jeffrey Wallin. Mechanisms of acquired resistance to the PI3K inhibitors in colorectal cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4470. doi:10.1158/1538-7445.AM2013-4470
Abstract 4534: Mutant KRAS2 mRNA PET imaging in spontaneous transgenic lung cancers.
Authors: Wickstrom Eric , Chen Chang-Po , Paudyal Bishnuhari , Wampole Matthew E. , Zhang Kaijun , Wang Antican , Lu Bo , Thakur Mathew L. 
Published: August 2014

Abstract
Treatment of lung cancer with anti-EGFR antibodies or tyrosine kinase inhibitors (TKIs) fails when KRAS2 cancer gene is activated by mutation. Mutation of the KRAS2 12th codon from the wild type GGU that encodes glycine (G) to a mutant GAU that encodes aspartate (D) occurs in some lung cancers. For this reason, we hypothesize that determining KRAS2 mutation status in vivo by external mRNA PET imaging will enable physicians to decide on alternatives to EGFR-directed therapy. To test the hypothesis, we designed wild type and mutant KRAS2 hybridization agents based on peptide nucleic acid (PNA), due to its strong, specific basepairing, and resistance to nucleases and proteases. At the C-terminus, we included a cyclized tetrapeptide based on insulin-like growth factor 1 (IGF1) to enable IGF1R-mediated cellular uptake. We included an N-terminal N2S2 chelator in order to bind 64Cu. We then administered the 64Cu-labeled agents by tail vein into mutant KRAS2 transgenic mice that develop spontaneous lung tumors. We demonstrated sequence-specific positron emission tomography (PET) imaging and quantitation of mutant KRAS2 G12D mRNA in the mice. The wild type control agent, differing by one base in the middle of the 12th codon, showed neglible images in the same mice. Wobble base agents with a hypoxanthine to detect either G12D or G12V KRAS2 mutants are under investigation. Supported by NIH CA148565; IP owned by EW/MLT, licensed to MTTI.
Citation Format: Eric Wickstrom, Chang-Po Chen, Bishnuhari Paudyal, Matthew E. Wampole, Kaijun Zhang, Antican Wang, Bo Lu, Mathew L. Thakur. Mutant KRAS2 mRNA PET imaging in spontaneous transgenic lung cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4534. doi:10.1158/1538-7445.AM2013-4534
Abstract 4570: Development of a proteolytically activatable EGFR Probody for cancer therapy.
Authors: Desnoyers Luc R. , Yang Annie , Liang Tony W. , Moore Stephen , Sagert Jason , Hostetter Daniel R. , Menendez Elizabeth , Han Fei , Krimm Michael , Wong Ken , Richardson Jennifer , West Jim W. , Liu Shouchun , Vasiljeva Olga , Lowman Henry B. 
Published: August 2014

Abstract
Antibodies directed to specific disease-related antigens have proven to be very successful therapeutics for a variety of disease indications. In spite of their high affinity and specificity for target antigen, target-mediated toxicity constitutes a major limitation for the development of antibodies to certain targets. We have addressed this type of on-target toxicity by developing a new class of targeting antibodies (Probody™ therapeutics) that remain in an inert, masked form until proteolytically activated at the site of disease. As a proof-of-concept for the construction of a Probody, we used cetuximab as a starting point. Cetuximab is an EGFR-targeted antibody approved for the treatment of colorectal and head-and-neck cancers that produces an on-target toxicity in the form of a skin rash that afflicts 88% of patients treated with the antibody. We engineered an EGFR Probody by incorporating an inhibitory masking peptide fused to the antibody light chain. Masking of the Probody is achieved through a linker that also incorporates a substrate that is cleaved by one or more proteases up-regulated in cancer. In vitro, EGFR binding and cell-based activities of the masked Probody were diminished compared to those of cetuximab, but treatment with exogenous target proteases activated the Probody and restored activity comparable to cetuximab. Using tumor xenograft models in mice, we demonstrated that the Probody remained masked in systemic circulation but was activated and accumulated in the tumor microenvironment. Tumor activation of the Probody translated to efficacy similar to that seen with cetuximab. Consistent with our results in mice, the Probody remained efficiently masked in non-human primates and did not cause skin toxicity such as that observed in animals treated with cetuximab. Together, these results demonstrate that antibody activity can be specifically targeted to diseased tissue by utilizing locally overexpressed proteases as activating agents, suggesting that a variety of antigens not previously amenable to an antibody therapeutic approach may be successfully addressed with Probodies.
Citation Format: Luc R. Desnoyers, Annie Yang, Tony W. Liang, Stephen Moore, Jason Sagert, Daniel R. Hostetter, Elizabeth Menendez, Fei Han, Michael Krimm, Ken Wong, Jennifer Richardson, Jim W. West, Shouchun Liu, Olga Vasiljeva, Henry B. Lowman. Development of a proteolytically activatable EGFR Probody for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4570. doi:10.1158/1538-7445.AM2013-4570
Abstract 4611: Multimodal activation of apoptosis by a hydrocarbon-stapled PUMA BH3 helix.
Authors: Edwards Amanda L. , Gavathiotis Evripidis , LaBelle James L. , Braun Craig R. , Opoku-Nsiah Kwadwo , Bird Gregory H. , Walensky Loren D. 
Published: August 2014

Abstract
The BH3 domain of BCL-2 family proteins is a critical interaction motif that mediates the crosstalk among anti- and pro-death members. We have applied hydrocarbon stapling to restore alpha-helical structure to synthetic BH3 domain peptides, recapitulating the architecture observed in the native context and/or when bound to their physiologic targets. By generating Stabilized Alpha-Helices of BCL-2 domains (SAHBs) modeled after the BID and BIM BH3 domains, we previously detected direct, quantifiable, and functional binding interactions with both anti- and pro-apoptotic BCL-2 family proteins. Like BIM BH3, PUMA BH3 is well known to broadly engage the variety of anti-apoptotic targets. However, the ability of PUMA BH3 to directly bind and activate BAX remains unresolved. Here, we report the synthesis of PUMA SAHB, a structurally-stabilized PUMA BH3 helix that, in addition to targeting the complete spectrum of anti-apoptotic proteins, directly binds to BAX. Structural analysis revealed that PUMA SAHB engages the α1/α6 trigger site of BAX in a manner analogous to the BIM BH3 helix. PUMA SAHB binding triggers functional BAX activation as reflected by dose-responsive and sequence-dependent BAX-mediated liposomal and mitochondrial release. Importantly, biotin-PUMA SAHB and Flag-PUMA protein pull-downs from cellular lysates confirm binding to the corresponding native multidomain anti- and pro-apoptotic targets. As PUMA has been implicated in driving apoptosis of a variety of neuronal cell types, we explored the therapeutic potential of PUMA SAHB activity in the context of neuroblastoma. Treatment of a variety of neuroblastoma cell lines, including SH SY5Y, Kelly and IMR5, induced dose-responsive caspase 3/7 activation and cell death. To confirm the on-target effects of PUMA SAHB, genetically modified cells lacking BAX and BAX were similarly treated, but no caspase 3/7 activation or viability effects were observed. Thus, we find that a stapled PUMA BH3 helix is a dual anti-apoptotic inhibitor and pro-apoptotic direct activator that may serve as an effective pharmacologic trigger of apoptosis in cancers of neural origin.
This work was supported by NIH grant R01 CA050239 to L.D.W. and an NSF Graduate Research Fellowship to A.L.E.
Citation Format: Amanda L. Edwards, Evripidis Gavathiotis, James L. LaBelle, Craig R. Braun, Kwadwo Opoku-Nsiah, Gregory H. Bird, Loren D. Walensky. Multimodal activation of apoptosis by a hydrocarbon-stapled PUMA BH3 helix. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4611. doi:10.1158/1538-7445.AM2013-4611
Abstract 4674: Pilot study of intrahepatic artery chemotherapy in combination with sorafenib in hepatocellular carcinoma patients.
Authors: Feun Lynn G. , Narayanan Govindarajan , Yrizarry Jose , Dinh Vy , Savaraj Niramol , O'Brien Christopher , Martin Paul 
Published: August 2014

Abstract
Background: Sorafenib and chemoembolization of the liver (TACE) have both produced increased survival in patients (pts) with hepatocellular carcinoma (HCC). However, not all HCC pts can tolerate or accept TACE due to portal vein thrombosis or risk of liver failure.Chemotherapy infused via intrahepatic artery infusion (IA) may potentially increase drug delivery to the tumor while reducing systemic toxicity. In this pilot trial, we combined IA cisplatin or IA carboplatin with oral sorafenib for pts with unresectable HCC and report our results herein.
Methods: Major inclusion criteria into this study include:unresectable HCC, Child's A or early Child's B (maximum 7 points on Child-Pugh scale), serum bilirubin &lt;3 mg/dl, ECOG performance status 0-1.
Treatment plan:IA cisplatin 60 mg/m2 or carboplatin AUC =6 was infused percutaneously IA on day 1 and then every 6 weeks. Sorafenib 400 mg po bid was given on day 1 and continuously. MRI or CT abdomen was done every 6 weeks. Recist criteria was used to measure response.
Results: 11 pts were accrued onto the study.Median age was 65 (range 48-84), median number of cycles 2 (range 1-7). Of 10 evaluable pts, 6 had clinical benefit (4 partial responses for 2+, 3+, 8+ and 18 months, 2 minor responses). Two of the responding pts withdrew to have ablation therapy or liver transplant after their HCC was able to be downstaged and remain free of disease for 32+ and 36+ months. Toxicity was generally tolerable and no pt withdrew due to drug toxicity.
Conclusion: Preliminary results with IA cisplatin or IA carboplatin with sorafenib are encouraging and this combination may downstage some pts with unresectable HCC. Further studies with this regimen are indicated.
Supported by Bayer HealthCare and Onyx Pharmaceuticals, Inc.
Citation Format: Lynn G. Feun, Govindarajan Narayanan, Jose Yrizarry, Vy Dinh, Niramol Savaraj, Christopher O'Brien, Paul Martin. Pilot study of intrahepatic artery chemotherapy in combination with sorafenib in hepatocellular carcinoma patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4674. doi:10.1158/1538-7445.AM2013-4674