bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2085: Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize tumor killing effect of an anti-VISTA monoclonal antibody in tumor bearing mice
Authors: Jiang Xiling , Leu Jocelyn , Singh Indrajeet , Snyder Linda A. , Wang Weirong 
Published: July 2016

Abstract
The V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a recently discovered co-inhibitory molecule that shares limited sequence homology with the IgV domain of immune regulators of the B7 family. A first-in-class monoclonal antibody (mAb) that targets VISTA is currently in development for evaluation in patients with non-small cell lung cancer and other types of cancer. Data from a preclinical mouse model (in human VISTA knock-in mice) showed that treatment with its surrogate antibody demonstrated tumor growth inhibition, which is believed to be associated with modulation of the myelomonocytic and T cell compartments. A mechanistic pharmacokinetic/ pharmacodynamic (PK/PD) modeling approach was applied that integrated the in vitro and in vivo information (PK, target occupancy (TO) and tumor growth), and incorporated key physiological processes. A one-compartment pharmacokinetic model with Michaelis-Menten elimination kinetics was used to characterize the nonlinear clearance of the surrogate antibody. The growth and killing of tumor cells was described with a cell distribution tumor growth/ killing model. Tumor killing effects can be described well by a linear relationship to VISTA TO. The developed PK/PD model captured the observed data in mice. This work also presents the potential of how mechanistic modeling and simulation can support first-in-human dose selection and dosing regimen optimization for immunomodulatory mAbs for anticancer immunotherapy.
Citation Format: Xiling Jiang, Jocelyn Leu, Indrajeet Singh, Linda A. Snyder, Weirong Wang. Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize tumor killing effect of an anti-VISTA monoclonal antibody in tumor bearing mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2085.
Abstract 2097: Translating a mutant p53 reactivating drug (ZMC1) in murine pancreatic cancer models
Authors: Yu Xin , Tsang Ashley T. , Withers Tracy , Gelleran John , Augeri David , Kimball S. David , Carpizo Darren R. 
Published: July 2016

Abstract
Pancreatic cancer therapy suffers from a lack of effective chemotherapy. TP53 is second only to KRAS as the most commonly mutated gene in pancreatic cancer with point mutations occurring in 75% of patients. We identified ZMC1 as an allele specific mutant p53 reactivator and lead compound for mutant p53 targeted drug development. ZMC1 restores wildtype structure and function by functioning as a zinc metallochaperone to restore zinc binding to mutant p53 proteins with impaired zinc binding. Our aim was to translate this novel mechanism in vivo using murine pancreatic cancer models. We investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of ZMC1 and performed efficacy studies for allele specificity in nude mice with subcutaneous tumors from murine pancreatic cancer cell lines derived from a genetically engineered mouse model (KPC) expressing mutant KrasG12D and different alleles of TP53 (WT, null, p53R172H, p53R270H). Tumor growth inhibition became apparent only in KPCp53-R172H xenografts but not in KPCp53-R270H. We then performed efficacy studies in the autochthonous KPC model and found that, ZMC1 extended the median survival from 15 to 26 days in the KPCp53-R172H mice (p = 0.05) but not in the KPCp53-R270H mice. We sought to improve the efficacy of ZMC1 by synthesizing it complexed with zinc (Zn-1) in a 2:1 molar ratio. Zn-1 significanlty increased the median survival of KPCp53-R172H mice from 15 to 35 days (p = 0.0042). The apoptosis rate in the tumors (by Immunohistochemistry staining with Cleaved Caspase 3) was also increased by treatment of ZMC1 and Zn-1. These studies indicate that ZMC1 can function in vivo as a mutant p53 targeted anti-cancer drug at doses that are well tolerated. Furthermore, ZMC1 can be optimized by synthesizing it complexed with zinc.
Citation Format: Xin Yu, Ashley T. Tsang, Tracy Withers, John Gelleran, David Augeri, S. David Kimball, Darren R. Carpizo. Translating a mutant p53 reactivating drug (ZMC1) in murine pancreatic cancer models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2097.
Abstract 2098: Understanding the synergy between temozolomide and PARP inhibition in Ewing sarcoma
Authors: Carlson Ruth , Kurmasheva Raushan 
Published: July 2016

Abstract
Ewing sarcoma is the fourth most common highly malignant childhood cancer; it is defined by a tumor-specific chromosomal translocation. In approximately 85% of all tumors, the EWSR1 gene on chromosome 22 is fused to a member of E26 transformation-specific sequence family of transcription factors, the FLI1 gene on chromosome 11. DNA damage induced by expression of EWSR1-FLI1 fusion gene is potentiated by PARP1 inhibition in Ewing cells, where EWSR1-FLI1 genes act in a positive feedback loop to maintain the expression of PARP1. As single agents, PARP inhibitors have shown promising activity in vitro, but only modest activity in in vivo models. In our previous work (in PPTP), we showed that low level damage to DNA by temozolomide (TMZ) can be potentiated up to 40-fold through inhibition of PARP by BMN-673, leading to dramatic tumor regressions in 5 of the 10 Ewing sarcoma xenograft models. Therefore, we were aimed to determine the differences between the tumors that respond to treatment with BMN-673 and those intrinsically resistant to it, and to understand the underlying mechanisms of such resistance, with the ultimate goal to develop more effective therapy for Ewing sarcoma.
We have used the same cell lines to investigate biochemical differences between those Ewing sarcoma lines where there is synergy in xenograft models in mice, and those where the combination is inactive. Our studies using cell lines show that, 1) in vitro BMN-673 and TMZ are synergistic in all cell lines, irrespective of their response as xenografts; 2) In vivo synergy correlates with intrinsic sensitivity to BMN-673 and TMZ in vitro. For Ewing lines, where there is no in vivo synergy when they are grown as xenografts, they are ∼9-fold resistant to BMN-673, and ∼15-fold resistant to TMZ relative to lines where there is synergy as xenografts.
The resistance of the Ewing sarcoma xenografts to the synergy of the combination of BMN-673 and TMZ in mice is a consequence of intrinsic resistance to either or both of the drugs.
The combination of BMN-673 and TMZ in Ewing sarcoma xenografts is the most dramatic synergy between two drugs to be reported. The synergy in vivo is restricted to Ewing sarcoma, yet only half of the models respond to combination treatment with the other half completely resistant. Studies proposed in this application will potentially identify biomarkers that will allow identification of patients likely to benefit from such treatment, and spare toxicity for those unlikely to respond.
Citation Format: Ruth Carlson, Raushan Kurmasheva. Understanding the synergy between temozolomide and PARP inhibition in Ewing sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2098.
Abstract 211: The mitochondrial protein MTP18 enhances chemosensitivity by promoting mitochondrial fission
Authors: Aung Lynn Htet Htet , Li Peifeng 
Published: July 2016

Abstract
Background: Chemotherapy plays a major role in cancer therapy. Yet, one of its greatest obstacles is the development of chemotherapy resistance. Hence, understanding the molecular basis of chemoresistance is crucial to improve its therapeutic outcome. A close relationship between mitochondrial dynamic and cellular apoptosis has recently been identified. Mitochondrial fission is necessary for initiation of cellular apoptosis, whereas mitochondrial fusion is able to inhibit apoptosis. However, the association of mitochondrial fission and chemo-sensitivity has not been widely explored. Recently, mitochondrial protein MTP18 has been shown to promote mitochondrial fragmentation in various cancer cell lines. However, its role in apoptosis and chemotherapeutic resistance remains elusive. Here, we aimed to detect 1) whether MTP18 is able to regulate mitochondrial fission and apoptosis in gastric cancer cells, and 2) by which mechanism it regulates these events.
Methods and Results: Doxorubicin is one of the most widely used chemotherapeutic agents in variety of cancers. Mitochondrial staining with MitoTracker Red CMXRos revealed doxorubicin was able to induce mitochondrial fission both in vitro and in vivo gastric cancer models. We observed doxorubicin led to a decreasing level of MTP18 expression in gastric cancer cell lines, and this effect was concentration- and time-dependent. To understand the role of MTP18 in doxorubicin-induced mitochondrial fission and apoptosis, endogenous MTP18 expression was knockdown using MTP18-shRNA. Strikingly, doxorubicin could not induce mitochondrial fission in gastric cancer cells transfected with MTP18-shRNA. On the other hand, upon enforced expression of MTP18, the same concentration of doxorubicin sensitized a significantly higher number of gastric cancer cells to undergo mitochondrial fission and apoptosis. These findings suggest that MTP18 is required for doxorubicin-induced mitochondrial fission and apoptosis. In exploring the molecular mechanism of MTP18, we found that MTP18 enriched dynamin-related protein Drp1 accumulation in mitochondria and mediated the signal of doxorubicin to induce mitochondrial fission. Drp1 accumulation in mitochondria caused the release of cytochrome-c to cytosol and subsequently promoted apoptosis.
Conclusion: Taken together, our findings suggest that MTP18 induces mitochondrial fission and enhances apoptosis in gastric cancer cells, by promoting Drp1 accumulation in mitochondria. Thus, it is compelling us to conclude that MTP18 enhances doxorubicin sensitivity of gastric cancer cells by targeting mitochondrial fission machinery.
Citation Format: Lynn Htet Htet Aung, Peifeng Li. The mitochondrial protein MTP18 enhances chemosensitivity by promoting mitochondrial fission. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 211.
Abstract 2112: ABCC11/MRP8 and ABCB1/MDR1 confer eribulin resistance to breast cancer cells
Authors: Oba Takaaki , Ito Ken-ichi , Taniguchi Shun’ichiro 
Published: July 2016

Abstract
Background: Eribulin is a key drug for the patients with metastatic breast cancer; however, the mechanisms of how breast cancer cells become resistant to eribulin have not been fully elucidated. The purpose of this study is to analyze the mechanisms of eribulin resistance in breast cancer cells.
Cell lines:
Eribulin resistant cell lines were established for three estrogen receptor (ER) positive cell lines (MCF7/E, BT474/E,ZR75-1/E), three triple negative cell lines (MDA-MB-231/E, Hs578T/E, MDA-MB-157/E), and one HER2 positive cell line (SKBR3/E) by exposing to stepwise increased doses of eribulin.
Results: The mRNA and protein expressions of both ABCC11 and ABCB1 were increased in all eribulin resistant cell lines regardless of their subtype. Inhibition of either ABCC11 or ABCB1 by small interfering RNA (siRNA) partially restored the sensitivity to eribulin in MCF7/E, BT474/E, and ZR75-1/E cells. Moreover, dual inhibition of ABCC11 and ABCB1 additively restored the sensitivity to eribulin in MCF7/E cells. On the other hand, overexpression of exogenous ABCC11 caused eribulin resistance in MCF7 and MDA-MB-231 cells (resistance ratio; MCF7; 13.8±0.85, MDA-MB-231; 11.4±0.74). Interestingly, inhibition of ER expression by siRNA or down regulation of ER by fluvestrant decreased ABCC11 expression and increased the sensitivity to eribulin in MCF7/E cells.
Discussion: Our data demonstrates that ABCC11/MRP8 and ABCB1/MDR1 confer eribulin resistance to breast cancer cells regardless of their subtype; moreover, our data suggests the possibility of involvement of ER pathway in the regulation of ABCC11 expression in the ER positive breast cancer cells. Although further studies should be required, the expression of ABCC11/ABCB1 may be used as biomarkers for prediction of response to eribulin in breast cancer. In addition, the inhibition of ABCC11/ ABCB1 might be of service in a novel strategy to enhance the antitumor effect of eribulin.
Citation Format: Takaaki Oba, Ken-ichi Ito, Shun’ichiro Taniguchi. ABCC11/MRP8 and ABCB1/MDR1 confer eribulin resistance to breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2112.
Abstract 2154: TX1111: a peptide homologue of Topoisomerase-1 sensitizes pancreatic cancer cells to gemcitabine
Authors: Gnanamony Manu , Stepanova Victoria , Criscione Lily , Boyineni Jerusha , Marshall Stephen J. , Holterman AiXuan , Gondi Christopher S. 
Published: July 2016

Abstract
Pancreatic Ductal Adeno Carcinoma (PDAC) is the fourth most common cause of cancer deaths in the United States and accounts for over 95% of all pancreatic cancers. The combined 1- and 5-year survival rates for PDAC are very poor, at 25% and 6% respectively. A major hallmark of pancreatic cancer is tumor recurrence and extremely poor response to chemotherapy. The current standard of care for patients with advanced pancreatic cancer is a chemotherapy regimen that includes gemcitabine. This treatment results in a modest benefit i.e., an increase in survival of only 5 weeks. The high mortality in patients diagnosed with this pancreatic cancer is primarily due to its drug-resistant nature and the lack of effective therapeutic strategies to overcome drug resistance. This disappointing situation strongly suggests that an improved and increased understanding of drug resistance mechanisms could lead to the development of novel therapeutic strategies for the successful treatment of patients with pancreatic cancer.
Our studies have shown that one of the contributing factors that lead to chemotherapy resistance is the protease activator urokinase plasminogen activator (uPA). To validate the contribution of uPA in chemoresistance, we overexpressed uPA in MIAPaCa-2 and PANC-1 cells and determined chemoresistance. We observed that uPA overexpressed cells showed increased chemoresistance in both Mia PaCa-2 (&gt;25 fold) and PANC-1 (&gt;6 fold). Mass-Spec analysis of nuclear uPA-IP from pancreatic cancer cells revealed that uPA interacts with Topoisomerase-1 (TOPO-1). This was further validated by western blot analysis of nuclear co-IP in pancreatic cancer cells. Further the binding domains of TOPO-1 to uPA were identified using overlapping a peptides array (PepSpot-JPT) followed by synthesis of these peptides. We observed that a TOPO-1 homologous peptide designated TX1111 was capable of significantly suppressing gemcitabine resistance in pancreatic cancer cells. Our observations show that the specific peptide TX1111 suppresses chemoresistance by 45% in Mia Paca-2 cells (p&lt;0.001) and by 40% in PANC cells (p = 0.002).
These results demonstrate that:
1. Overexpression of uPA promotes gemcitabine resistance in pancreatic cancer cells
2. uPA and TOPO-1 interact in the nucleus of pancreatic cancer cells
3. The peptide homologue of TOPO-1, TX1111 sensitizes gemcitabine resistant pancreatic cancer cells.
Citation Format: Manu Gnanamony, Victoria Stepanova, Lily Criscione, Jerusha Boyineni, Stephen J. Marshall, AiXuan Holterman, Christopher S. Gondi. TX1111: a peptide homologue of Topoisomerase-1 sensitizes pancreatic cancer cells to gemcitabine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2154.
Abstract 2156: Targeting estrogen receptor mutations for treatment of endocrine therapy resistance in breast cancer
Authors: Alluri Prasanna G. , Larios Jose , Malik Rohit , Rae James , Chiinaiyan Arul M. 
Published: July 2016

Abstract
Approximately 70% of all breast cancers express the Estrogen Receptor (ER) and inhibition of the ER signaling remains the mainstay of systemic therapy in such cancers. The advent of endocrine therapies (ET) have contributed significantly to reduction in the incidence, recurrence and mortality associated with breast cancer. However, approximately one-third of patients with ER-positive breast cancer do not benefit from adjuvant ET, and nearly all patients with ER-positive metastatic breast cancer (MBC) ultimately become refractory to all known ETs. While several mechanisms of resistance to ET have been proposed, there are currently no clinically effective treatments for ET resistance. Thus, ET resistance remains a major obstacle to the effective treatment of a significant subset of ER-positive breast cancers. We have recently reported recurrent somatic mutations in the ligand binding domain (LBD) of the Estrogen Receptor gene (ESR1) in metastatic breast cancer patients with a history of prior treatment with ET. The ESR1 mutations result in constitutive activation of the ER and confer ET resistance when ectopically expressed in ER-positive cell lines. In an attempt to develop novel therapeutic strategies to treat ET-resistant breast cancer, we have evaluated OTX015, a clinical bromodomain and extraterminal (BET) domain inhibitor, in pre-clinical models of ET resistance due to ESR1 mutations. Our studies suggest that BET inhibition may serve as an attractive strategy for treatment of ET resistance due to ESR1 mutations.
Citation Format: Prasanna G. Alluri, Jose Larios, Rohit Malik, James Rae, Arul M. Chiinaiyan. Targeting estrogen receptor mutations for treatment of endocrine therapy resistance in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2156.
Abstract 2171: Beta-hairpin peptide hydrogels as scaffolds for 3D high-throughput cancer drug discovery
Authors: Worthington Peter , Drake Katherine M. , Napper Andrew D. , Pochan Darrin J. , Langhans Sigrid A. 
Published: July 2016

Abstract
High-throughput screening (HTS) remains a promising initial step in discovering novel lead compounds for cancer therapy, but its value is limited by the poor predictability of clinical effectiveness of candidate compounds. One compelling reason for this lack of reliability to predict in vivo efficacy is the fact that most HTS is done using traditional two-dimensional (2D) cell cultures. While 2D cultures are convenient and can easily be automated, compelling evidence suggests that cells cultured in these non-physiological conditions differ from cells grown in the more in vivo like three-dimensional (3D) systems that better mimic microenvironments. Thus, a 3D culture model is expected to be a better platform for cancer drug discovery. Here we demonstrate the feasibility of a beta-hairpin hydrogel as a novel platform for 3D HTS. MAX8 forms a bonded fibrillar hydrogel network under physiological conditions and moreover, due to its unique shear-thinning abilities can be incorporated into standard HTS equipment. MAX8 is biocompatible with a variety of cancer cell lines, can be tuned for porosity, permeability and stiffness, and can be functionalized with common and cell-type specific ligands to more closely resemble an in vivo-like tumor environment. Using medulloblastoma cells that are known to display more immature, tumor-like features in 3D and that were automatically dispensed onto 384-well plates we have developed a robust assay to measure cell viability on a HTS platform that will have broad applicability for other cancers for which 3D HTS is desirable.
Citation Format: Peter Worthington, Katherine M. Drake, Andrew D. Napper, Darrin J. Pochan, Sigrid A. Langhans. Beta-hairpin peptide hydrogels as scaffolds for 3D high-throughput cancer drug discovery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2171.
Abstract 2176: Targeting eEF-2Kinase by thymoquinone in triple negative breast cancer
Authors: Kabil Nashwa N. , Bayraktar Recep , Kahraman Nermin , Ozpolat Bulent 
Published: July 2016

Abstract
Triple-negative breast cancers (TNBCs) constitute a heterogeneous subtype of breast cancers that present a significant challenge for the treatment and management, and have a poor clinical outcome. Eukaryotic elongation factor-2 kinase (eEF-2K) is an atypical calcium/calmodulin (Ca2++/CaM)-dependent Ser/Thr-kinase that regulates peptide chain elongation by phosphorylating its substrate elongation factor 2 (eEF2), resulting in decreased protein translation. Recently, we have reported that eEF-2K expression is significantly upregulated in TNBC cell lines and is associated with poor survival and worse prognosis, indicating that eEF-2K is a potential therapeutic target in TNBC. Moreover, we demonstrated that eEF-2K promotes TNBC cell proliferation, invasion/migration, and tumorigenesis. Its inhibition by systemically administered liposomal siRNA resulted in marked inhibition of tumor growth and enhancement in the efficacy of chemotherapy in orthotopic TNBC mouse models (Tekedereli 2012). Currently, there are no reported inhibitors of eEF-2K. Natural dietary poly phenolic compounds have been shown to inhibit various cancers by regulating various kinases and molecular targets, with both in-vitro and in-vivo activity. Thymoquinone (TQ) is an active ingredient isolated from Nigella sativa and has been investigated for its antioxidant, anti-inflammatory, and anticancer activities in several in-vitro and in-vivo models. However, the mechanism by which TQ mediates its effects not well understood. Here, we investigated if TQ inhibits eEF-2K in TNBC cells. We demonstrated, for the first time, that treatment with TQ decreases the expression of eEF-2K in a dose dependent manner as wells as its downstream targets, resulting in decreased proliferation, colony formation, migration, and invasion of TNBC cells. Furthermore, eEF-2K knockdown by siRNA recapitulates the effects of TQ, including cell proliferation, migration/invasion, and correlated events. Additionally, TQ treatment inhibits Src activity and other molecular targets, and induces significant apoptosis in TNBC cells in a caspase independent manner. Currently, we are investigating the downstream effects of TQ by RPPA analysis and its in-vivo efficacy in orthotopic xenograft mouse models of TNBC. Overall, our studies suggest that TQ could present a novel therapeutic strategy in targeting eEF-2K and inhibition of TNBCs.
Citation Format: Nashwa N. Kabil, Recep Bayraktar, Nermin Kahraman, Bulent Ozpolat. Targeting eEF-2Kinase by thymoquinone in triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2176.