bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2522: Molecular and cellular mechanisms underlying the therapeutic efficacy of the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011, in a preclinical model of myeloproliferative neoplasia
Authors: Pinzon-Ortiz Maria , Longmire Tyler , Rong Xianhui , Caponigro Giordano , Vanasse Gary , Lee Benjamin H. , Cao Z. Alexander 
Published: August 2015

Abstract
The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. The genetic aberration of JAK2V617F and the associated activation of STAT in myeloproliferative neoplasia (MPN) is one example of the involvement of this pathway in human cancer. We have previously shown the combination benefits of combining ruxolitinib (Jak1,2 inhibitor), with LGH447 (PIM inhibitor) and LEE011 (CDK4/6 inhibitor) in a Ba/F3-JAK2V617F-driven MPN model. Here, we set to explore the molecular and cellular mechanisms underlying this combination benefit in the JAK2V617F UKE-1 model of MPN.
The triple combination of ruxolitinib, LGH447 and LEE011 resulted in sustained tumor regression in the UKE-1 model. Ruxolitinib, LGH447 and LEE011 inhibited pSTAT5, pBAD and pRb respectively. The monotherapies and the combination of ruxolitinib + LGH447 did not affect G1-S cycle. In contrast, the combination of ruxolitinib+LEE011, LGH447+LEE011 and the triple combination resulted in significant inhibition of G1-S progression. Consequently, after 72 hours of treatment, the percentage of cells in S phase decreased from 67% under DMSO to 15.8% under ruxolitinib+LEE011, and to 1.6% under the triple combination. Furthermore, monotherapies of LGH447 or LEE011 did not affect cell viability. Ruxolitinib monotherapy and ruxolitinib+LGH447 combination reduced viable cell% by 47% and 86%, respectively. The triple combination reduced it by 91%.
Our data suggest that the triple combination efficacy is the result of both cell killing and cell cycle blockade. The inhibition of JAK-PIM pathway significantly reduced cell viability. And the inclusion of CDK4/6 inhibition by LEE011 lead to more potent cell killing and cell growth arrest. Taken together, the triple combination achieves sustained tumor regression in preclinical models of MPN.
Citation Format: Maria Pinzon-Ortiz, Tyler Longmire, Xianhui Rong, Giordano Caponigro, Gary Vanasse, Benjamin H. Lee, Z. Alexander Cao. Molecular and cellular mechanisms underlying the therapeutic efficacy of the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011, in a preclinical model of myeloproliferative neoplasia. [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 2522. doi:10.1158/1538-7445.AM2015-2522
Abstract 253: Synergistic antitumor activity of PD-1 signaling blockade and CD27 costimulation correlates with enhanced ratio of effector to regulatory T cells at the tumor site
Authors: Thomas Lawrence J. , He Li-Zhen , Wasiuk Anna , Gergel Lauren E. , Boyer James M. , Round Sarah M. , Marsh Henry C. , Keler Tibor 
Published: August 2015

Abstract
Varlilumab (CDX-1127) is a fully human agonist antibody to CD27, a TNF receptor superfamily member expressed on the majority of T cells and subsets of NK cells and B cells. As such, varlilumab is an immunotherapy designed to harness the body's natural immune response by enhancing the activation of T cells that can specifically recognize and kill cancer cells. In an ongoing Phase 1 clinical trial, varlilumab has been very well tolerated and has demonstrated clear biologic activity and promising signs of clinical activity in advanced, treatment-refractory patient populations. This clinical data provides the rationale for combination studies with other immunomodulatory therapies, including inhibitors of PD-1 signaling. In this study we investigated the activity of varlilumab in combination with anti-PD-L1 using a disseminated murine B cell tumor, BCL1 in human CD27 transgenic mice. In this model of i.v. inoculated BCL1 cells, we have previously shown that varlilumab can delay tumor growth, but rarely results in cures. Despite expression of PD-L1, the BCL1 tumors were completely resistant to anti-PD-L1 monotherapy. However, the combination of varlilumab and anti-PD-L1 resulted in a significant improvement in survival and approximately 50% long-term survivors. To investigate the mechanism resulting in the synergistic activity, we collected spleens (the major site of tumor growth) from tumor bearing animals treated with individual or combined regimens and processed them for flow cytometry analysis. We found that animals treated with the combination of varlilumab and anti-PD-L1 had a higher ratio of infiltrating immune cells to tumor cells relative to monotherapy or saline controls. In particular, the ratio of effector (CD8+) T cells to Treg and the number of IFNγ+ CD4 and CD8 T cells were highly increased with the combination treatment. These data demonstrate that CD27 costimulation combined with checkpoint inhibition with anti-PD-L1 can result in improved immune profile in the tumor and synergistic survival benefit. This study, along with the good safety profile of varlilumab reported in the Phase 1 study, support the design of future combination studies in patients with cancer.
Citation Format: Lawrence J. Thomas, Li-Zhen He, Anna Wasiuk, Lauren E. Gergel, James M. Boyer, Sarah M. Round, Henry C. Marsh, Tibor Keler. Synergistic antitumor activity of PD-1 signaling blockade and CD27 costimulation correlates with enhanced ratio of effector to regulatory T cells at the tumor site. [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 253. doi:10.1158/1538-7445.AM2015-253
Abstract 2535: Synergistic anti-tumor activity of the Notch gamma secretase inhibitor BMS-906024 and paclitaxel in the treatment of lung adenocarcinoma
Authors: Morgan Katherine M. , Lee Francis , Michaud Erin , Bertino Joseph R. , Fischer Bruce S. , Pine Sharon R. 
Published: August 2015

Abstract
Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancer cases, primarily through loss of the endogenous Notch inhibitor, Numb, or via gain-of-function mutations in the Notch1 receptor. Notch activity is associated with poor overall survival among non-small cell lung cancer patients whose tumors are wildtype for TP53. We set out to evaluate the combination of Notch-targeted therapy with front-line chemotherapy as an effective treatment for non-small cell lung cancer. Our study focused on lung adenocarcinoma, the most common histological subtype in lung cancer. To target Notch, we utilized the gamma secretase inhibitor (GSI) BMS-906024 which inhibits Notch activation. BMS-906024 is currently in Phase 1 clinical trials for patients with T-cell acute lymphoblastic leukemia and metastatic solid tumors, including lung cancer. Human cell lines representing the major genetic subtypes of lung cancer, most of which were derived from adenocarcinomas, underwent MTS drug synergy assays consisting of treatment with BMS-906024, cisplatin or paclitaxel, or the combination of GSI and chemotherapy. The dosing and timing for BMS-906024 administration were optimized by examination of maximal Notch1 inhibition. Analysis of the drug effects with CalcuSyn yielded Combination Index (CI) values, in which a CI of 0.5 or less was considered as strong synergism for the drug combination. We found that there were significantly lower CI values for the GSI BMS-906024 combined with paclitaxel than with cisplatin (average CI = 0.54 vs 0.85, respectively; P = 0.001). We then grouped the cell lines by major genetic subtype (wildtype versus mutant or null for EGFR, Kras or TP53). The synergy between BMS-906024 and paclitaxel was significantly greater in Kras-wildtype than Kras-mutant cells (average CI = 0.39 vs 0.68, respectively; P = 0.009), while there was no correlation with EGFR or TP53 status. These results are a step toward identification of potential biomarkers that could be used to predict patient response to Notch-targeted therapy, which could have a positive impact on the care of lung adenocarcinoma patients and be informative for treatment decisions.
Citation Format: Katherine M. Morgan, Francis Lee, Erin Michaud, Joseph R. Bertino, Bruce S. Fischer, Sharon R. Pine. Synergistic anti-tumor activity of the Notch gamma secretase inhibitor BMS-906024 and paclitaxel in the treatment of lung adenocarcinoma. [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 2535. doi:10.1158/1538-7445.AM2015-2535
Abstract 2536: Assessing combinations of FDA approved chemotherapy in malignant peripheral nerve sheath tumor (MPNST) cell lines
Authors: Kahen Elliott , Yu Diana , Cubitt Christopher , Sullivan Dan , Reed Damon R. 
Published: August 2015

Abstract
Background: Malignant Peripheral Neural Sheath Tumors (MPNST) are a type of sarcoma that arise spontaneously from a peripheral nerve or plexiform neurofibroma. Approximately 1 in 10 people with a constitutional mutation in the NF1 gene, a negative regulator of RAS function, develop MPNST with a peak incidence in the adolescent and young adult years. Available chemotherapy treatment for MPNST has low response rates, and the prognosis for unresectable or metastatic tumors is poor. A clinically relevant system to rapidly evaluate the efficacy of many agents and combinations of agents on MPNSTs which can be translated into clinical trials is needed.
Methods: Here, we seek to identify promising single drug and combination therapies using FDA approved and other agents of interest via high-throughput screening platforms, based on established MPNST cell line models (SNF02.2, SNF10.1, SNF94.3, and SNF96.2). Taking into consideration past lessons learned from in vitro experiments, we designed stringent screening conditions that assess the candidate compounds and combinations at clinically-relevant concentrations and exposure times that mimic the in vivo pharmacokinetics in an effort to maximize the translational potential of these results. Fifty-four agents with roughly ¼ inhibitors of the RAS downstream pathways, another ¼ kinase inhibitors, and the remainder a representation of many classes of agents with diverse mechanisms of action were screened across 4 cell lines with biological replicates. The majority of the agents are FDA approved. Others are in active clinical trials, demonstrate a promising mechanism of action, or have published preclinical data in MPNST models. CellTiter Glo assays were used to assess cell viability at the maximal achievable serum concentration from phase I studies and at two lower concentrations. Promising agents were then studied in two-drug combinations to evaluate for synergy in addition to efficacy of the combination. The combinations were selected with careful attention to known drug-drug interactions, metabolism, schedule and non-overlapping toxicities.
Results: Our screening results indicate that a number of FDA approved chemotherapy agents, evaluated at clinically relevant concentrations and exposure times, significantly reduced cell viability across all cell lines tested. These findings suggest promising opportunities for developing combination clinical trials.
Citation Format: Elliott Kahen, Diana Yu, Christopher Cubitt, Dan Sullivan, Damon R. Reed. Assessing combinations of FDA approved chemotherapy in malignant peripheral nerve sheath tumor (MPNST) 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 2536. doi:10.1158/1538-7445.AM2015-2536
Abstract 2560: The cisplatin and Chal-24 combination synergistically kills cancer cells through IAP and c-FLIP degradation, Ripoptosome formation and autophagy-mediated apoptosis
Authors: Shi Shaoqing , Wang Qiong , Xu Jennings , Padilla Mabel T. , Nyunoya Toru , Xing Chengguo , Zhang Lin , Lin Yong 
Published: August 2015

Abstract
Because chemoresistance is the major hurdle of anticancer therapy, sensitizing cancer cells to chemotherapy is a main challenge for improving survival in cancer patients. Combined therapy by using drugs with distinct functioning mechanisms may increase anticancer efficacy. We have recently identified the novel chalcone derivative chalcone-24 (Chal-24) as a potential therapeutic that kills cancer cells through activation of an autophagy-mediated necroptosis pathway. In this study, we investigated if Chal-24 can be combined with the frontline genotoxic anticancer drug cisplatin for cancer therapy. The combination of Chal-24 and cisplatin synergistically induced apoptotic cytotoxicity in lung cancer cell lines, which was dependent on Chal-24-induced autophagy. While cisplatin slightly potentiated the JNK/Bcl2/Beklin1 pathway for autophagy activation, it strongly triggered Chal-24-induced proteasomal degradation of the cellular inhibitor of apoptosis proteins (c-IAPs) and formation of the Ripoptosome complex that contains RIP1, FADD and caspase 8. Furthermore, cisplatin induced dramatic degradation of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (cFLIPL) which suppresses Ripoptosome-mediated apoptosis activation. These results establish a dual mechanism for potentiation of anticancer activity with combination of Chal-24 and cisplatin: to enhance apoptosis signaling through Ripoptosome formation and to release the apoptosis brake through c-FLIP degradation. Altogether, our work suggests that combination of Chal-24 and cisplatin could be employed for improving chemotherapy efficacy. (Supported by R01ES017328 (NIEHS/NIH) and DE-FG02-09ER64783 (DOE).
Citation Format: Shaoqing Shi, Qiong Wang, Jennings Xu, Mabel T. Padilla, Toru Nyunoya, Chengguo Xing, Lin Zhang, Yong Lin. The cisplatin and Chal-24 combination synergistically kills cancer cells through IAP and c-FLIP degradation, Ripoptosome formation and autophagy-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 2560. doi:10.1158/1538-7445.AM2015-2560
Abstract 2573: Investigation of factors involved in the hypersensitivity to KP1339-treatment
Authors: Alte Beatrix , Pirker Christine , Mohr Thomas , Kryeziu Kushtrim , Keppler Bernhard K. , Heffeter Petra , Berger Walter 
Published: August 2015

Abstract
The ruthenium-based compound KP1339 (trans-(tetrachlorobis(1H-indazole)ruthenate(III)), which is currently in Phase I/II trial, is already known for its promising anticancer activity. In course of a recent screening using diverse cancer cell lines of different origin (n = 25), a small subgroup with exceptional sensitivity to KP1339-treatment was discovered. The aim of the here presented study was to identify factors that underlie this sensitivity or which are connected to resistance to KP1339. Due to the fact that KP1339 comprises a metal center, interpretations of it's mode of action tend towards either generation of ROS or DNA binding. To avoid a biased approach, whole genome expression arrays were performed with mRNA isolated from hypersensitive and normal responsive cells that were either untreated or treated with KP1339 for 3 h and 6 h. Subsequent bioinformatic analysis of the gained data indicated that while hypersensitive cell lines activated pathways indicative for response to chemical stimuli (“metal ion”, “organic compound”), in normal responsive ones preferentially genes involved in pathways controlling cell cycle, DNA repair and metabolism were found. Subsequent investigations confirmed that upon KP1339-treatment hypersensitive cell lines showed pronounced apoptosis induction (indicated by caspase-mediated PARP cleavage and appearance of apoptotic nuclei visualized by DAPI staining). In contrast, normal responsive cells rather reacted with prolonged duration of the G2 phase to KP1339 treatment (video evaluation). This was confirmed by FACS analysis of ethanol-fixed and propidium iodide-stained cells indicating a profound increase in the percentage of cells with double DNA content upon KP1339 treatment. Moreover, in accordance to previous studies, KP1339 induced strong phosphorylation of ERK, p38 and JNK especially in normal responsive cell lines. This is of interest as p38 and JNK activation are known to be pro-survival factors within the extrinsic pathway of apoptosis. The relevance of this particular pathway is supported by preliminary results of activation of caspase 8 upon KP1339 treatment in hypersensitive cells. This knowledge can help to better understand the mechanisms underlying the promising anticancer activity of KP1339.
Citation Format: Beatrix Alte, Christine Pirker, Thomas Mohr, Kushtrim Kryeziu, Bernhard K. Keppler, Petra Heffeter, Walter Berger. Investigation of factors involved in the hypersensitivity to KP1339-treatment. [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 2573. doi:10.1158/1538-7445.AM2015-2573
Abstract 2583: Refinement of inhibitors of the KRAS-signaling naocluster protein, CNKSR1, that block oncogenic KRAS signaling and growth
Authors: Kirkpatrick D. Lynn , Indarte Martin , Scott Mike , Madrigal Assael , Grandjean Geoffrey , Powis Garth 
Published: August 2015

Abstract
Introduction: KRAS, the predominant form of mutated RAS (mut-KRAS), is found in ∼25% of patient tumors across many cancer types and plays a critical role in driving tumor growth and resistance to therapy. CNKSR1 (connector enhancer of kinase suppressor of Ras 1) a protein associated with KRAS in the RAS membrane signaling nanocluster and we have shown it is critical for mut-KRAS but not wild type (wt)-KRAS signaling and cell proliferation. CNKSR1 is a multi-domain protein with a pleckstrin homology (PH) domain, which we have exploited to discover inhibitors that selectively inhibit mut-KRAS tumor growth. The initial leads identified were found to inhibit mut-KRAS signaling and growth of mut-KRAS isogenic NSCLC cell lines (IC50 ∼ 30 μM) and compound refinement provided PHT-7390 and 7391 (IC50 5 to 10 μM). Importantly, they did not block the growth of wt-KRAS cell lines at concentrations up to 100 μM. In mice the agents had antitumor activity againsta mut-KRAS xenograft model and improved the activity of EGFR inhibitors without observable toxicity, but had poor pharmacokinetic properties.Methods: PHusis has used its in silico computational modeling of the PH-domain of CNK1 to optimize its lead inhibitors to improve potency and pharmacokinetic properties. In silico compound refinement has been paired with surface plasmon resonance spectroscopy (SPR) and in vitro cell line screening to provide the latest panel of highly potent CNK1 inhibitors that are moving toward late preclinical development.
Results: A panel of analogues of PHT-7390 and 7391 were synthesized with the aim of improving potency and pharmacokinetic properties. This structural optimization yielded several analogues with up to 100 fold greater potency than PHT-7390 to mut-KRAS NSCLC lines (IC50 10-100 nM) while retaining the differential in effect against wt-KRAS lines without activity up to 100 μM. Target engagement studies have shown that the agents inhibit mut-KRAS signaling in similar fashion as KRAS knockdown with siRNA, confirming on target effects in cells. Pharmacokinetic properties were also improved and agents have moved to clinical candidate selection. Conclusion: Potent and specific inhibitors of CNK1 PH-domain with improved pharmacokinetics have been identified. These novel PH-domain inhibitors now provide a therapeutic potential for patients with oncogenic KRAS for which there is currently no effective therapy.
Citation Format: D. Lynn Kirkpatrick, Martin Indarte, Mike Scott, Assael Madrigal, Geoffrey Grandjean, Garth Powis. Refinement of inhibitors of the KRAS-signaling naocluster protein, CNKSR1, that block oncogenic KRAS signaling and growth. [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 2583. doi:10.1158/1538-7445.AM2015-2583
Abstract 2599: Discovery and pharmacological characterization of the second generation of Btk inhibitors with improved target selectivity and enhanced in vivo efficacy
Authors: Zhang Jiayin , Liu Dong , Shen Ru , Yan Yinfa , Yang Liuqing , Zhang Minsheng , Feng Jun , Fu Beibei , Hu Jerry , Lu Biao , Wan Hong , Zhang Lei , Tao Weikang , Zhang Lianshan , Cao Jingsong 
Published: August 2015

Abstract
Bruton's tyrosine kinase (Btk) is an essential component of the B-cell receptor (BCR) signaling pathways regulating survival, activation, proliferation, and differentiation of B lymphocytes. The first Btk inhibitor, Ibrutinib, has demonstrated a significant clinical efficacy in a variety of B-cell malignancies. Through structure-guided approach, we have discovered two series of novel and potent Btk inhibitors, represented by EBI-1266 and EBI-1367, respectively. Both of these compounds showed high potency in inhibiting Btk kinase activity and growth of a number of aggressive lymphoma cell lines driven by aberrant BCR signaling, with IC50 value within low nanomolar range. Mechanistic studies examining BCR signaling pathway in related B cell lymphoma cell lines revealed that both EBI-1266 and EBI-1367 potently inhibited Btk phosphorylation and downstream Erk phosphorylation, similar to Ibrutinib. Furthermore, each compound showed unique and significant superiority over Ibrutinib: EBI-1266 had a cleaner selectivity profile against a panel of kinases with a cysteine residue in the conserved catalytic domain, and EBI-1367 exhibited &gt;10-fold higher in vivo exposure in multiple preclinical species. In a tumor xenograft mouse model where tumor growth is dependent on Btk activity, both EBI-1266 and EBI-1367 showed significant oral anti-tumor activities, with EBI-1367 being more efficacious than Ibrutinib, consistent with a higher exposure of EBI-1367 in both blood and tumor tissues. No evidence of overt toxicities was observed in rodents with prolonged oral administration for two weeks with doses at least 3-fold above a highly efficacious dose. In summary, the pharmacological profiles of EBI-1266 and EBI-1367 indicate that these compounds have a great potential to become the next generation of Btk inhibitors, offering advantages in pharmaceutical development, enhanced in vivo efficacy and reduced toxicities. We are currently performing IND-enabling studies aiming to initiate phase I clinical trials for these Btk inhibitors.
Citation Format: Jiayin Zhang, Dong Liu, Ru Shen, Yinfa Yan, Liuqing Yang, Minsheng Zhang, Jun Feng, Beibei Fu, Jerry Hu, Biao Lu, Hong Wan, Lei Zhang, Weikang Tao, Lianshan Zhang, Jingsong Cao. Discovery and pharmacological characterization of the second generation of Btk inhibitors with improved target selectivity and enhanced in vivo efficacy. [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 2599. doi:10.1158/1538-7445.AM2015-2599