bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR15: Primary resistance to MAPK inhibition in BRAF-mutant cancer is determined by kinetics of feedback release
Authors: Sos Martin L. , Gordan John D. , Shokat Kevan M. 
Published: August 2014

Abstract
Activating mutations in the serine/threonine kinase BRAF are among the most common genetic lesions across all cancers. Despite the clinical success of drugs that either inhibit the oncogene or its downstream effects on the MAPK pathway, only subgroups of BRAF-mutant patients enriched in different tumor lineages will respond to these therapeutics. Here, we show that MAPK-inhibition results in feedback-mediated reactivation of RAS signaling and a resulting paradoxical activation of BRAF/CRAF dimerization. We find, that the formation of paradoxical BRAF/CRAF dimers is dependent on the levels of GTP-RAS whereas transcriptional regulation of ERK signaling modulators as well as activation of receptor tyrosine kinases does not primarily contribute to this process. Using inhibitor-coupled beads, we provide evidence that MAPK inhibition leads to hyperactivation of BRAF and CRAF that results in reactivation of downstream effectors and therefore leads to primary resistance to MAPK inhibition. This feedback-dependent resistance can be suppressed by either genetic depletion of BRAF or the combination of MEK and RAF inhibitors. Overall, our data provide novel insights into the kinetics of primary resistance to MAPK inhibitors in BRAF-mutant tumors and might help to improve the efficacy of targeted therapies in these patients.
This abstract is also presented as Poster B03.
Citation Format: Martin L. Sos, John D. Gordan, Kevan M. Shokat. Primary resistance to MAPK inhibition in BRAF-mutant cancer is determined by kinetics of feedback release. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR15.
Abstract A127: Long-term cell culture models enable drug response determination for epigenetic therapeutics.
Authors: Hnilo Jim , Snead Katie , Bernards Karen , Nelson Brian , McKinley Keith , Waikins Kate , Crane Jonathan M. , Warrior Usha , Shah O. Jameel 
Published: August 2014

Abstract
There has been renewed interest in the field of cancer epigenetics from the pharmaceutical and biotech sectors owing to the discovery of druggable epigenetic modulators that undergo oncogenic mutation and thus represent attractive cancer drug targets. A challenge in this field has been that inhibition of some epigenetic targets results in a significantly delayed drug response that is not revealed by conventional, short-term cell growth assays. We therefore set out to define the two- and three-dimensional assay conditions necessary to yield robust cell line profiling data for therapeutics requiring an extended assay duration. The Eurofins Panlabs’ OncoPanel is a collection of 240 genomically characterized cell lines for which doubling times have been meticulously recorded and compiled over the last several years. Using historical doubling times to compute seeding densities, we demonstrate here that subconfluent, exponential growth can be achieved in the majority of OncoPanel cell lines over the course of 6- or 10-day, two-dimensional growth assays. The EZH2-selective inhibitor, GSK343, elicits a drug response that is dependent both on assay duration and EZH2 mutational status, whereas other less targeted inhibitors show little or no preference for either condition, illustrating the utility of this assay. Similar results were obtained using three-dimensional tumor spheroid assays. Collectively, these data demonstrate the advantages of cell line profiling under long-term assay conditions when drug response reflects a protracted mechanism of action.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A127.
Citation Format: Jim Hnilo, Katie Snead, Karen Bernards, Brian Nelson, Keith McKinley, Kate Waikins, Jonathan M. Crane, Usha Warrior, O. Jameel Shah. Long-term cell culture models enable drug response determination for epigenetic therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A127.
Abstract A217: Impact of pharmacokinetic (PK) variability on dose finding in phase 1 oncology studies.
Authors: Zhou Xiaofei , Liu Yi , Venkatakrishnan Karthik 
Published: August 2014

Abstract
Background: The key objective of Phase 1 dose escalation studies in patients for oncology compounds is to define the maximum tolerated dose (MTD) or biologically active dose range with high confidence. Small patient numbers and inter-patient heterogeneity are unavoidable factors in traditional “3+3” designs and contribute to uncertainty in MTD determination. It is hypothesized that PK variability in systemic exposures can increase uncertainty in defining the dose-toxicity (and dose-pharmacodynamics) relationship, thereby impacting the accuracy of dose finding in Ph 1. We herein performed simulations to quantitatively assess the impact of PK variability on MTD selection.
Materials and Methods: Three virtual scenarios of varying steepness of the exposure-toxicity relationship and 4 scenarios of PK variability (coefficient of variation [CV]: 80% [High], 40% [Moderate], 20% [Low], 0% [None]) were considered for simulations. Dose-linear PK was assumed and a standard “3+3” escalation design was used for simulations. The hypothetical starting dose was 1 mg and dose escalations used a modified Fibonacci scheme. 10,000 simulations were performed for each of the 12 scenarios, and the frequency of each dose selected as MTD was reported. The selected MTD was defined to have 20-33% dose-limiting toxicity rate.
Results: The simulation results are summarized as follows:

Regardless of the dose-toxicity relationship, increases in PK variability lead to a higher likelihood of underestimation of the MTD. Selecting the correct MTD is approximately 3 - 4 times more likely with low PK variability than with high PK variability.
Conclusions: Substantial PK variability can compromise the accuracy of MTD or recommended phase 2 dose determination in Ph 1/ Ph 1b dose escalation studies, emphasizing the importance of controlling PK variability in dose-finding oncology studies through optimal drug formulations and inclusion/ exclusion criteria that are customized to the predicted ADME (Absorption, Distribution, Metabolism, Excretion) properties of the development candidate.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A217.
Citation Format: Xiaofei Zhou, Yi Liu, Karthik Venkatakrishnan. Impact of pharmacokinetic (PK) variability on dose finding in phase 1 oncology studies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A217.
Abstract A221: Novel PARP6 inhibitors demonstrate in vivo efficacy in xenograft models.
Authors: Mayo Michele F. , Grosskurth Shaun , Wang Xin , Petteruti Philip , Nadella Prasad , Reimer Corinne , Mikule Keith 
Published: August 2014

Abstract
The poly (ADP-ribose) polymerase (PARP) family of enzymes are functionally implicated in DNA repair, transcriptional regulation, glucose metabolism, mitosis, and other cellular mechanisms. To date, the focus has been on defining the role of PARPs 1-3 in DNA damage repair. Currently, PARP1-3 inhibitors are in clinical trials for BRCA1/2 mutant ovarian and breast cancers. The roles of other PARP family members are starting to emerge. Using a cell-based assay measuring multi-polar spindle induction, PARP6 was identified as novel target with therapeutic potential. AZ482 and AZ108 were developed as potent PARP6 inhibitors. These compounds exhibited a unique and selective growth inhibition profile when screened in large panels of tumor cells and suitable pharmacokinetics in vivo. In sensitive hematological and solid tumor models, these compounds had low nanomolar potency in vitro and anti-tumor efficacy in vivo. Mechanistic studies suggest PARP6 inhibitors disrupt spindle pole clustering resulting in mitotic catastrophe and may show selectivity toward tumor cell lines with supernumary centrosomes.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A221.
Citation Format: Michele F. Mayo, Shaun Grosskurth, Xin Wang, Philip Petteruti, Prasad Nadella, Corinne Reimer, Keith Mikule. Novel PARP6 inhibitors demonstrate in vivo efficacy in xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A221.
Abstract A225: Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through structural optimization.
Authors: Han Kunkun , Xu Xin , Chen Guodong , Zeng Yuanying , Zhu Jingyu , Du Xiaolin , Zhang Zubin , Cao Biyin , Liu Zhaopeng , Mao Xinliang 
Published: August 2014

Abstract
Multiple myeloma (MM) is an incurable malignancy of plasma cells, which is associated with the overactivated phosphatidylinositol 3-kinases (PI3Ks)/AKT signaling pathway. Stimulated by interleukin 6 and or insulin-like growth factor 1, PI3K/AKT plays a key role in MM survival and chemoresistance, while genetic knockdown of these PI3-kinases by small interfering RNA (siRNA) leads to MM cell apoptosis and decreased proliferation. Therefore, PI3K is granted as a promising therapeutic target for MM. We previously identified the small molecule compound S14161 an inhibitor of pan-Class I PI3K isoforms by a high throughput screening strategy (Mao et al., 2011). S14161 displayed potent preclinical activity against MM and leukemia in vitro and in vivo. In the present study, we synthesized a panel of S14161 analogs based on the structure-activity relationship, of which BENC-511 was demonstrated to be more potent than S14161 in suppressing PI3K activity and inducing MM cell death. BENC-511 was derived from S14161 by removing 4-fluorophenyl group at the 2-position of the chromene core. Different from S14161, BENC-511 presented as a specific inhibitor for PI3K α and δ, but had no inhibitory effects on PI3K β, γ, AKT, or mTOR in the cell-free enzymatic assays. BENC-511 inhibited phosphorylation of AKT and its downstream signals mTOR, P70S6K, and 4E-BP-1 at low micromolar concentrations. Consistent with its effects on PI3K activity and cancer cell proliferation, BENC-511 induced MM cell apoptosis. Notably, addition of insulin-like growth factor 1 and interleukin-6, two important triggers for PI3K activation in MM cells, partly blocked BENC-511-induced MM cell death. BENC-511 also showed potent anti-myeloma activity in vivo. Oral administration of BENC-511 decreased tumor growth up to 80% within 3 weeks in two independent MM xenograft models, but presented minimal toxicity. Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis. Because of its robust potential and low toxicity (LD50 oral &gt;1.5 g/kg), BENC-511 could be developed as a promising agent for the treatment of multiple myeloma by targeting the PI3K/AKT signaling pathway.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A225.
Citation Format: Kunkun Han, Xin Xu, Guodong Chen, Yuanying Zeng, Jingyu Zhu, Xiaolin Du, Zubin Zhang, Biyin Cao, Zhaopeng Liu, Xinliang Mao. Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through structural optimization. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A225.
Abstract A231: Let 7a regulates IL-6 expression in malignant mesothelioma.
Authors: Tanino Mishie A. , Kohsaka Shinji , Yachi Kazuhiro , Tsuda Masumi , Kimura Taichi , Nishihara Hiroshi , Tanaka Shinya 
Published: August 2014

Abstract
IL-6-dependent signaling pathway leading to Stat3 phosphorylation is reported to be involved in malignant phenotype of mesothelima. Altered expression of microRNA (miR) is observed in many cancers, however, the mechanism how miR regulates IL-6 expression in masothelioma is still unknown. We performed immunohistochemistry for phosphorylated Stat3 (pStat3) in 12 human mesotheliomas. Next, using 7 mesothelioma cell lines, mRNA expression of IL-6 and IL-6R, together with several miRs that regulated IL-6, and Stat 3 phosphorylation were examined by RT-PCR and immunoblotting. Five of 12 mesotheliomas showed strong expression of pStat3 in their nuclei and let 7a was identified as one of the candidate molecules that regulate IL-6 expression in mesothelioma by using 3’UTR reporter system. Moreover, IL-6 was found to regulate miR-153, miR-340, and miR-410 expressions. These findings suggest that let 7a, miR-153, -340, and 410 may be involved in malignant phenotype through regulation of IL-6 pathway in mesothelioma.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A231.
Citation Format: Mishie A. Tanino, Shinji Kohsaka, Kazuhiro Yachi, Masumi Tsuda, Taichi Kimura, Hiroshi Nishihara, Shinya Tanaka. Let 7a regulates IL-6 expression in malignant mesothelioma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A231.
Abstract A234: In vivo RNAi screening to identify major players in pancreatic tumor maintenance and growth.
Authors: Fenoglio Silvia , Soto-Feliciano Yadira , Hannon Gregory , Hemann Michael 
Published: August 2014

Abstract
Pancreatic cancer is one of the leading causes of cancer-related death in the United States and no effective therapeutic options are currently available. The lethality of pancreatic cancer, due to the aggressiveness of the disease and the lack of effective treatment, underscores the urgency for a clinical solution. Nevertheless the multiple failures suffered in clinical trials involving diverse compounds and approaches point to the necessity of a better understanding of the disease, in particular of the molecular and cellular mechanisms underlying tumor development and progression. We aim to identify new therapeutic targets for pancreatic cancer treatment by performing in vivo RNAi screens, either in combination with Gemcitabine treatment to isolate modulators of drug response or without any treatment seeking for genes that play a fundamental role in tumor growth and maintenance.
Our model system is a cancer cell line derived from a genetically engineered mouse model that develops spontaneous pancreatic ductal adenocarcinoma (PDAC) after activation of a kras mutant (G12D) allele concomitantly with the deletion of the tumor suppressor p53 specifically in the pancreas. This cell line can be effectively transplanted orthotopically in syngeneic mice and preliminary data suggest that we can represent about 3.000 hairpins out of 10.000 per tumor when injecting 30.000 cells orthotopically in the pancreas in the absence of chemotherapy. Genes with established function in pancreatic cancer like Claudin4 and PDGFR scored as hits in the screening, and about 8 more were selected for further validation. In addition, our data show that the transplanted tumors are partially resistant to Gemcitabine treatment in vivo, despite the in vitro sensitivity, which indicate that the system is suitable for a synthetic lethal screen. We have established a model system suitable for in vivo screening in pancreatic cancer, either with or without chemotherapy. We challenged the complexity of pancreatic cancer by functional screening in order to focus our attention on potential key player of tumor progression with plausible clinical relevance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A234.
Citation Format: Silvia Fenoglio, Yadira Soto-Feliciano, Gregory Hannon, Michael Hemann. In vivo RNAi screening to identify major players in pancreatic tumor maintenance and growth. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A234.
Abstract A255: Antitumor activity and antioxidant status of fungal lovastatin against Dalton's lymphoma ascites in Swiss albino mice.
Authors: Velusamy Kavitha , Balraj Janani , Muthusamy Palaniswamy , Jayaraman Angayarkanni 
Published: August 2014

Abstract
Lovastatin, an inhibitor of the rate-limiting enzyme in the cholesterol biosynthetic pathway, hydroxymethylglutaryl coenzyme A reductase, has shown interesting antiproliferative activities in cell culture and in animal models of cancer. The present study was carried out to evaluate the anticancer potentials of lovastatin against Dalton's lymphoma ascites (DLA). The lovastatin given orally to mice at the dose of 5, 25, 50 mg/kg body weight for 10 days caused significant reduction in percent increase in body weight when compared to the mice of the DLA control group. Restoration of hematological and biochemical parameters towards normal was also observed. Tumor control animals inoculated with DLA showed a major decrease in the level of catalase (CAT), superoxide dismutase (SOD) and increase in thio-barbituric acid reactive substances (TBARS) levels in liver. Treatment with lovastatin (5, 25, and 50 mg/kg body weight) doses given orally caused a reversal of these changes towards the normal. This confirms the potent hepatoprotective and antioxidant nature of lovastatin. Lovastatin (50 mg/kg body wt, i.p) was effective to accelerate the apoptosis in the ascites tumor bearing mice that was evident from the fragmentation of DNA in gel electrophoresis. Further the morphological analysis of DLA cells aspirated from the lovastatin treated animals showed a significant (P&lt;0.01) increase of apoptotic cells than the control animals. The proapoptotic and antioxidant activities of the lipid lowering drug lovastatin may further suggest its possible therapeutic use as a cancer chemopreventive agent.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A255.
Citation Format: Kavitha Velusamy, Janani Balraj, Palaniswamy Muthusamy, Angayarkanni Jayaraman. Antitumor activity and antioxidant status of fungal lovastatin against Dalton's lymphoma ascites in Swiss albino mice. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A255.
Abstract A26: Translation of isoform-level gene signature into robust diagnostic assay for glioblastoma subtyping.
Authors: Bi Yingtao , Pal Sharmistha , Macyszyn Luke , Showe Louise C. , O'Rourke Donald , Davuluri Ramana V. 
Published: August 2014

Abstract
Translating the molecular signatures from classification strategies into robust diagnostic assays is essential for cancer therapy guidance and prognosis determination. To develop a clinically applicable molecular stratification assay for Glioblastoma multiforme (GBM) with significant prognostic value, we designed a novel classification system based on isoform-level gene expression profiles; an avenue unexplored for diagnostic and prognostic use. Using isoform-level expression clustering of The Cancer Genome Atlas (TCGA) samples, we identified four GBM subgroups with significant (p=0.0103) survival differences. A four-class classifier, built with 121 transcript-variants, assigns GBM patients’ molecular subtype with 92% accuracy. The classifier was translated to a high-throughput RT-qPCR assay and validated on an independent cohort of 206 glioblastoma samples. We found that proneural patients have the worst prognosis except for younger patients (&lt;40 years), while a better prognosis is observed for neural group among older patients (≥40 years). The isoform-level classifier, transformed from a high-dimensional platform to a low-dimensional RT-qPCR platform, provides a quantitative and reproducible stratification of GBM patients with prognostic significance, a requirement towards personalized medicine. The resulting diagnostic assay from the classifier has immediate clinical implications towards prioritizing patients for standard care versus aggressive therapy regimen.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A26.
Citation Format: Yingtao Bi, Sharmistha Pal, Luke Macyszyn, Louise C. Showe, Donald O'Rourke, Ramana V. Davuluri. Translation of isoform-level gene signature into robust diagnostic assay for glioblastoma subtyping. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A26.
Abstract A261: NPV-LDE-225 (Erismodegib) inhibits human prostate cancer stem cell growth in NOD/SCID IL2γnull mice by regulating Bmi-1 and microRNA-128.
Authors: Nanta Rajesh , Meeker Daniel , Rodova Mariana , Van Veldhuizen Peter J. , Shankar Sharmila , Srivastava Rakesh K. 
Published: August 2014

Abstract
Prostate cancer stem cells (CSCs) are defined by their extensive self-renewal, differentiation, and tumor initiation properties. It is now clear that CSCs are involved in tumor growth and recurrence, and resistance to conventional treatments. Thus, the strategy that suppresses stemness and consequently tumorigenic potential of CSCs could be considered for the management of prostate cancer. The objectives of this study were to examine the molecular mechanisms by which NPV-LDE-225 / Erismodegib (smoothened inhibitor) regulates stem cell characteristics in prostate cancer. Effects of NPV-LDE-225 on CSC's viability, sphere formation, apoptosis, transcriptional activity, and epithelial-mesenchymal transition (EMT) were measured. NPV-LDE-225 inhibited cell viability and spheroid formation, and induced apoptosis by activation of caspase-3 and cleavage of PARP. NPV-LDE-225 induced expression of Bax and Bak, and inhibited the expression of Bcl-2, Bcl-XL, XIAP, cIAP1, cIAP2 and survivin. NPV-LDE-225 inhibited Gli transcriptional activity, Gli-DNA interaction, and the expression of Gli1, Gli2, Patched1 and Patched 2 in prostate CSCs. Interestingly, NPV-LDE-225 induced PDCD4 and apoptosis and inhibited cell viability by suppressing miR-21. Furthermore, NPV-LDE-225 inhibited pluripotency maintaining factors Nanog, Oct4, cMyc and Sox-2. The inhibition of Bmi-1 by NPV-LDE-225 was regulated by up-regulation of miR-128. NPV-LDE-225 suppressed EMT by up-regulating E-cadherin and inhibiting N-cadherin, Snail, Slug and Zeb1 through regulating miR-200 family. Finally, NPV-LDE-225 inhibited CSC tumor growth which was associated with the suppression of Gli1, Gli2, Patched-1, Patched-2, Cyclin D1 and PCNA, and cleaved caspase-3 and PARP in tumor tissues derived from NOD/SCID IL2Rϒnull mice. Overall, our findings suggest that inhibition of the Shh signaling pathway in CSCs is a potential therapeutic strategy for prostate cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A261.
Citation Format: Rajesh Nanta, Daniel Meeker, Mariana Rodova, Peter J. Van Veldhuizen, Sharmila Shankar, Rakesh K. Srivastava. NPV-LDE-225 (Erismodegib) inhibits human prostate cancer stem cell growth in NOD/SCID IL2γnull mice by regulating Bmi-1 and microRNA-128. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A261.