bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2385: Identification of a molecular marker for cetuximab sensitivity and development of a novel combination therapy for non-small cell lung cancers.
Authors: Takata Miyako , Chikumi Hiroki , Yamaguchi Kosuke , Kurai Jun , Nakamoto Masaki , Burioka Naoto , Igishi Tadashi , Shimizu Eiji 
Published: August 2014

Abstract
The epidermal growth factor receptor (EGFR) is an important molecular target for non-small-cell lung cancers (NSCLCs). A recent phase III study (the FLEX study) revealed that the combination of the anti-EGFR antibody cetuximab with conventional chemotherapy improved the survival of patients with NSCLCs. However, the survival benefit was only about 5 weeks. Therefore, the identification of a molecular marker for cetuximab sensitivity is urgently needed. In this study, we investigated a new molecular marker for cetuximab sensitivity and developed a combination therapy to improve the effectiveness of cetuximab. First, we established a NSCLC cell line that showed resistance to cetuximab by culturing a parental sensitive NSCLC cell line in the presence of increasing concentrations of cetuximab. Next, we performed microarray analysis to compare the gene expression patterns of cetuximab-sensitive and -resistant cell lines. Using pathway analysis, we found that the Akt and Wnt pathways were significantly activated in the resistant cell line as compared to their activation in the sensitive cell line. We confirmed this result by performing western blot analysis, which showed Akt phosphorylation and beta-catenin dephosphorylation in the resistant cell line. Therefore, the activation status of either the Akt or Wnt pathway is the candidate pathway that influences cetuximab sensitivity. Finally, we focused on the Akt pathway and treated both resistant and parental sensitive cell lines with the PI3-K inhibitor LY294002 in combination with cetuximab. This combination therapy induced a synergistic growth-inhibiting effect in both cell lines. The data suggest that the activation status of the Akt pathway is one of the markers for cetuximab sensitivity and the combination of an Akt pathway inhibitor and cetuximab would be a promising anti-EGFR therapy for NSCLCs.
Citation Format: Miyako Takata, Hiroki Chikumi, Kosuke Yamaguchi, Jun Kurai, Masaki Nakamoto, Naoto Burioka, Tadashi Igishi, Eiji Shimizu. Identification of a molecular marker for cetuximab sensitivity and development of a novel combination therapy for non-small cell 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 2385. doi:10.1158/1538-7445.AM2013-2385
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2391: HPV status predicts therapy response in patients with locally advanced HNSCC receiving cetuximab-based radioimmunotherapy.
Authors: Stenzinger Albrecht , Wolf Janina , Jensen Alexandra , Endris Volker , Dietel Manfred , Weichert Wilko 
Published: August 2014

Abstract
HPV+ HNSCC show better therapy responses and improved survival when compared to HPV- HNSCC. No data exist on the prognostic value of HPV and combined HPV/EGFR status in patients with locally advanced HNSCC (LAHNSCC) treated with radiotherapy and cetuximab. The HPV status defined by p16INK4A immunohistochemistry and PCR-based chip analysis was assessed in a clinically well-characterized cohort of patients with LAHNSCC. Outcome was estimated using Kaplan-Meier analysis. Additionally, the EGFR expression levels and the effect of radioimmunotherapy in HPV+ and HPV- HNSCC cell lines were determined. 34% of the cases were p16INK4A/HPV positive. p16INK4A significantly correlated with male sex, younger patients and oropharnygeal localization and was a powerful predictor of OS (p=0.001) and PFS (p≤0.001). The HRs for HPV+ tumors were 0.17 (95%CI: 0.056-0.524, p=0.002) for OS and 0.12 (95%CI: 0.033-0.438, p=0.001) for PFS. P16INK4A correlated well with the HPV status (p≤0.001). The HPV+ UD-SCC2 cells had higher EGFR levels when compared to HPV- FaDu cells and the efficacy of combined radioimmunotherapy was stronger. This is the first study that demonstrates the prognostic value of HPV in patients with LAHNSCC receiving cetuximab-based radioimmunotherapy.
Citation Format: Albrecht Stenzinger, Janina Wolf, Alexandra Jensen, Volker Endris, Manfred Dietel, Wilko Weichert. HPV status predicts therapy response in patients with locally advanced HNSCC receiving cetuximab-based radioimmunotherapy. [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 2391. doi:10.1158/1538-7445.AM2013-2391
Abstract 2400: Differential phosphorylation of signaling targets as a function of RAS mutation status and tumor histology in non-small cell lung cancer.
Authors: Um Sang-Won , Chen Jingxiang , Lee Carrie , Sharpless Norman E. , Roberts Patrick J. , Hayes D. Neil 
Published: August 2014

Abstract
Background: While the importance of RAS and mTOR signaling pathways in non-small cell lung cancer (NSCLC) is well known, the activation status of key components in the pathway as a function of histology and oncogene mutation status has been not completely described. The purpose of this study is to investigate phosphorylation status of signal transduction pathway members and to elucidate their prognostic significance in relation to adenocarcinoma and squamous cell carcinoma.
Methods: Phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK), MEK 1 and 2 (pMEK), and mammalian target of rapamycin (pmTOR) were immunohistochemically examined using tissue microarray samples of 269 surgically resected primary NSCLC. Thyroid transcription factor-1 (TTF-1) expression and mutation status of EGFR and KRAS were also evaluated. The relationships between 5-year progression free survival (PFS) and phospho-protein expression were investigated by univariate analyses of log-rank test and multivariate analyses using Cox regression model.
Results: A total of 98 adenocarcinomas and 134 squamous cell carcinomas were included in the analyses. In adenocarcinoma, pERK expression was significantly related to pMEK (P = 0.001), pmTOR (P &lt; 0.001), and TTF-1 (P = 0.013) expression. In squamous cell carcinoma, pERK expression was significantly related to pMEK (P &lt; 0.001) expression. EGFR or KRAS mutations were significantly associated with TTF-1 expression (P = 0.014) in adenocarcinoma. However, EGFR and KRAS mutation status were not significantly associated with pERK, pMEK, and pmTOR expressions in adenocarcinoma. By univariate analyses, high pERK expression was associated with better 5-year PFS (P = 0.018) in adenocarcinoma and high pMEK expression was associated with worse 5-year PFS (P = 0.043) in squamous cell carcinoma. In multivariate analyses, pERK (P = 0.040) and pMEK (P = 0.048) expression were independent prognostic factors.
Conclusions: There were different patterns of phospho-protein expression in adenocarcinoma and squamous cell carcinoma. pERK expression was a good prognostic factor only in adenocarcinoma and pMEK expression was a poor prognostic factor only in lung squamous cell carcinoma.
Citation Format: Sang-Won Um, Jingxiang Chen, Carrie Lee, Norman E. Sharpless, Patrick J. Roberts, D. Neil Hayes. Differential phosphorylation of signaling targets as a function of RAS mutation status and tumor histology in non-small cell lung 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 2400. doi:10.1158/1538-7445.AM2013-2400
Abstract 2417: The INHERIT EGFR study: Investigating hereditary risk from T790M.
Authors: Oxnard Geoffrey R. , Root Elizabeth J. , Sable-Hunt Alicia , Rainville Irene , Dahlberg Suzanne E. , Heng Jennifer C. , Jackman David M. , Janne Pasi A. , Garber Judy E. 
Published: August 2014

Abstract
Background: The EGFR T790M mutation, commonly associated with acquired resistance to EGFR kinase inhibitors, has also been described rarely as a germline mutation in association with familial lung cancer. In collaboration with the Addario Lung Cancer Medical Institute (www.ALCMI.net), we initiated a prospective trial to identify patients and families carrying germline EGFR mutations in order to characterize their lung cancer risk.
Preliminary data: In a prior study (GR Oxnard et al, JTO, 2012), it was identified that patients with lung cancers found to harbor EGFR T790M at diagnosis have a 50% chance of carrying an underlying germline T790M mutation. This suggests that by focusing on patients already identified to carry T790M in their cancer, it is possible to enrich for a germline mutation that may be otherwise too rare to study prospectively.
Subject eligibility: The following groups are eligible: (1) Patients with a cancer (lung or other) harboring an EGFR T790M mutation on tumor genotyping; lung cancers that acquired EGFR T790M only following treatment with an EGFR kinase inhibitor are ineligible. (2) First-degree relatives of patients found to carry a germline EGFR mutation. (3) Patients who already are known to carry a germline EGFR mutation on prior testing. Subjects are referred to cohort 1 based upon genotyping results from academic centers, oncology practices, or partnering commercial laboratories (e.g. Response Genetics, Los Angeles, CA).
Trial design: Subjects may present at a participating cancer center or may participate remotely through a study website (www.Dana-Farber.org/T790Mstudy). Eligible patients submit a saliva and/or blood specimen for central testing in a CLIA lab. After counseling, patients carrying germline EGFR mutations have the option of inviting first-degree relatives to participate. Genetic counseling is coordinated at the participating center or offered over the phone. Chest CT scans are collected from germline carriers and analyzed centrally to study nodule prevalence and characteristics. Patients are then clinically followed for 2 years.
Funding: Supported by grants from the Conquer Cancer Foundation of ASCO and the Bonnie J. Addario Lung Cancer Foundation.
Citation Format: Geoffrey R. Oxnard, Elizabeth J. Root, Alicia Sable-Hunt, Irene Rainville, Suzanne E. Dahlberg, Jennifer C. Heng, David M. Jackman, Pasi A. Janne, Judy E. Garber. The INHERIT EGFR study: Investigating hereditary risk from T790M. [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 2417. doi:10.1158/1538-7445.AM2013-2417
Abstract 2421: Smoking, cancer treatment, and design of clinical trials.
Authors: Warren Graham W. , Marshall James R. , Cummings K. Michael 
Published: August 2014

Abstract
Purpose: Smoking has been associated with poor outcomes in cancer patients, but a detailed review of the effects of smoking on cancer treatment outcomes is necessary to effectively implement structured tobacco assessments and cessation into clinical trials design.
Methods: We searched Pubmed citations between 1950 and 2011 with the objective of identifying any reports relating smoking with cancer and non-cancer related outcomes in cancer patients. Our search yielded 34,000 pertinent citations of on smoking and cancer. Over 5000 of these citations appeared to include data on smoking as it might be related to cancer treatment outcomes and of these more than 800 were felt to have sufficient information to examine how smoking affects cancer treatment outcomes. Results were cataloged in tables and cross-references according to cancer disease site.
Results: The vast majority of pertinent reports provide evidence showing that smoking increases the risk of cancer and non-cancer related mortality as well as treatment related adverse events. The adverse effects of smoking and treatment outcomes are observed in all major cancer disease sites (lung, head/neck, breast, gastrointestinal, gynecologic, leukemia/lymphoma, prostate, and non-prostate genitourinary). A limited number of studies examine how smoking cessation affects treatment outcomes and generally these studies show that cessation of tobacco use is associated with fewer adverse treatment outcomes. Measurement of smoking behavior is a problem due to the reliance on self-reported behavior and lack of standardization in classifying smoking status. In most studies a patients’ cigarette use is categorized into ever smoking or current/former/never smoking; however, there is a broad diversity of definitions used making it less clear exactly how smoking affects treatment outcomes. Despite methodologic issues in published reports, results demonstrate a consistent pattern that smoking increases the risk of adverse outcomes across a broad spectrum of cancer disease sites. Conclusions: This review provides evidence that smoking adversely affects cancer related and non-cancer related outcomes in patients. What is less certain is how past and/or current smoking might differentially modify treatment outcomes for patients. Clinical trials must give strong consideration for prior tobacco history, current tobacco use, and efforts to track tobacco cessation during and following cancer treatment.
Citation Format: Graham W. Warren, James R. Marshall, K. Michael Cummings. Smoking, cancer treatment, and design of clinical trials. [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 2421. doi:10.1158/1538-7445.AM2013-2421
Abstract 2439: Obatoclax (GX15-070) potently induces apoptosis in head and neck squamous cell carcinoma (HNSCC) cell lines and enhances the activity of EGFR inhibitors.
Authors: Yazbeck Victor Y. , Dorritie Kathleen , Li Changyou , Grandis Jennifer , Zang Yan , Johnson Daniel E. 
Published: August 2014

Abstract
HNSCC represents 90% of head and neck tumors. More than half of HNSCC patients are initially treated with curative intent, but will relapse over the course of their disease and have poor prognosis with a median survival of 6-9 months. Novel therapeutic approaches are in desperate need for this patient population. The antiapoptotic BCL-2 family proteins like BCL-2, BCL-XL, and MCL-1 are involved in oncogenesis and chemoresistance and are overexpressed in HNSCC. Obatoclax is a small-molecule antagonist of the BH3-binding groove of the prosurvival (or anti-apoptotic) members of the BCL-2 family of proteins. It is the only compound among the current BCL-2 inhibitors in clinical trials that is capable of inhibiting MCL-1, in addition to BCL-2 and BCL-XL. We determined the activity of obatoclax in 4 HNSCC cell lines (UMSCC-1, Cal-33, 1483, UMSCC-22A). Cell viability was determined by MTT assay, and apoptosis by Annexin-V binding, FACS analysis and immunoblotting. All four HNSCC cell lines were highly sensitive to single agent obatoclax with IC50’s ranging from 50-300 nM. Obatoclax induced apoptosis in all four HNSCC cell lines as evidenced by increased Annexin-V binding at 48 hours from 10% in vehicle treated cells to 30-60% and through cleavage of caspase 3 and PARP. Interestingly, obatoclax enhanced the activity of the two small tyrosine kinase inhibitors of EGFR (erlotinib and gefitinib). We are the first to show the activity of obatoclax in HNSCC alone and in combination with EGFR inhibitors. In vivo study of obatoclax using human HNSCC xenograft tumors is currently underway. This preclinical study suggests that obatoclax might have a therapeutic role in HNSCC either alone or in combination with EGFR inhibitors.
Citation Format: Victor Y. Yazbeck, Kathleen Dorritie, Changyou Li, Jennifer Grandis, Yan Zang, Daniel E. Johnson. Obatoclax (GX15-070) potently induces apoptosis in head and neck squamous cell carcinoma (HNSCC) cell lines and enhances the activity of EGFR inhibitors. [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 2439. doi:10.1158/1538-7445.AM2013-2439
Abstract 2471: Chemical optimization of direct and selective molecular activators of pro-apoptotic BAX for cancer therapy.
Authors: Bellairs Joseph A. , Reyna Denis , Sethumadhavan Divakaramenon , Neelagiri Madhavi , Broadhead Alex , Baccei Christopher , Koss Brian , Opferman Joseph T. , Gavathiotis Evripidis , Walensky Loren D. 
Published: August 2014

Abstract
BAX is a pro-apoptotic BCL-2 family member that lies dormant in the cytosol until triggered by cellular stress to translocate to the mitochondria and form toxic oligomeric pores. The majority of cancer cells retain wild-type BAX and instead neutralize the death pathway by overexpressing anti-apoptotic BCL-2 family proteins. Thus, direct activation of BAX represents a pharmacologic opportunity to lower the apoptotic threshold in the setting of chemoresistance. Using a Stabilized Alpha-Helix of BCL-2 domain (SAHB) modeled after the BIM BH3 helix, we previously identified the “trigger site” for direct BAX activation at the confluence of alpha-helices 1 and 6. In silico screening for small molecule modulators of BAX led to our identification of BAX activator molecule 7 (BAM7), which selectively engages the trigger site and promotes BAX-mediated cell death (Gavathiotis et al, Nat Chem Biol, 2012). Here, we applied BAM7 to a panel of acute lymphoblastic leukemia cells and observe dose-responsive killing in the micromolar range. To improve the potency of anti-ALL activity, we undertook a systematic medicinal chemistry-based iteration of BAM7’s molecular features. A series of analogs demonstrate improved BAX binding activity based on a FITC-BIM SAHB/BAX competitive fluorescence polarization assay. The most potent binders were advanced to testing in a cellular model of anti-apoptotic protein-dependent chemoresistance. Whereas select BAM7 derivatives exhibited a potency similar to or greater than the BCL-2/BCL-XL inhibitor ABT-737 in a BCL-XL-dependent ALL cell line, the compounds significantly outperformed ABT-737 in the isogenic MCL-1-dependent ALL cells. Preliminary studies revealed favorable pharmacokinetic profiles for lead BAM7 derivatives, including oral bioavailability and central nervous system penetration. These early encouraging structure-activity relationship and pharmacokinetic data on chemically-optimized BAM7 analogs suggest that direct and selective activation of BAX may be a viable strategy for therapeutic induction of apoptosis in the context of cancer chemoresistance.
Citation Format: Joseph A. Bellairs, Denis Reyna, Divakaramenon Sethumadhavan, Madhavi Neelagiri, Alex Broadhead, Christopher Baccei, Brian Koss, Joseph T. Opferman, Evripidis Gavathiotis, Loren D. Walensky. Chemical optimization of direct and selective molecular activators of pro-apoptotic BAX 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 2471. doi:10.1158/1538-7445.AM2013-2471
Abstract 2479: Bz-423: A novel benzodiazephine mitochondrial-targeted drug, cytotoxic to human ovarian cancer cells.
Authors: He Gong , Tan Lijun , Wang Weimin , Boitano Anthony E. , Vandeven Natalie A. , Opipari Anthony W. , Liu J Rebecca 
Published: August 2014

Abstract
Objectives: Bz-423 is a chemically synthesized 1,4-benzodiazepine with cytotoxic activity in several cell types. We sought to determine the anti-neoplastic potential and mechanism of action in human ovarian cancer cells.
Methods: A total of 12 human ovarian cancer cell lines were used. Cultured cells were treated with Bz-423 or vehicle control in dose-response and time-course experiments. Viability was determined on the basis of plasma membrane integrity using flow cytometry. The mechanism leading to death in these cells was characterized ultrastructurally using electron micrscopy and by determining changes in reaction oxygen species, glutathione, mitochondrial function, caspase and Bak activation. Cytochrome c release from mitochondria was analyzed by immunofluorescence. Apoptosome complex formation was monitored by gel filtration chromatography.
Results: Bz-423 induced apoptosis in all ovarian cell lines at low micromolar concentrations by generating an intracellular superoxide signal from the mitochondria. The apoptotic response was associated with the release of cytochrome c from the mitochondria, collapse of the mitochondrial transmembrane gradient, and formation of the apoptosome complex containing Apaf-1 and caspase-9. The release of cytochrome c and a decrease in mitochondria glutathione within 2 hours of treatment was identified by ultrastructural evidence of mitochondrial swelling. Furthermore, Bak activation was necessary for apoptosis. Bz-423 effectively induced apoptosis in chemoresistant ovarian cancer cells overexpressing Bcl-2 and Bcl-xL.
Conclusion: Bz-423 is a novel compound that effectively kills human ovarian cancer cells, including cells that are resistant to conventional chemotherapies such as Cisplatinum. This compound has cytotoxic qualities that are unique among benzodiazepines. The mechanism of action involves both proximal and direct effects on the cell mitochondria that lead to apoptosis. Bz-423 is a novel compound that may have broad clinical impact in the treatment of ovarian cancer patients.
Citation Format: Gong He, Lijun Tan, Weimin Wang, Anthony E. Boitano, Natalie A. Vandeven, Anthony W. Opipari, J Rebecca Liu. Bz-423: A novel benzodiazephine mitochondrial-targeted drug, cytotoxic to human ovarian cancer 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 2479. doi:10.1158/1538-7445.AM2013-2479
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.