bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3060: Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib and carfilzomib
Authors: Hasinoff Brian B. , Wu Xing , Patel Daywin 
Published: July 2016

Abstract
Bortezomib and carfilzomib are anticancer drugs that target the proteasomal system. Case reports indicate that the use of these drugs can result in cardiotoxicity. These drugs may also be used in combination with doxorubicin, which is itself cardiotoxic. Thus, in order to determine the mechanism of this cardiotoxicity studies were undertaken using a neonatal rat myocyte primary cell model. Using LDH release as a measure of damage in the myocyte model we showed that even brief exposure (6 h) to submicromolar concentrations of bortezomib resulted in significant myocyte damage. Carfilzomib was slightly less toxic and displayed myocyte damage in the low micromolar concentration range. Utilizing a fluorogenic substrate both bortezomib and carfilzomib inhibited the chymotrypsin-like proteasomal activity of myocyte lysate in the submicromolar concentration range. The inhibition kinetics were consistent with formation of an essentially irreversible covalent complex at the active site. Bortezomib irreversibly inhibited proteasomal activity about four-fold faster than carfilzomib. Thus, the reduced toxicity of carfilzomib may be due to its slower inhibition kinetics. A brief pre-exposure (6 h) of myocytes to low non-toxic nanomolar concentrations of bortezomib greatly increased doxorubicin-mediated damage. The doxorubicin cardioprotective agent dexrazoxane partially protected the myocytes from doxorubicin treatment and from bortezomib plus doxorubicin treatment under these conditions. However, at slightly toxic bortezomib concentrations dexrazoxane offered little protection against bortezomib plus doxorubicin treatment. Bortezomib, at least over short times, did not induce oxidative damage in myocytes as measured with a fluorogenic DCF assay. Likewise, a 6 h bortezomib treatment did not affect the mitochondrial membrane potential of myocytes as measured in a JC-1 ratiometric assay. In conclusion both bortezomib and carfilzomib are potently toxic to myocytes at submicromolar concentrations, likely through their ability to irreversibly inhibit myocyte proteasomal activity. Support: CIHR; a Canada Research Chair in Drug Development.
Citation Format: Brian B. Hasinoff, Xing Wu, Daywin Patel. Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib and carfilzomib. [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 3060.
Abstract 3063: Discovery of a third-generation EGFR inhibitor, which is highly selective and potent against both resistant and activating EGFR mutations for NSCLC therapy
Authors: Bao Rudi , Gao Peng , Zhang Fujun , Tong Zhaolong , Yu Hongping , Xu Yaochang 
Published: July 2016

Abstract
EGFR T790M mutation which renders resistance to the first-generation EGFR inhibitors,accounts for about 50% of all originally responsive non-small cell lung cancer patients. In order to overcome this type of resistance, we have developed a small molecular drug candidate with unique structural features that offer differentiated pharmacological and safety profiles pre-clinically when compared with other leading third-generation EGFR inhibitors. The compound selectively inhibits T790M as well as activating EGFR mutations, with much less inhibition to the wild type EGFR. Enzymatic inhibition IC50 against EGFR T790M,T790M/Del19 and T790M/L858R is less than 1nM. In addition, enzymatic inhibition IC50 against EGFR activating mutations Del19 and L858R is around 1nM, with much less inhibition to the wild type EGFR, a 10-time selection ratio. In cell based assays, the compound potently inhibits proliferation of EGFR T790M mutated NSCLC cell lines H1975(T790M/L858R)and PC9-GR(T790M/Del19)with an IC50 around 3nM. Similarly, it potently inhibits EGFR activating mutant NSCLC cell lines HCC827(Del19)and PC9(Del19). However, the compound displays about 200-fold less sensitivity to the EGFR wild type cancer cell line A431, with an IC50 around 600nM. When dosed to tumor-bearing animals, the compound dose-dependently induces profound regression of xenografts derived from both H1975 and primary human lung cancer LU1868, both of which carry an EGFR T790M mutation. It also induces regression of HCC827 xenografts potently, similarly to the first- and second-generation EGFR inhibitors; whereas it displays much less inhibition to the EGFR wild type A431 xenografts, demonstrating a higher specificity to the mutated EGFR forms when compared with the EGFR inhibitors on market. The drug candidate displays favorable PK and safety profiles. These properties warrant further development of this compound as first- as well as second-line therapy for NSCLC.
Citation Format: Rudi Bao, Peng Gao, Fujun Zhang, Zhaolong Tong, Hongping Yu, Yaochang Xu. Discovery of a third-generation EGFR inhibitor, which is highly selective and potent against both resistant and activating EGFR mutations for NSCLC therapy. [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 3063.
Abstract 3066: Anti-angiogenic properties of PM060184
Authors: Galmarini Carlos M. , Guillen Maria J. , Martinez-Leal Juan F. , Martinez-Diez Marta , Aviles Pablo 
Published: July 2016

Abstract
Vascular supply of tumors is one of the main targets for cancer therapy. Different studies have shown that most of the microtubule-binding agents present antiangiogenic and vascular-disrupting effects. PM060184 is a new marine-derived drug that binds to a new site in β-tubulin inhibiting tubulin polymerization. The compound is currently being evaluated in phase 1/2 studies in patients with advanced malignancies. The present study describes the antiangiogenic and vascular-disrupting properties of PM060184. Treatment of HUVEC endothelial cells with PM060184 resulted in depolymerization of the microtubule network. Differently from untreated cells, PM060184-treated cells showed a rounded morphology with a well-developed actin filament structure and plasma membrane blebs. Using transwell chambers pre-coated with matrigel™ or collagen matrix, we showed that PM060184 inhibited migration and invasion of HUVEC endothelial cells. We finally found that PM060184 interfered with the correct formation of the HUVEC capillary network grown on matrigel™; moreover, drug treatment also resulted in a significant disruption of the previously formed capillary-like network. This rapid collapse of the endothelial tubular network in vitro occurred in a concentration-dependent manner and was observed at concentrations lower than those affecting cells survival. These in vitro findings were confirmed in nude mice bearing MDA-MB-231 (breast) xenografts: after the administration of a single dose of PM060184 (at its MTD, 16 mg/kg,) a very strong reduction in the number of vessels was quantified in serial tumor sections stained with H&E. Moreover, nude mice xenografted with H-460 (NSCLC) tumors and treated with a single dose of either 2 or 16 mg/kg of PM060184, experienced a strong and dose-dependent decrease of the intratumoral fluorescence after the administration of Angiosense™ 680, a fluorescence vascular imaging probe. Altogether, these data suggest that an anti-vascular mechanism is also contributing to the anti-tumor activities of PM060184.
Citation Format: Carlos M. Galmarini, Maria J. Guillen, Juan F. Martinez-Leal, Marta Martinez-Diez, Pablo Aviles. Anti-angiogenic properties of PM060184. [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 3066.
Abstract 3075: Nuclear export inhibitor selinexor (KPT-330) demonstrates anti-tumor efficacy alone and in combination with chemotherapy in multiple breast cancer models
Authors: Paez Arango Natalia , Evans Kurt , Zhao Ming , Yuca Erkan , Scott Stephen , Kim Charissa , Naing Aung , Meric-Bernstam Funda 
Published: July 2016

Abstract
Background: The nuclear exporter XPO1 (Exportin1 or CRM1), mediates the transport of over 200 proteins, including several tumor suppressors. For this reason, XPO1 is being pursued as a promising target for cancer therapy options. Selinexor (KPT-330), a selective inhibitor of nuclear export, is an oral agent that has been shown to inhibit XPO1 and is currently in phase 2 trials for hematologic and solid tumors. We sought to determine the antitumor effect of selinexor in breast cancer cells in vitro and in vivo
Methods: We studied the effects of selinexor in vitro using cell proliferation assays; the half maximal inhibitory concentration (IC50) was calculated using isobologram curves after 3 days of treatment. We also tested the effects in combination with chemotherapy and calculated the combination index by the method of Chou and Talalay. In vivo efficacy was tested in triple negative breast cancer (TNBC) patient derived xenografts (PDXs) with varying levels of paclitaxel sensitivity, as single agent and in combination therapy. T/C ratio was calculated using the formula: [(median tumor volume of treated group)/(median tumor volume of control group) x 100]
Results: Selinexor treatment inhibited growth of 12 breast cancer cell lines representing different subtypes (TNBC as well as ER+, HER+) with a median IC50 of 375nM (range 3-750nM). Selinexor significantly reduced tumor growth in vivo in 4 of 5 different TNBC PDX models (with varying status of TP53 and PIK3CA, and gene expression subtypes), with a median T/C score of 48% (range 34-59%) In Multiple TNBC cell lines, selinexor was synergistic with paclitaxel, carboplatin, eribulin and doxorubicin in vitro. In vivo, selinexor in combination with paclitaxel or eribulin had greater antitumor efficacy than either agent alone.
Conclusions: Collectively these findings strongly suggest that selinexor is a promising therapeutic option for breast cancer.
Citation Format: Natalia Paez Arango, Kurt Evans, Ming Zhao, Erkan Yuca, Stephen Scott, Charissa Kim, Aung Naing, Funda Meric-Bernstam. Nuclear export inhibitor selinexor (KPT-330) demonstrates anti-tumor efficacy alone and in combination with chemotherapy in multiple breast 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 3075.
Abstract 3084: The effects of NT-1044, a novel AMPK activator, on endometrial cancer cell proliferation, apoptosis, cell stress, and tumor growth
Authors: Roque Dario R. , Wysham Weiya Z. , Zhou Chunxiao , Batchelor Ken W. , Brewster Wendy R. , Bae-Jump Victoria L. 
Published: July 2016

Abstract
Objectives: Obesity and diabetes are associated with increased risk and worse outcomes in endometrial cancer (EC). Anti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 (NovaTarg Therapeutics) is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and 3. We sought to compare the effects of NT-1044 on cell proliferation in human EC cell lines and on tumor growth in an endometrioid EC mouse model.
Methods: Cell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044. Apoptosis was analyzed by Annexin V-FITC assay. Cell cycle progression was evaluated by flow cytometry. Reactive oxygen species (ROS) were measured using a DCFH-DA assay. Western immunoblotting was performed to evaluate the effects of NT-1044 on the downstream targets of the AMPK/mTOR pathway and proteins related to cell cycle and cellular stress. For in vivo studies, we utilized the LKB1f/f/p53f/f mouse model of endometrioid endometrial cancer. Mice were treated with placebo or NT-1044 (200 mg/kg/day, oral gavage) following tumor onset for 4 weeks.
Results: NT-1044 significantly inhibited proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 uM for ECC-1; 87 uM for Ishikawa). Treatment with NT-1044 resulted in G1 cell cycle arrest, induced apoptosis and increased ROS production in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of the cell cycle proteins CDK4, CDK6 and cyclin D1 decreased in a dose dependent-fashion while cellular stress protein expression was induced in both cell lines. As compared to placebo, NT-1044 inhibited endometrial tumor weight in the LKB1f/f/p53f/f mice by 56% (p = 0.031).
Conclusions: NT-1044 suppressed EC cell growth through G1 cell cycle arrest, induction of apoptosis, cellular stress and inhibition of the AMPK/mTOR pathway. In addition, NT-1044 inhibited EC tumor growth in vivo. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes.
Citation Format: Dario R. Roque, Weiya Z. Wysham, Chunxiao Zhou, Ken W. Batchelor, Wendy R. Brewster, Victoria L. Bae-Jump. The effects of NT-1044, a novel AMPK activator, on endometrial cancer cell proliferation, apoptosis, cell stress, and tumor growth. [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 3084.
Abstract 3085: The BET family bromodomain inhibitor ABBV-075 targets multiple pathogenesis factors in multiple myeloma and exhibits robust in vivo efficacies as a single agent and in combination with bortezomib
Authors: Uziel Tamar , Lin Xiaoyu , Faivre Emily , Sarthy Aparna , Albert Daniel H. , Li Leiming , Wilcox Denise , Huang Xiaoli , Magoc Terry , Lam Lloyd , Elmore Steven W. , McDaniel Keith , Kati Warren , Shen Yu 
Published: July 2016

Abstract
Small molecule inhibitors of the bromodomain and extraterminal domain (BET) proteins represent a potential new class of cancer therapeutic agents. ABBV-075 is a potent and selective BET family bromodomain inhibitor that was recently advanced to Phase 1 studies. Here we report the in vitro and in vivo characterization of ABBV-075 in preclinical models of multiple myeloma. ABBV-075 exhibited significant anti-proliferative activities and triggered robust apoptosis across many multiple myeloma cell lines, including cell lines that were engineered to become resistant to bortezomib. As reported for other BET inhibitors, ABBV-075 potently inhibited super-enhancer regulated potential cancer drivers such as Myc, IRF8 etc. In addition to directly impacting multiple myeloma cell growth and survival, ABBV-075 also diminished stroma cell derived IL-6 secretion and prevented HUVEC cell proliferation in vitro. Given the importance of angiogenesis and the survival factor IL-6 for multiple myeloma pathogenesis, ABBV-075 could potentially produce significant therapeutic benefits in myeloma by simultaneously targeting multiple critical pathogenesis mechanisms for this disease. ABBV-075 caused significant tumor growth delay in the OPM2 flank tumor model as a monotherapy. Combining ABBV-075 with Bortezomib provided further therapeutic benefit compared with the treatment of either of the two agents individually. Taken together, our results suggest that ABBV-075 could be a promising option to explore for the treatment of multiple myeloma.
Citation Format: Tamar Uziel, Xiaoyu Lin, Emily Faivre, Aparna Sarthy, Daniel H. Albert, Leiming Li, Denise Wilcox, Xiaoli Huang, Terry Magoc, Lloyd Lam, Steven W. Elmore, Keith McDaniel, Warren Kati, Yu Shen. The BET family bromodomain inhibitor ABBV-075 targets multiple pathogenesis factors in multiple myeloma and exhibits robust in vivo efficacies as a single agent and in combination with bortezomib. [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 3085.
Abstract 3108: PD-L1 expressing circulating tumor cells (CTCs) in patients with head and neck squamous cell carcinoma (HNSCC)
Authors: Strati Areti , Koutsodontis George , Angelidis Ilias , Sasaki Clarence , Avgeris Margaritis , Psyrri Amanda , Lianidou Evi S. 
Published: July 2016

Abstract
Background: Predictive biomarkers for response to anti-PD1 therapy are lacking. Because therapy with checkpoint inhibitors is cost intensive, noninvasive tools for prediction of responders are of major interest.
Methods: The “Liquid Biopsy’’in head and neck squamous cell carcinoma (HNSCC) project involved the isolation of Circulating Tumor Cells (CTC) from patients with HNSCC at baseline, at different time points during treatment and at relapse. Herein, we assessed gene expression of PD-L1 on CTCs in a prospective fashion in a cohort of locally advanced inoperable HNSCC patients treated with curative intent (n = 61), in a second cohort of recurrent/metastatic HNSCC patients (n = 18) and in 20 healthy individuals, used as normal controls. For the quantification of PD-L1mRNA in CTCs, we developed a highly sensitive, specific, and robust RT-qPCR assay that was firstly analytically validated prior to its application in HNSCC patients.
Results: In patients with locally advanced disease, 54/61(88.5%) samples were evaluable for CTCs at baseline. Twenty four samples were obtained after induction chemotherapy (IC) and 34(55.7%) at the end of concurrent chemo-radiation. At baseline 22/54(40.7%) pts were found to be positive for PD-L1 overexpression, at the post-IC samples 12/24(50%) patients were positive for PD-L1overexpressionand at the end of treatment, 11/34 (32.4%) patients were positive for PD-L1 overexpression. Patients with PD-L1 positive CTCs at the end of treatment had shorter progression-free survival (PFS) (p = 0.011) and overall survival (OS) (p = 0.004). Multivariate analysis showed that PD-L1 overexpression in patients at the end of treatment was independent prognostic factor of PFS (HR = 2422.4; p = 0.014) and OS (HR = 32.23; p = 0.014). Five R/M patients were found to be positive for PD-L1 out of the 18 (27.8%) at baseline.
Conclusions: We demonstrate for the first time that detection of PD-L1+ CTCs at the end of treatment in patients with locally advanced disease is associated with shorter PFS and OS. Serial PD-L1 expression assessment has potential to select and monitor pts for PD-1 checkpoint inhibitors. These data support testing of PD-1 inhibitors in the adjuvant setting in patients with locally advanced HNSCC in whom PD-L1 positive CTCs are detected at the end of treatment.
Citation Format: Areti Strati, George Koutsodontis, Ilias Angelidis, Clarence Sasaki, Margaritis Avgeris, Amanda Psyrri, Evi S. Lianidou. PD-L1 expressing circulating tumor cells (CTCs) in patients with head and neck squamous cell carcinoma (HNSCC). [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 3108.
Abstract 3132: Genome-wide scan for genetic markers modifying survival of pancreatic cancer patients
Authors: Tang Hongwei 
Published: July 2016

Abstract
Background: Genetic factors that are associated with pancreatic cancer survival have previously been examined in Genome-Wide Association Studies (GWAS), but the results are inconsistent due to limited sample size.
Method: We performed a two-stage study on pancreatic cancer survival. The discovery phase took advantage of the existing GWAS data of 868 patients with European descendent from a case-control study conducted at MD Anderson. The validation study on ten top hits was conducted in another 820 white patients with Taqman. The missing genotypes were imputed using IMPUTE2 based on 1000 Genomes Project. Cox regression model was fitted to calculate allele-specific hazard ratios (HR) and 95% confidence intervals (95% CI) with adjustment for demographics, tumor stage, resection, and chemotherapy.
Results: After imputation, 7,738,399 SNPs with a Quality Score &gt;0.03, minor allele frequency &gt;0.01, and Hardy-Weinberg equilibrium were obtained for analysis. Three loci in complete LD at chromosome 2 were associated with overall survival (OS) at genome-wide significance (P = 1 ×): rs113988120 in PAIP2B (poly(A) binding protein interacting protein 2B), rs112493246 and rs138529893 in DYSF (dysferlin). The variant allele was associated with 3.02 fold higher risk of dying (95% CI: 2.07-4.40). SNP rs113988120 and nine others were examined in the validation study and rs113988120 remained nominally significant (P = 2.85 ×; HR: 1.45, 95% CI: 1.04-2.03). In the combined datasets of 1688 patients, this SNP was significantly associated with OS (P = 1.46 × and HR = 1.80 (95% CI: 1.42-2.30).
Conclusion: These observations support our hypothesis that genetic variations to a certain degree influence patient survival in pancreatic cancer.
Key words: Pancreatic cancer, GWAS, Survival
Citation Format: Hongwei Tang. Genome-wide scan for genetic markers modifying survival of pancreatic cancer patients. [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 3132.
Abstract 3168: Your targeted population might not be what you predict: Changes in tumor genetic landscapes post standard of care
Authors: Greenawalt Danielle , Dulak Austin , Ramakrishna Manasa , Lai Zhongwu , Johnson Justin , Dai Hongyue , Mitchell Melissa , Barrett Carl , Fawell Stephen , Dry Jonathan 
Published: July 2016

Abstract
Our current understanding of the mutation spectrum of relapse/refractory patients is limited. Public sequencing efforts have focused by design, on primary tumors, while re-biopsy of patients who are refractory to first line therapy or who relapse on treatment is not standard protocol. We have performed whole exome sequencing on post standard of care biopsies from 3 patient cohorts, 47 DLBCL patients post-relapse following R-CHOP, 49 triple negative breast (TNBC) following taxol alone or in combination and 41 lung adenocarcinoma (LUAD) following platinum alone or in combination. Comparative analysis of the mutation spectrum of these cohorts was performed against available clinically matched primary tumor cohorts. Comparison of the mutational signatures, somatic variant frequencies and copy number variation between matched pre- and post-treatment samples, and treated-primary tumor cohorts were performed. Significant differences were identified in the frequency of oncogenic drivers including PIK3CA in TNBC and KRAS in LUAD. We also observed mutational signature differences between cohorts that could impact treatment regimens post standard of care. Collectively these data further highlight the value of re-assessing the tumor genetic landscape at the time of treatment rather than relying on primary tumor samples, which may not be representative of the cohort to be treated.
Citation Format: Danielle Greenawalt, Austin Dulak, Manasa Ramakrishna, Zhongwu Lai, Justin Johnson, Hongyue Dai, Melissa Mitchell, Carl Barrett, Stephen Fawell, Jonathan Dry. Your targeted population might not be what you predict: Changes in tumor genetic landscapes post standard of care. [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 3168.