bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2947: MicroRNA 10b, 27a and 27b are involved in the resistance to treatment with epidermal growth factor tyrosine inhibitor (EGFR-TKI) in EGFR mutant lung cancer cell line
Authors: Montes Hannah , Reyes Emma B D , Sharma Mukut , Huang Chao H. 
Published: July 2016

Abstract
EGFR TKIs are now standard of care in lung cancer patients with EGFR mutation. Invariably, these patients develop resistance and require treatment with another EGFR TKI or chemotherapy. The gate-keeper mutation T790M is responsible for about 50% of resistance. Rocelitinib(R) is a third generation EGFR TKI active in lung cancer cells with T790M mutation. Other mechanisms may also confer resistance in these patients. High expression of microRNA (miR)-10 is associated with worse prognosis in resected lung cancer patients with EGFR mutation. Both miR-27a and 27b are associated with increased expression of c-met which is a potential mechanism of resistance to EGFR TKI. We hypothesized that miR 10b and 27a and 27b modulate resistance in E-resistant lung cancer cells.
Material and Methods
Lung cancer cell lines with EGFR mutation HCC827 and HCC4006 were treated with 5 nM of Erlotinib (E) for 72 hours. E-resistant cells were then treated with R at 21.5 nM for 72h. The cells were harvested and microRNA profiling was performed by real time PCR. HTB177 cell line without EGFR mutation was used as control.
Results
We observed increased expression of miR-10b and miR-27a in HCC4006 compared to control cells HTB 177 cells; miR-27b is upregulated in HCC827 cell line. The increased expression of miR-10b and miR 27a were higher in CRL-2871 than the control cells 9-fold and 8-fold, respectively. MicroRNA- 27b was increased 300-fold in HCC827 compared with control.
Treatment with R reduced the proliferation in HCC827 to 30% and in HCC4006 to 50% compared to control. It did not inhibit the proliferation of HTB177 cells. R increase miR-10b in HCC4006 by 3-fold, miR-27a by 1.5-fold; in HCC827 it reduced miR-10b to 0.4, miR-27a to 0.4 and miR-27B 0.5.
Conclusion
We observed upregulation of miR-10b, 27a and 27b in lung cancer cells lines with EGFR mutation that were resistant to E treatment. Treatment of E resistant cells with R reduced proliferation and changed the expression of miR-10b, 27a and 27b. Our results suggest an epigenetic mechanism of resistance in addition to the T790M mutation. MicroRNAs may be studied as targets for developing novel approach for to treating patients with EGFR TKI resistance.
Citation Format: Hannah Montes, Emma B D Reyes, Mukut Sharma, Chao H. Huang. MicroRNA 10b, 27a and 27b are involved in the resistance to treatment with epidermal growth factor tyrosine inhibitor (EGFR-TKI) in EGFR mutant lung cancer cell line. [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 2947.
Abstract 2948: Glucose-6-phosphate dehydrogenase mediates drug resistance in diffuse large B-cell lymphoma
Authors: Maxwell Steve A. , Mousavi-Fard Seyed , Davis Timothy , Wallils Deeann , Sacchettini Jim 
Published: July 2016

Abstract
A leading cause of mortality in diffuse large B-cell lymphoma patients is the development of resistance to the CHOP chemotherapy regimen. We have discovered that CHOP-resistant DLBCL cells express higher G6PDH activities and lower reactive oxygen (predominantly superoxide) levels than CHOP-sensitive cells. Glucose-6-phosphate dehydrogenase (G6PDH) is the rate-limiting enzyme of the NADPH-producing pentose phosphate shunt (PPP). The PPP is the most important pathway for recycling of cellular glutathione (GSH), a key scavenger of reactive oxygen species (ROS). In the PPP oxidative phase, glucose 6-phosphate is irreversibly converted into ribulose 5-phosphate and CO2 leading to the synthesis of NADPH, a redox cofactor for many antioxidant enzymes. The NADPH produced is used by glutathione reductase to reduce GSSG (glutathione disulfide) to GSH. We hypothesized that increased activity of the G6PDH pathway leads to higher GSH production, lower oxidative state (ROS), and CHOP-resistance. In support of our hypothesis, downregulation of G6PDH lowered NADPH and GSH levels, increased ROS, and reversed CHOP-resistance in DLBCL cells. These results indicate an important role for the G6DPH pathway in mediating CHOP resistance in DLBCL.
Citation Format: Steve A. Maxwell, Seyed Mousavi-Fard, Timothy Davis, Deeann Wallils, Jim Sacchettini. Glucose-6-phosphate dehydrogenase mediates drug resistance in diffuse large B-cell lymphoma. [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 2948.
Abstract 2966: Preclinical combinations of the antibody-drug conjugate SGN-LIV1A with chemotherapies show increased activity
Authors: Li Fu , Anderson Martha , Hunter Joshua , Miyamoto Jaime , Ulrich Michelle , Kostic Ana , Law Che-Leung , Sussman Django 
Published: July 2016

Abstract
SGN-LIV1A is an antibody-drug conjugate (ADC) currently being evaluated in a phase 1 clinical trial for metastatic breast cancer. SGN-LIV1A consists of the microtubule disrupting agent, monomethyl auristatin E (MMAE), conjugated to the anti-LIV-1 humanized monoclonal antibody hLIV22. LIV-1, as a downstream target of STAT3, promotes the epithelial to mesenchymal transition that is important in the malignant progression to metastasis. We have previously shown that as a single agent, SGN-LIV1A displays target specific internalization and cytotoxic activity against a breast cancer cell line in vitro and also demonstrates antitumor activity in in vivo preclinical xenograft models with significant delay of tumor growth. We report here additive and synergistic effects when combining SGN-LIV1A with current chemotherapeutic modalities used in the treatment of metastatic breast cancer. Specifically, we show synergy between SGN-LIV1A in combination with either doxorubicin or Abraxane in MCF-7 breast cancer tumor model. In addition, we show additive effects when carboplatin or protein kinase inhibitors are dosed in combination with SGN-LIV1A in this tumor model. These findings support further evaluation and development of SGN-LIV1A in combination with standard of care chemotherapeutic agents for the treatment of breast cancer.
Citation Format: Fu Li, Martha Anderson, Joshua Hunter, Jaime Miyamoto, Michelle Ulrich, Ana Kostic, Che-Leung Law, Django Sussman. Preclinical combinations of the antibody-drug conjugate SGN-LIV1A with chemotherapies show increased activity. [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 2966.
Abstract 2968: A novel bispecific CD3/CDH19 antibody construct (CDH19 BiTE) directs potent killing of melanoma cells in vitro and in vivo and is enhanced by blockade of PD-L1
Authors: Moody Gordon E. , Moriguchi Jodi , Li Shyun , Lee Fei , Frank Brendon , Gilbert Amy , Case Ryan , Dang Khue , Hinkle Beth , Coberly Suzanne , Rottman James , Merriam Kim , Bailis Julie , Beltran Pedro J. 
Published: July 2016

Abstract
CDH19 is an unconventional type 2 cadherin widely expressed in malignant melanoma with limited expression in normal tissues. RNAseq and immunohistochemical analysis of
CDH19 in human samples confirmed its over-expression in &gt;60% of melanoma, whereas normal expression primarily occurred in tissues derived from the neural crest such as nerve fibers and autonomic ganglia. CD3 based bi-specific T-cell engagers (BiTEs) were used to determine if redirected lysis of T-cells against CDH19 would drive anti-tumor efficacy. In vitro, the CDH19 BiTEs were high affinity binders to both human and cyno CDH19, and were able to induce specific T-cell activation and cytotoxicity against a panel of melanoma cell lines. In addition, soluble CDH19 levels were detected in human serum and the effects of BiTE cytotoxicity toward melanoma cells in the presence of soluble CDH19 was investigated. In vivo studies were conducted to confirm the specificity and activity of CDH19 BiTEs in xenograft models of melanoma. The CDH19 BiTE AMG-CDH19X was able to cause tumor growth inhibition in models expressing as few as 250 receptors per cell, and inhibition of tumor growth was enhanced by the addition of a blocking antibody against PD-L1. Immunohistochemical analysis of post-treatment xenograft samples suggested that anti-PD-L1 the persistence of tumor reactive T cells, and provided rationale for combining a BiTE against CDH19 with a PD-1 or PD-L1 blocking antibody in melanoma. In summary, targeting CDH19 presents a promising novel opportunity for BiTEs in the treatment of melanoma, both alone and in combination with current standard of care.
Citation Format: Gordon E. Moody, Jodi Moriguchi, Shyun Li, Fei Lee, Brendon Frank, Amy Gilbert, Ryan Case, Khue Dang, Beth Hinkle, Suzanne Coberly, James Rottman, Kim Merriam, Julie Bailis, Pedro J. Beltran. A novel bispecific CD3/CDH19 antibody construct (CDH19 BiTE) directs potent killing of melanoma cells in vitro and in vivo and is enhanced by blockade of PD-L1. [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 2968.
Abstract 2971: Optides (optimized knottin peptides) computationally designed to target the oncogenic HIPPO pathway
Authors: Crook Zachary R. , Bradley Philip , King Chris , Mhyre Andrew J. , Baker David , Olson James M. 
Published: July 2016

Abstract
The HIPPO pathway plays a critical role in contact inhibition, a pathway that is commonly dysregulated in many human cancers (including liver, colon, ovarian, and lung) and which relies on the intranuclear interaction of the transcriptional coactivator YAP and the transcription factor TEAD(1-4). This pathway also plays a crucial role in recovery from injury; for example, its regulated repression allows hepatocytes to divide and replace tissue lost to a partial hepatectomy, after which its activation suppresses cell growth and prevents tissue overgrowth. While small molecule enzyme inhibitors have proven to be a revelation in cancer therapy, cell growth signaling via protein-protein interactions has proven much more difficult to drug. While Antibodies can be effective in targeting extracellular or cell surface epitopes, intracellular targets, such as the interaction between YAP and TEAD, are not amenable to antibody-based therapeutics. Optides are small disulfide-knotted peptides (knottins) and serve to bridge these capabilities; they are large enough to interfere with protein-protein interactions, but small enough to penetrate into the cytosol. Examples include imperatoxin, an activator of mitochondrial ryanodine receptors, and Tumor Paint, which contains an optimized variant of chlorotoxin conjugated to a fluorescent probe and is capable of accumulating in a wide range of tumor types.
To test whether Optides can abrogate oncogenic signaling mediated by protein-protein interactions, we created libraries of computationally designed candidates to target the TEAD/YAP interface. The library is expressed on the surface of mammalian cells, chosen for the improved fidelity of disulfide bridge connectivity observed in the mammalian secretory pathway as compared to that found in yeast. By repetitive screening against soluble TEAD protein, we are optimizing the pool of candidates for targeting TEAD. The lead Optides will be characterized for their ability to reduce YAP-TEAD interaction, and to impair YAP-mediated cell growth. Owing to the wide variety of knottin scaffolds, both natural and in silico designed, this flexible technology could be applied to other targets in order to impair oncogenic protein-protein interactions.
Citation Format: Zachary R. Crook, Philip Bradley, Chris King, Andrew J. Mhyre, David Baker, James M. Olson. Optides (optimized knottin peptides) computationally designed to target the oncogenic HIPPO pathway. [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 2971.
Abstract 300: Inhibition of oncogenic MAPK signaling in melanoma triggers SOX2-dependent adaptive drug resistance
Authors: Flueckiger Stefanie , Aloia Andrea , Frischknecht Lukas , Tuozzo Amanda , Croci Davide , Shakhova Olga , Britschgi Christian , Dummer Reinhard , Levesque Mitchell Paul , Krek Wilhelm 
Published: July 2016

Abstract
Treatment of metastatic melanoma with BRAFV600E-specific small molecule inhibitors (BRAFi) provides dramatic clinical relief response but fails to suppress long-term tumor growth in the long-term. Extensive studies have uncovered identified a number of resistance-causing genetic alterations that, which are acquired upon continued drug exposure. However, little is known about the changes in gene expression programs changes during the critical time before drug resistance is manifested on at the genomic level. These changes may lead to adaptive drug resistance and hence, represent vital mechanisms by which tumor cells survive the acute drug insult prior to acquisition of resistance-causing mutations. Using a combination of RNAseq and molecular analyses, we find that acute inhibition of oncogenic MAPK signaling by BRAFi or MEKi in established and primary patient-derived melanoma cell cultures, leads to a rapid induction of the stem cell maintenance and pluripotency factor SOX2. Immunohistochemical analysis of Sox2 expression in melanoma sections derived from BrafV600E/Pten−/−-mice treated for 36 hours with BRAFi/MEKi confirmed the emergence of a Sox2-positive melanoma subpopulation in vivo. SOX2 Ectopic ectopic expression of SOX2 protected melanoma cells from the anti-proliferative effects of BRAFi indicative ofindicating a role for SOX2 in mediating drug resistance. Furthermore, siRNA-mediated depletion or overexpression experiments of SOX2 unveiled revealed that it is necessary and sufficient for the expansion of a drug-tolerant SOX2+CD24+ cell population. This subpopulation is characterized by increased migratory and invasive behavior as well as an increased proliferative potential in the presence of BRAFi when compared to SOX2+CD24− cells. These results imply that BRAFi treatment induces a SOX2-dependent cellular program with features of adaptive drug resistance. Suppression of drug-dependent induction of SOX2 or its downstream effector pathways could potentially extend the clinical efficacy of BRAFi.
Citation Format: Stefanie Flueckiger, Andrea Aloia, Lukas Frischknecht, Amanda Tuozzo, Davide Croci, Olga Shakhova, Christian Britschgi, Reinhard Dummer, Mitchell Paul Levesque, Wilhelm Krek. Inhibition of oncogenic MAPK signaling in melanoma triggers SOX2-dependent adaptive drug resistance. [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 300.
Abstract 3005: The impact of mitochondrially targeted oncology agents on mitochondrial DNA (mtDNA) integrity
Authors: Pokrzywinski Kaytee L. , Biel Thomas G. , Kryndushkin Dmitry , Rao. V. Ashutosh 
Published: July 2016

Abstract
Reactive oxygen species (ROS) are natural byproducts of mitochondrial oxidative phosphorylation. Dysfunction in electron shuttling leads to enhanced ROS production that is notorious for inflicting damage to macromolecules. Mitochondrial DNA (mtDNA) is particularly sensitive to ROS as it is located in close proximity to the respiratory chain. Additionally, mtDNA lack histones which are known to provide protection from ROS. Mitochondria also have limited DNA repair mechanisms making damage to mtDNA more detrimental to mitochondrial physiology. Recent evidence suggests that oxidative insult, leads to mtDNA degradation to prevent the accumulation of mutagenic base lesions, which is enabled by the high redundancy of mtDNA. The primary objectives of this study were to determine the impact of redox-active mitochondrial-targeted chemotherapeutic agents on mitochondrial physiology and mtDNA integrity. All experiments were performed in two cancer cell lines [MDA-MB-231 (breast) and H23 (lung)] that were treated with 2 uM of the mitochondrial-targeted redox-active compounds: MitoTempol [C4 (MT4)], MitoQuinone (MQ) and MitoChromanol-Acetate (MCA) for 1 or 24 hrs. Mitochondrial status was determined by measuring mitochondrial membrane potential, superoxide production, oxygen consumption rate (OCR) and protein levels of the respiratory chain complexes using the JC-1 and MitoSOX assays, Seahorse XF analysis, and immunoblotting, respectively. Next, mtDNA integrity was analyzed by quantifying the degree of mtDNA fragmentation using PCR amplification of a 10kb fragment compared to a short 100bp fragment. Moreover, changes in the mtDNA replication machinery were assessed using immunoblotting. MQ and MCA induced a loss in mitochondrial function and mtDNA replication machinery as indicated by a reduction in membrane potential, OCR and protein levels. Furthermore, increases in superoxide levels and mtDNA fragmentation were observed with MQ and MCA treatment. Finally, we assessed mitochondrial content using two methods. The first method being the ratio of mitochondrial to nuclear DNA, determined by qPCR of short (∼100bp) nuclear and mitochondrial sequences. The second method was the ratio of mitochondrial outer membrane proteins to cytoplasmic housekeeping proteins, determined by immunoblotting. Both mitochondria DNA and outer membrane proteins decreased with MQ and MCA treatment suggesting that redox-active mitochondrial-targeted agents may reduce the mitochondrial content in cancer cells.
Citation Format: Kaytee L. Pokrzywinski, Thomas G. Biel, Dmitry Kryndushkin, V. Ashutosh Rao. The impact of mitochondrially targeted oncology agents on mitochondrial DNA (mtDNA) integrity. [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 3005.
Abstract 3018: Cotargeting MEK and CDK4/6 to treat pancreatic adenocarcinoma
Authors: Maust Joel D. , Simeone Diane , Sebolt-Leopold Judith 
Published: July 2016

Abstract
Hyperactivation of KRAS and inactivation of CDKN2A [p16] play a prominent role in tumor initiation and progression in a broad spectrum of human cancers. In pancreatic adenocarcinoma, KRAS mutation occurs in 90-95% of cases and is often coupled with inactivation of CDKN2A (&gt;90% incidence), typically by homozygous deletion. Based on the high incidence of these genetic events, the present study addresses the hypothesis that dual targeting of MEK and CDK4/6 represents a viable therapeutic strategy for the treatment of pancreatic adenocarcinoma. A panel of primary and high passage xenograft models was screened for in vitro synergy to the antiproliferative effects of the MEK inhibitor trametinib and the CDK4/6 inhibitor palbociclib. Two models that emerged as highly sensitive to this combination treatment strategy, L3.6pl and UM59, both exhibited G1 cell cycle arrest that was significantly more pronounced in response to the combination compared to either single agent. In vivo studies were subsequently carried out to evaluate the efficacy of this combination in tumor-bearing mice. Mice implanted subcutaneously with L3.6pl or UM59 cells were treated daily by oral gavage for ten days with trametinib (3 mg/kg), palbociclib (100 mg/kg), or the combination of these two agents at these doses. Consistent with in vitro synergy observations, both models proved to be exceptional responders in vivo to this combination treatment strategy, showing a robust response to the combination not seen with either single agent. These results suggest that the combined inhibition of MEK and CDK4/6 may offer a valuable therapeutic strategy for the treatment of pancreatic adenocarcinoma. Studies are ongoing to identify molecular determinants of response in pancreatic tumors that are highly sensitive to this combination approach to guide future patient enrichment strategies.
Citation Format: Joel D. Maust, Diane Simeone, Judith Sebolt-Leopold. Cotargeting MEK and CDK4/6 to treat pancreatic adenocarcinoma. [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 3018.
Abstract 3019: High throughput drug screening identified spleen tyrosine kinase as a novel therapeutic target in head and neck cancer with potent in vitro and in vivo activity
Authors: Black Morgan , Ailles Laurie , Sun Ren , Datti Alessandro , Vizeacoumar Frederick , Pinto Nicole , Ruicci Kara , Yoo John , Fung Kevin , MacNeil Danielle , Palma David A. , Winquist Eric , Mymryk Joe S. , Boutros Paul C. , Barrett John W. , Nichols Anthony C. 
Published: July 2016

Abstract
Background and Significance: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and survival remains poor highlighting the need for novel treatments for the treatment of HNSCC. High throughput drug screening has shown the potential to discover novel therapeutics in other cancers.
Methods: Twenty-eight HNSCC cell lines, including 5 HPV-positive lines, were characterized with whole exome sequencing and copy number arrays and screened with 1505 potential anti-cancer agents on a robotic liquid handling platform at a single dose (4uM). The most potent hits were confirmed with 10-point dose response curves. Novel therapeutic targets were further investigated with mechanistic and xenograft studies.
Results: Drug screening identified 10 agents with broad activity across our cell line panel. One of the most potent agents was ER27319 maleate, reported to be a spleen tyrosine kinase (Syk) inhibitor. We confirmed that this molecule inhibited Syk phosphorylation specifically at tyrosine residues 525/526. Additionally, ER27319 maleate as well as a more clinically relevant Syk inhibitor, Fostamatinib, were observed to significantly impaired cellular migration and invasion. Additionally, siRNA knockdown of Syk in HNSCC cells was found to decrease HNSCC cell line growth. Finally, inhibition of Syk was observed to control HNSCC tumour growth in vivo in cell line-derived xenografts.
Conclusions: High throughput drug screening of HNSCC cell lines identified Syk as a novel target and confirmed potent in vitro and in vivo activity. Further preclinical evaluation is planned with a panel of patient-derived xenografts. Should these results yield significant activity, we will aim to repurpose approved Syk inhibitors to improve outcomes for patients suffering from HNSCC.
Citation Format: Morgan Black, Laurie Ailles, Ren Sun, Alessandro Datti, Frederick Vizeacoumar, Nicole Pinto, Kara Ruicci, John Yoo, Kevin Fung, Danielle MacNeil, David A. Palma, Eric Winquist, Joe S. Mymryk, Paul C. Boutros, John W. Barrett, Anthony C. Nichols. High throughput drug screening identified spleen tyrosine kinase as a novel therapeutic target in head and neck cancer with potent in vitro and in vivo activity. [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 3019.