bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4050: Multifaceted targeting of drug-resistant EGFR+ and HER2+ breast tumors
Authors: Law Brian K. , Law Mary E. , Ferreira Renan B. , Wang Mengxiong , Davis Bradley J. , Castellano Ronald K. , Heldermon Coy D. 
Published: July 2017

Abstract
Unmet needs in the breast cancer field include the development of effective treatments for 1) drug-resistant HER2+ breast cancers, 2) Triple-Negative (HER2-, ER-, PR-) Breast Cancers (TNBCs), and 3) Inflammatory Breast Cancers (IBCs). Treatment-refractory HER2+ tumors retain HER2 expression after acquiring drug resistance, and large fractions of TNBCs and IBCs overexpress either HER2 or EGFR. Thus, drugs that selectively kill breast tumors that overexpress EGFR or HER2 could benefit patients suffering from these three classes of treatment-refractory tumors. Our team has identified a class of compounds termed Disulfide bond Disrupting Agents (DDAs) that selectively kill cancer cells that overexpress HER2 or EGFR. DDA-mediated cancer-selective cytotoxicity results from A) downregulation of the EGFR/HER2/HER3 proteins, B) inactivation of the Akt oncogene, and C) activation of the Unfolded Protein Response (UPR). Importantly DDAs only elicit these responses in cancer cells that overexpress EGFR or HER2. DDAs exhibit striking anticancer activity in human HER2+ xenograft tumors grown orthotopically in mice, with no evidence of toxicity. DDAs function through mechanisms distinct from those of HER2 specific monoclonal antibodies and tyrosine kinase inhibitors, and biochemical studies indicate that DDAs are complementary with Lapatinib with respect to blockade of HER2 driven proliferative and survival signaling. Current efforts are directed toward identifying mechanism-based drugs that synergize with DDAs to potentiate HER1-3 downregulation, Akt inhibition, and UPR, and to kill HER2+/EGFR+ patient-derived xenograft tumors that are refractory to current therapies.
Citation Format: Brian K. Law, Mary E. Law, Renan B. Ferreira, Mengxiong Wang, Bradley J. Davis, Ronald K. Castellano, Coy D. Heldermon. Multifaceted targeting of drug-resistant EGFR+ and HER2+ breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4050. doi:10.1158/1538-7445.AM2017-4050
Abstract 4060: Pharmacological targeting of the Aurora A and Histone 3 lysine 9 methyltransferase pathways in pancreatic cancer induces mitotic catastrophe
Authors: Mathison Angela , Salmonson Ann , Missfeldt Mckenna , Assuncao Thiago de , Bintz Jennifer , Christensen Trace , Kossak Sarah , Nair Asha , Iovanna Juan , Huebert Robert , Lomberk Gwen 
Published: July 2017

Abstract
By regulating gene expression networks that mediate neoplastic behavior, epigenetic protein complexes are the ultimate effectors of oncogenic pathways. This hierarchical position of epigenetic pathways within the mechanisms that regulate cancer makes them ideal candidates for therapeutic targets. The current work was designed to characterize the role of the K9H3 Histone Methyltransferase (HMT) pathway in mediating oncogenic signals downstream of Aurora Kinase A (AurkA), with the goal of designing efficient combinatorial therapies against PDAC. Affinity protein purification, combined with mass spectrometry, demonstrates that HP1γ isolated from mitotic cells interacts with AurkA and the HMTs, G9a and GLP. We also find that this complex is critical for mitotic progression and cell proliferation. Congruently, treatment of PDAC cells with individual drugs against AurkA or HP1-HMT inhibits cell growth by inducing senescence, a cytostatic response. However, the combination of these agents has a synergistic effect of reducing cell growth in both, monolayer and spheroid cultures to result in a cytotoxic effect. Confocal and electron microscopy, along with cell cycle analysis, demonstrate that the cytotoxic effect of this combination is due to induction of mitotic catastrophe, a distinct form of cell death that occurs during mitosis. Molecularly, the combination of AurkA and HP1-HMT inhibition bypasses G2/M arrest with downregulation of the Chk1-Cdc25c pathway. In vivo treatment of PDAC orthotopic xenografts with the HP1-HMT inhibitor alone demonstrated reduced PDAC growth, and increased efficacy in PDAC growth reduction was observed in combination with the AurkA inhibitor over either individual treatment. Thus, our data demonstrate a novel AurkA-HP1-HMT mitotic pathway that holds promise for potential pharmacological targeting in combinatorial therapy for this malignancy.
Citation Format: Angela Mathison, Ann Salmonson, Mckenna Missfeldt, Thiago de Assuncao, Jennifer Bintz, Trace Christensen, Sarah Kossak, Asha Nair, Juan Iovanna, Robert Huebert, Gwen Lomberk. Pharmacological targeting of the Aurora A and Histone 3 lysine 9 methyltransferase pathways in pancreatic cancer induces mitotic catastrophe [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4060. doi:10.1158/1538-7445.AM2017-4060
Abstract 4061: Computational exploration of mechanistic determinants of antibody drug-conjugate pharmacokinetics using quantitative systems pharmacology modeling strategies
Authors: Wilkins A. Katharina , Matteson Andrew , Gruenbaum Lore , Park Jennifer , Burke John M. , Apgar Joshua 
Published: July 2017

Abstract
The pharmacokinetics of antibody drug conjugate (ADC) therapeutics typically show a discrepancy between the PK of total antibody (conjugated and unconjugated antibody) and that of conjugated antibody, carrying one or more payload molecules. This discrepancy is often attributed to deconjugation (Kamath, 2014), however recent evidence suggests that the underlying mechanisms may be more complex. This work employs a computational quantitative systems pharmacology (QSP), or mechabistic PK/PD approach to understand the impact of drug antibody ratio (DAR) and the resulting changes in molecular properties on overall PK and relative payload disposition as observed in preclinical and clinical studies. Our work establishes the benefit of using computational models to design novel ADCs and to optimize the discovery and development of existing ADCs.
Citation Format: A. Katharina Wilkins, Andrew Matteson, Lore Gruenbaum, Jennifer Park, John M. Burke, Joshua Apgar. Computational exploration of mechanistic determinants of antibody drug-conjugate pharmacokinetics using quantitative systems pharmacology modeling strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4061. doi:10.1158/1538-7445.AM2017-4061
Abstract 4065: Association study between iron and cholesterol for the treatment of drug resistant neuroblastoma
Authors: Lee Sang Y. , Slagle-Webb Becky , Schengrund Cara-Lynne , Connor James 
Published: July 2017

Abstract
Neuroblastoma is the most common childhood extracranial solid malignancy. Although cancer cells need more iron and lipids for their active cell metabolism, possible links between iron, mutations in genes involved in iron metabolism (e.g., HFE) and lipid metabolism have not been studied well. We determined the HFE genotype in human neuroblastoma cells as well as patients. Neuroblastoma cells and patients have C282Y HFE mutation rates (~12%) that are similar to those of the general Caucasian population. While cultured cells derived from drug resistant neuroblastomas had less cholesterol, they expressed more ferritin, and contained more iron, than cells derived from drug susceptible tumors. In drug resistant neuroblastoma CHLA-171 cells, siRNA induced alteration of HFE expression had no effect on their iron levels but decreased their cholesterol. Results of in vitro experiments indicated that simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR), was cytotoxic to drug resistant cells as was the iron chelator di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). In vivo, the anti-tumor effect of simvastatin administered orally was minimal. In summary, we found i) an inverse association between ferritin and HMG-CoAR expression in neuroblastoma cells that was reflected in their iron and cholesterol levels, and ii) that the most cytotoxic cholesterol inhibitor of neuroblastoma cells was simvastatin, while the most cytotoxic iron chelation agent was DpC. Our results indicate that it may be possible to use HFE genotype to develop a precision medicine approach to use certain iron chelators and/or cholesterol decreasing agents in the treatment of drug resistant neuroblastomas. Our results also indicate that alterations in iron and cholesterol metabolism are part of the cell’s drug resistance mechanism in neuroblastomas.
Citation Format: Sang Y. Lee, Becky Slagle-Webb, Cara-Lynne Schengrund, James Connor. Association study between iron and cholesterol for the treatment of drug resistant neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4065. doi:10.1158/1538-7445.AM2017-4065
Abstract 4069: Trimethylation and acetylation of Histone H3K27 modulates 5-fluorouracil response by regulating DPYD expression
Authors: Wu Rentian , Nie Qian , Tapper Erin E. , Jerde Calvin R. , Offer Steven M. , Diasio Robert B. 
Published: July 2017

Abstract
The antimetabolite 5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs. Dihydropyrimidine dehydrogenase (DPD) initiates the catabolic degradation of 5-FU to inactive metabolites and is widely accepted as a major determinant of 5-FU response and toxicity. While genetic variants in DPYD have been shown to variants may affect 5-FU metabolism, they are rare events and do not completely explain the reported variability in DPD function or the resultant differences in treatment response. Here, we report that DPYD expression is epigenetically regulated by histone modification at relevant promoter and enhancer regions. Using both chemical inhibitors and genetic approaches, we show that that H3K27 tri-methylation (H3K27me3) at the DPYD promoter is regulated by the epigenetic modifiers Ezh2 and UTX. Promoter H3K27me3 suppresses DPYD expression by inhibiting the binding of the transcription factor PU.1 bindingto the promoter and ,increases sensitivity leading to increased resistance to 5-FU. In a cohort of healthy volunteers, H3K27me3 levels were inversely correlated with An enhancer that regulates DPYD expression was also identified. Modifying the H3K27 status of the DPYD promoter or enhancer modulates DPYD gene expression. Deletions and mutations on the DPYD promoter or enhancer abolish their transcription regulation function. Enrichment of H3K27me3 at the DPYD promoter was negatively correlated with both DPYD expression and DPD enzyme activity in peripheral blood mononuclear cellsspecimens from healthy volunteers. Lastly, tumor expression data suggests that DPYD repression by Ezh2 is a strong predictor ofs poor survival in 5-FU treated cancers. By using a combination of in silico prediction and in vitro reporter assays we also identified a functional enhancer region for DPYD that is also likely to be clinically relevant to 5-FU treatment outcome. Collectively, the presentthese findings suggest that a previously uncharacterized mechanisms regulates DPD expression and may likely contribute to tumor resistance to 5-FU.
Citation Format: Rentian Wu, Qian Nie, Erin E. Tapper, Calvin R. Jerde, Steven M. Offer, Robert B. Diasio. Trimethylation and acetylation of Histone H3K27 modulates 5-fluorouracil response by regulating DPYD expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4069. doi:10.1158/1538-7445.AM2017-4069
Abstract 4074: Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of brain metastases of breast cancer
Authors: Mohammad Afroz Shareef , Adkins Chris E. , Shah Neal , Aljammal Rawaa , Griffith Jessica , Lockman Paul R. 
Published: July 2017

Abstract
Background: Brain metastases vasculature is compromised and more permeable than that of vasculature in normal brain. Unfortunately, little is known about vascular permeability changes in brain adjacent to tumor (BAT). It is critical to understand the potential changes as chemotherapy penetration and accumulation brain tumors positively correlate with breakdown of the brain vasculature. Herein, we evaluate quantitatively measure permeability, drug accumulation and cytotoxicity in normal brain that is adjacent (&lt;500 microns) to a tumor.
Methods: The subclone population of brain seeking metastatic breast cancer cells (MDA-MB-231Br) were injected into the left ventricle of female NuNu mice. Mice were given a chemotherapeutic regimen of vinorelbine (10mg/kg), erubilin (1.5mg/kg) or docetaxel (10mg/kg). Progression occurred until neurological compromise was noted, at which time animals were injected with texas red 625 Da(TR) and texas red dextran 3kDa (TRD). Dye concentrations (measuring passive permeability changes) were determined in lesions and the BAT using quantitative fluorescent microscopy. Chemotherapeutic induced cytotoxicity was observed by staining for activated astrocytes and DNA damage in neurons, glia and endothelia.
Results: We observed permeability of TR is highly heterogeneous both within and between the tumors (normal brain Kin TR: 1.2 x10-5)with 2-40-fold increase in permeability over normal brain region. TR concentrations in BAT (100µm from tumor edge) is consistently 40% of the tumor but significantly higher than that of normal brain and TR permeability in BAT increased 1-2.5-fold over normal brain. The permeability of TRD in tumor increased 2.7- 8.4-fold over normal brain, whereas in BAT, the permeability increased 1-1.6-fold over normal brain. We also observed animals treated with chemotherapy showed activated astrocytes in BAT, along with some cellular death. In vehicle treated animals there were little activated astrocytes and little cell death in the BAT.
Conclusions: Our data suggests that the tracer and drugs accumulate in regions around tumors in the brain which result in neurotoxic changes.
Citation Format: Afroz Shareef Mohammad, Chris E. Adkins, Neal Shah, Rawaa Aljammal, Jessica Griffith, Paul R. Lockman. Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of brain metastases of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4074. doi:10.1158/1538-7445.AM2017-4074
Abstract 4077: Application of drug sensitivity and resistance testing to identify novel therapeutic agents for Down syndrome patients with AML
Authors: Patel Apurvi R. , Montoya Justin J. , Wai Daniel H. , Lee David W. , Arceci Robert J. , Azorsa David O. 
Published: July 2017

Abstract
Patients with Down’s syndrome who develop acute myeloid leukemia (AML) are at increased risk of toxicity secondary to chemotherapy regimens. These patients are harder to treat with conventional therapies at relapse. Overall, the use of targeted drug therapy is rising in the pediatric oncology field. Development of drug sensitivity and resistance test allows identification of specific targeted therapies for patient’s with difficult to treat leukemia. Our laboratory is working on the development of a drug sensitivity and resistance screening assay that would provide functionally relevant drug response data of the patient’s leukemia cells. Development of this assay included the preparation of pre-dosed drug library plates allowing for rapid initiation of the assay. AML cells are then added to the plate and treated for 72 hours after which cell viability was determined. Previous work in our laboratory tested a library of 56 anti-cancer and targeted agents on a panel of 16 AML cell lines that included two Down’s syndrome AML cell lines CMK and CMY. Drug dose response data including IC50 values and Area Under the Curve (AUC) were calculated for each cell line. Hierarchical clustering was performed to determine similar responses between cell lines. Down’s syndrome cell lines, CMK and CMY were found to be resistant to most conventional chemotherapeutic agents, but susceptible to targeted therapies such as Navitoclax and 17-AAG. We further tested several cell lines with the drug sensitivity and resistance assay under hypoxic conditions. Our screening results showed improved sensitivity of the CMK and CMY cells to Navitoclax and 17-AAG under normoxic and hypoxic conditions. Validation of the screening results was done using a 10-concentration drug dose response assay. Future studies will explore the mechanism by which the Down’s syndrome AML cells have increased sensitivity to these targeted agents under both normoxic and hypoxic conditions. Furthermore, we will investigate the activity of combinations of these targeted therapies with conventional therapies. The results from these studies could lead to the establishment of improved therapeutic regimens for Down’s syndrome patients with AML.
Citation Format: Apurvi R. Patel, Justin J. Montoya, Daniel H. Wai, David W. Lee, Robert J. Arceci, David O. Azorsa. Application of drug sensitivity and resistance testing to identify novel therapeutic agents for Down syndrome patients with AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4077. doi:10.1158/1538-7445.AM2017-4077
Abstract 4078: Tumors with class 3 BRAF mutants are sensitive to the inhibition of activated RAS
Authors: Yao Zhan , Yaeger Rona , Rodrik-Outmezguine Vanessa S. , Tao Anthony , Torres Neilawattie M. , Chang Matthew T. , Drosten Matthias , Zhao Huiyong , Cecchi Fabiola , Hembrough Todd , Michels Judith , Baumert Hervé , Miles Linde , Campbell Naomi M. , Stanchina Elisa de , Solit David B. , Barbacid Mariano , Taylor Barry S. , Rosen Neal 
Published: July 2017

Abstract
Approximately two hundred mutant BRAF alleles have been identified in human tumors. Physiologic activation of RAF isoforms requires RAS-dependent induction of their dimerization. Activating BRAF mutants cause ERK dependent feedback inhibition of RAS.GTP and are RAS independent. As we have shown previously, they signal either as active monomers or RAS-independent constitutively active dimers. Here, we characterized a third class of BRAF mutants—those that have impaired kinase activity or are kinase dead. These class 3 BRAF mutants are sensitive to ERK-mediated feedback and they function in a RAS-dependent manner. In tumors, they bind more tightly to active RAS, thus enhancing their heterodimerization with CRAF. This is associated with the amplification of RAS-RAF-MEK-ERK signaling.
Since these mutants are sensitive to ERK-dependent feedback inhibition of RAS, their enhancement of ERK signaling in tumors requires concurrent dysregulation of RAS activation. Thus, melanomas with Class 3 mutations usually harbor coexistent RAS mutation or NF1 mutants/deletion, whereas receptor tyrosine kinase signaling is activated in lung and colorectal cancers with these mutants. Our model suggests that these tumors will be sensitive to the inhibition of RAS activation. Currently, no direct inhibitors of RAS activation are available. However, in support of this idea, inhibitors of activated RTK signaling in carcinomas with Class 3 BRAF mutants and wild type RAS is sufficient to markedly inhibit ERK signaling and their growth in in vivo murine models and in patients. We have thus defined a third subset of BRAF mutants, which is RAS-dependent. Tumors harboring such mutants are sensitive to tyrosine kinase inhibitors in tumors expressing wild type RAS and NF1.
Citation Format: Zhan Yao, Rona Yaeger, Vanessa S. Rodrik-Outmezguine, Anthony Tao, Neilawattie M. Torres, Matthew T. Chang, Matthias Drosten, Huiyong Zhao, Fabiola Cecchi, Todd Hembrough, Judith Michels, Hervé Baumert, Linde Miles, Naomi M. Campbell, Elisa de Stanchina, David B. Solit, Mariano Barbacid, Barry S. Taylor, Neal Rosen. Tumors with class 3 BRAF mutants are sensitive to the inhibition of activated RAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4078. doi:10.1158/1538-7445.AM2017-4078
Abstract 4083: Basic mechanisms of Vernonia amygdalina exert antitumor activities in breast cancer cells
Authors: Yedjou Clement G. , Tchounwou Paul B. 
Published: July 2017

Abstract
Breast cancer continues to represent the largest cause of mortality in the world especially among women. It is estimated that cancer kills more women in the USA than any other illness and it is also the leading cause of death among all Americans. Traditional medicine represents the first-choice of healthcare treatment for at least 80% of people living in developing countries. Preliminary studies from our laboratory have shown that a novel natural product, extracts of Vernonia amygdalina (VA) leaf exerts DNA-damaging anticancer activities against breast cancer. There is a need to develop targeted approaches for the treatment of human breast cancer. Therefore, the goal of this research was to determine the therapeutic mechanisms of V. amygdalina leaf extracts as anti-cancer agent in the management of breast cancer. To achieve our goal, cell viability, live and death cells were determined by trypan blue exclusion test. The extent of oxidative cell/tissue damage was determined by measuring malondialdehydes (MDA) levels. Expression of p53 tumor suppressor gene was assessed both by immunofluorescent and western blot analyses. Cell apoptosis was measured both by flow cytometry analysis and DNA laddering assay. Data obtained from the Trypan blue indicated that V. amygdalina significantly reduced the viability of MCF-7 cells in a dose-dependent response, showing gradual increase in the loss of viability in V. amygdalina-treated cells due to membrane damage. We observed an up-regulation of p53 tumor suppressor gene in V. amygdalina-treated cells compared to the control. Flow cytometry data showed a strong dose-response relationship between V. amygdalina exposure and caspase-3 positive cells. These results were confirmed by data of DNA laddering assay showing a clear evidence of nucleosomal DNA fragmentation in V. amygdalina-treated cells. Collectively, data generated from the present study demonstrated that V. amygdalina destroys breast cancer cells by reducing the percentage of cell viability and inducing apoptosis through up-regulation of p53 tumor suppressor gene, activation of caspase-3, and induction of nucleosomal DNA fragmentation associated with the formation of MDA, a by-product of lipid peroxidation and biomarker of oxidative stress. This result suggests that V. amygdalina treatment may be a good anti-cancer candidate for the treatment of breast cancer. Research supported by NIH Grant No. NIMHDG12MD007581)
Citation Format: Clement G. Yedjou, Paul B. Tchounwou. Basic mechanisms of Vernonia amygdalina exert antitumor activities in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4083. doi:10.1158/1538-7445.AM2017-4083