bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2129: Assessing the efficacy of targeting mitochondrial respiration in delaying lung tumor growth by using subcutaneous xenografts in mouse models
Authors: Kalainayakan Sarada Preeta , Ghosh Poorva , Dey Sanchareeka , Zhang Li 
Published: July 2017

Abstract
Previously, studies have focused mainly on the precept that tumors depend on glycolysis for energy and growth (the Warburg effect) and that the mitochondria are dysfunctional in cancer cells. However, there is mounting evidence that some cancer cells exhibit elevated mitochondrial respiration. Recent studies in our lab have demonstrated that Non-Small Cell Lung Cancer (NSCLC) cells exhibit intensified mitochondrial respiration and oxygen consumption. We further demonstrated that targeting increased mitochondrial respiration by a therapeutic agent effectively hampers proliferation of Non-Small cell lung cancer (NSCLC) cells in vitro. The purpose of the study is to determine to what extent mitochondrial respiration is affected by the therapeutic agent in vivo.
In order to achieve this goal, NSCLC cells were transduced with lentiviral particles carrying luciferase sequence. NSCLC cells expressing luciferase cells were implanted on the right flank of 4-6 weeks old female NOD/SCID mice to generate subcutaneous xenografts. The therapeutic agent was administered intravenously. Tumor implantation and growth were monitored by bioluminescence imaging (BLI) using Perkin Elmer’s IVIS Lumina III Imager. On sacrificing the mice, the tumors were harvested, formalin fixed and paraffin embedded for Immunohistochemistry (IHC).
Our BLI data suggest that there is a considerable reduction in radiance (total flux in photons per second) in the group of mice that were treated with therapeutic agent in comparison to control. Further, there is a significant reduction in tumor volume in mice that received treatment. Our IHC data suggest that there is a reduction in expression of a vital enzyme involved in heme synthesis and hemoproteins involved in mitochondrial respiration.
Our BLI and IHC data suggest that the therapeutic agent affects mitochondrial respiration by affecting mitochondrial complexes in vivo. Additional experiments to corroborate the results are underway.
Citation Format: Sarada Preeta Kalainayakan, Poorva Ghosh, Sanchareeka Dey, Li Zhang. Assessing the efficacy of targeting mitochondrial respiration in delaying lung tumor growth by using subcutaneous xenografts in mouse models [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 2129. doi:10.1158/1538-7445.AM2017-2129
Abstract 2133: Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent
Authors: Reddy Joseph A. , Nelson Melissa , Dircksen Christina , Johnson Theresa , Vetzel Marilynn , Hahn Spencer , Qi Longwu , Vlahov Iontcho , Leamon Christopher 
Published: July 2017

Abstract
Folate receptor (FR) targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety . This agent was found to be extremely potent with an in vitro IC50 ~ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (300 nmol/kg) using a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. Complete responses were also observed in other FR-positive drug resistant (paclitaxel and cisplatin) models. When evaluated against FR-positive PDX models of ovarian, endometrial and triple negative breast (TNBC) cancers, EC2629 showed significantly greater anti-tumor activity than EC1456 or standard of care (SOC) treatments. Taken together, these studies demonstrated that EC2629 with a distinct DNA reacting mechanism has significant anti-tumor growth activity in numerous models, including those which were drug resistant, thus lending support to our planned clinical development of this novel FR-targeted agent.
Citation Format: Joseph A. Reddy, Melissa Nelson, Christina Dircksen, Theresa Johnson, Marilynn Vetzel, Spencer Hahn, Longwu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent [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 2133. doi:10.1158/1538-7445.AM2017-2133
Abstract 2149A: CRISPR/Cas9 mutagenesis invalidates a genetic target of clinical trials in cancer
Authors: Lin Ann , Giuliano Christopher , Sayles Nicole , Smith Joan , Sheltzer Jason 
Published: July 2017

Abstract
The Maternal Embryonic Leucine Zipper Kinase MELK has been described as a genetic dependency in several cancer types, most notably in the highly-aggressive basal subtype of breast cancer; MELK inhibition through the use of both RNAi and small-molecule approaches appears to block the growth of cancer types with such dependency. Based on these results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in multiple clinical trials. Here, however, we report that mutagenizing MELK with CRISPR/Cas9 has no effect on the fitness of basal breast cancer cell lines or cell lines from other cancer types. Through seven guide RNAs targeting the kinase and kinase-associated domains of MELK, we demonstrate that mutagenesis of MELK causes no defect in proliferative ability or anchorage independent growth in these cancer types. Additionally, cells with mutagenized MELK remain sensitive to OTS167, suggesting that this drug blocks proliferation through an off-target mechanism. Finally, the patient tumor gene expression data that initially identified MELK as being significantly upregulated in patients with poor survival was reexamined. As MELK is thought to play a role in mitosis, we compared MELK expression to a set of well-known cell proliferation markers and show significant correlations of MELK with the proliferation genes; this suggests a role of MELK in representing the mitotic activity of a tumor, rather than possessing a transformative role in itself. In total, our results undermine the rationale for a series of current clinical trials based on MELK inhibition and provide an experimental approach for the use of CRISPR/Cas9 in preclinical target validation that can be broadly applied.
Citation Format: Ann Lin, Christopher Giuliano, Nicole Sayles, Joan Smith, Jason Sheltzer. CRISPR/Cas9 mutagenesis invalidates a genetic target of clinical trials in 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 2149A. doi:10.1158/1538-7445.AM2017-2149A
Abstract 2154: P53 pathway restoring compound P306 inhibits colorectal cancer growth
Authors: Tian Xiaobing , Zhang Shengliang , Lulla Amriti , El-Deiry wafik S. 
Published: July 2017

Abstract
We recently reported that P01 is a potent p53 pathway-restoring small molecule that acts through increasing levels of TAp73. Further, it also interferes with the p73-mutant p53 protein-protein interaction and by downregulation of ΔNp73 (Tian, Zhang and El-Deiry, abstract# 3830, AACR 2016). P01 is a member of the natural products that have been shown to have potent anti-cancer activity against tumors with mutated p53. Based on the structure of the pharmacophore of compound P01, we designed and synthesized new analogs based on published structure-activity relationship and organic synthesis papers. The newly synthesized analogs were potent in reducing both short-term and long-term proliferation in a broad panel of mutant p53 cell lines such as HT29, SW480, DLD-1, MDA-MB-231and H1975 with EC50s in the range of 0.16 μM to 0.26 μM. We are currently evaluating the anti-cancer effects of three analogs P301, P304 and P306, of which only two of these analogs induce TAp73 as assayed by western blot. We are currently characterizing the analog P306, which is the most potent compound among them. P306 engages the apoptosis pathway by upregulation of pro-apoptotic proteins like PUMA, DR5, and BIM and downregulation of anti-apoptotic markers such as Mcl-1 in a time-and dose-dependent manner in colorectal cancer cell lines. P306 treatment also downregulates both mRNA and protein level of MET and EGFR in HT29 cells that overexpress MET and EGFR receptors. We are currently investigating the mechanisms of induction of both PUMA and DR5 in mutant p53 cells and determining whether either gene is necessary for the apoptotic effects of P306 in colorectal cancer cells. Our preliminary data indicates that upregulation of DR5 is through the ATF4/CHOP pathway post-P306 treatment. It has been reported that Puma is a target gene of ATF4, CHOP and p73, however, we found that none of them is responsible for P306-induced upregulation of PUMA in p53 mutated DLD1, SW480 or HCT116 p53-null cell lines. Thus, our ongoing in vitro studies are focused on further understanding the mechanism of action of P306 in mutant p53 cells and potentially exploring combinations with FDA-approved therapies. We are also in the process of conducting, first-in animal studies of P306 as single agent or in combination with chemotherapy or targeted therapy.
Citation Format: Xiaobing Tian, Shengliang Zhang, Amriti Lulla, wafik S. El-Deiry. P53 pathway restoring compound P306 inhibits colorectal cancer growth [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 2154. doi:10.1158/1538-7445.AM2017-2154
Abstract 2160: Novel sulfonamide derivative inhibits JAK2-STAT3 signaling and induces ROS-mediated apoptosis in colorectal cancer cells
Authors: Ahmad Rehan , Vaali-Mohammed Mansoor-Ali , Al-Obeed Omar , Abdulla Maha 
Published: July 2017

Abstract
Colorectal cancer is a major worldwide health problem owing to its high prevalence and mortality rate. Developments in screening, prevention, biomarker, personalized therapies and chemotherapy have improved detection and treatment. However, despite these advances many patients with advanced metastatic tumors will still succumb to the disease. New anti-cancer agents are needed for treating advance stage colorectal cancer as most of the deaths occur due to cancer metastasis. A recently developed novel sulphonamide derivative, 4-((2-(4-(Dimethylamino)phenyl)quinazolin-4-yl)amino)benzenesulfonamide (3d) has shown to have potent antitumor effect; however the mechanism underlying the antitumor effect remains unknown. Our study revealed that 3d treatment significantly reduced the viability of human colorectal cancer cells HT-29 and SW620. This is further evidenced by the induction of p53 and Bax, release of cytochrome c, activation of caspase-9, caspase-7 and caspase-3 and cleavage of PARP in 3d treated cells. This compound was found to have significant effect on the inhibition of anti-apoptotic proteins, Bcl2, BclxL and XIAP. The results further demonstrate that 3d inhibited JAK2-STAT3 pathway by decreasing the constitutive and IL-6-induced phosphorylation of JAK2 and STAT3. 3d further decreased JAK2- STAT3 target genes like Cyclin D1 and Survivin. Furthermore 3d treatment induced the generation of reactive oxygen species (ROS) in human colorectal cancer cells. Confirming our observation, NAC significantly inhibited ROS production, induction of apoptosis, cytochrome c release and PARP cleavage. Additionally, treatment with 3d resulted in decreased glutathione (GSH) levels. The results further demonstrate that 3d inhibited cell migration by modulating EMT markers and inhibiting TGFβ-induced phosphorylation of Smad2 and Samd3. Collectively these findings indicate that 3d inhibited JAK2-STAT3 signaling; induced apoptosis via generation of reactive oxygen species and inhibition of cell migration by altering EMT markers and TGFβ-Smad pathway.
Note: This abstract was not presented at the meeting.
Citation Format: Rehan Ahmad, Mansoor-Ali Vaali-Mohammed, Omar Al-Obeed, Maha Abdulla. Novel sulfonamide derivative inhibits JAK2-STAT3 signaling and induces ROS-mediated apoptosis in colorectal 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 2160. doi:10.1158/1538-7445.AM2017-2160
Abstract 2161: Pharmacological downregulation of BFL-1 by the BET bromodomain inhibitor CPI203 overcomes ABT-199 resistance in MYC+/BCL2+ double hit lymphoma
Authors: Esteve-Arenys Anna , Garcia-Valero Juan , Gonzalez David , Chamorro-Jorganes Aránzazu , Rodriguez Vanina , Dlouhy Ivan , Salaverria Itziar , Campo Elias , Colomer Dolors , Martinez Antonio , Rymkiewicz Grzegorz , Pérez-Galán Patricia , Lopez-Guillermo Armando , Roué Gaël 
Published: July 2017

Abstract
Double-hit lymphoma (DHL) is a rare subtype of B-cell lymphoma characterized by MYC and either BCL2 or BCL6 chromosomal rearrangements. DHL cases may have different morphology and are included in the updated 2016 WHO classification as a new category of high grade B-cell lymphoma with rearrangements. DHL patients usually undergo a rapidly progressing clinical course and are poorly responsive to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival of approximately one year.
ABT-199 (venetoclax) is a potent and selective small-molecule antagonist of BCL-2 recently approved for the treatment of some lymphoid malignancies. In this study, we demonstrate that single-agent ABT-199 efficiently displaces pro-apoptotic BAX from BCL-2 complexes but fails to maintain a significant antitumor activity over time in most MYC+/BCL2+ DHL cell lines and primary cultures, as well as in a xenograft mouse model of DHL. We further identify the accumulation of the BCL2-like protein, BFL-1, to be a major mechanism involved in acquired resistance to ABT-199. We show this phenomenon to be manageable by the BET bromodomain inhibitor CPI203, since gene expression profiling identifies BCL2A1 as one of the top apoptosis-related gene modulated by the compound. Upon CPI203 treatment, simultaneous downregulation of MYC and BFL-1 at both mRNA and protein levels further overcomes resistance to ABT-199 both in vitro and in vivo, allowing DHL cultures and tumor xenografts to undergo synergistic caspase-mediated apoptosis.
Together, these findings highlight the relevance of BFL-1 in DHL-associated drug resistance and support the combined use of BCL-2 antagonist and BET inhibitor as a promising therapeutic strategy in patients with aggressive DHL.
Citation Format: Anna Esteve-Arenys, Juan Garcia-Valero, David Gonzalez, Aránzazu Chamorro-Jorganes, Vanina Rodriguez, Ivan Dlouhy, Itziar Salaverria, Elias Campo, Dolors Colomer, Antonio Martinez, Grzegorz Rymkiewicz, Patricia Pérez-Galán, Armando Lopez-Guillermo, Gaël Roué. Pharmacological downregulation of BFL-1 by the BET bromodomain inhibitor CPI203 overcomes ABT-199 resistance in MYC+/BCL2+ double hit lymphoma [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 2161. doi:10.1158/1538-7445.AM2017-2161
Abstract 2173: Targeting CDK1 and MEK/ERK overcome mutant BRAF-mediated apoptosis resistance in human colorectal cancer cells
Authors: Kawakami Hisato , Huang Shengbing , Sinicrope Frank A. 
Published: July 2017

Abstract
BRAFV600E mutation occurs in ~10% of human colorectal cancers (CRC) where it is associated with treatment resistance and poor prognosis. Data from TCGA and a clinical trial cohort identified a distinct subset of BRAF mutant colon cancers with deregulation of the cell cycle and overexpression of CDK1 (Barras D, et al, Clin Cancer Res. 2016). We tested the hypothesis that CDK1 inhibition can enhance apoptosis in BRAFV600E CRC cells. Since BRAF mutant cells show p-ERK activation, combined inhibition of CDK1 and MEK/ERK was evaluated. Using isogenic colon cancer cells, BRAF mutant alleles were shown to confer resistance to the CDK1 inhibitor, R0-3306, in a gene dose-dependent manner that was associated with reduced cleavage of caspase-3 and downstream PARP, and decreased pH2AX (DNA fragmentation marker). Ectopic BRAFV600E or constitutively active MEK mutant also conferred resistance to R0-3306. CDK1 siRNA was shown to increase cobimetinib-induced apoptosis, including annexin V labeling, and increased pH2AX. Furthermore, ERK siRNA or cobimetinib treatment attenuated CDK1 protein expression and increased R0-3306-induced pH2Ax. Moreover, treatment with R0-3306 plus cobimetinib significantly enhanced a caspase-dependent apoptosis and markedly reduced colony formation vs either drug alone in two CRC cell lines. Caspase-3 cleavage by R0-3306 + cobimetinib was dependent upon caspase-8. Mechanistically, CDK1 inhibition by R0-3306 suppressed the phosphorylation of procaspase-8 at Ser-387 shown by R0-3306 withdrawal which restored p-C8-S387 coincident with expression of the mitotic marker, pH3S10. In conclusion, inhibition of CDK1 can significantly augment apoptosis induction by MEK/ERK inhibition in BRAFV600E CRC cells, suggesting a novel therapeutic strategy to overcome mutant BRAF-mediated resistance.
Apoptosis induction by CDK1 inhibitor (R0-3306) ± MEK/ERK inhibitor cobimetinibTreatmentTreatmentTreatementTreatmentCRC cell linesDMSOR0-3306 (5 µM)cobimetinib (5 µM)combinationAnnexin V+ (%)RKO13.43 ± 1.4132.55 ± 2.9315.04 ± 0.2652.72 ± 3.16Annexin V+ (%)HT-2911.22 ± 1.8442.44 ± 2.7025.29 ± 0.1665.62 ± 4.11
Citation Format: Hisato Kawakami, Shengbing Huang, Frank A. Sinicrope. Targeting CDK1 and MEK/ERK overcome mutant BRAF-mediated apoptosis resistance in human colorectal 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 2173. doi:10.1158/1538-7445.AM2017-2173
Abstract 2184: Development and testing of nanoformulation of a vascular disrupting agent in rat glioma with MRI monitoring
Authors: Ali Meser M. , Jayasundara Sunalee , Ewing James R. 
Published: July 2017

Abstract
Anti-angiogenesis therapy VEGF-VEGF receptors (VEGFRs) axis alone or in combination with other therapeutic agents have demonstrated mixed results, with the majority of reports indicating that glioblastoma multiform (GBM) developed resistance against anti-angiogenesis therapy as well as small molecular receptor tyrosine kinase inhibitors. This result is perhaps not unexpected, because angiogenesis is obviously complex, involving dozen of different growth factors that trigger a cascade of subsequent events. Even if a drug effectively blocks one angiogenic growth factor, such as VEGF, blood vessels may still develop via activating alternative pathways. Yet without a sufficient blood supply, cancerous tumors can't grow larger than the head of a pin and are unlikely to become lethal. Therefore, tumor vascularization is a critical process that determines tumor growth, progression and metastasis. Thus, tumor vasculature has become an emerging target for new chemotherapeutic drugs Vascular disrupting agents (VDAs) for example, combretastatin (CA4), represent a new class of chemotherapeutic agent that targets the newly formed vasculature in solid tumors. Preclinical and early phase trials have demonstrated the promising therapeutic benefits of CA4. Nevertheless, the clinical translation of CA4 has been significantly hampered due to its poor systemic bioavailability and the non-specific distribution of CA4 throughout the body when administered intravenously. Thus, it is reasonable to explore novel formulations of CA4 that overcome the limitations mentioned above. To improve bioavailability combretastatin phosphate (CA4-P) has been synthesized. But, CA4-P showed short blood half life. We have engineered dendrimer-based nano-sized CA4 conjugate which demonstrates high water solubility. Preliminary intravenous (i.v.) delivery of nano-combretastatin in an orthotropic glioma model demonstrated a necrosis at the core of the tumor leaving a rim of viable tissue. The MRI-determined tissue parameters Ktrans, blood flow (CBF), DWI, ADC map, distribution volume and tumor size indicated the effectiveness of nano-combretastatin treatment.
Citation Format: Meser M. Ali, Sunalee Jayasundara, James R. Ewing. Development and testing of nanoformulation of a vascular disrupting agent in rat glioma with MRI monitoring [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 2184. doi:10.1158/1538-7445.AM2017-2184
Abstract 2188: Targeted delivery of pro-apoptotic peptide using ELP-based carrier for effective cancer therapy in various cancer model
Authors: Vijaya Sarangthem , Park Rang-Woon 
Published: July 2017

Abstract
Therapeutic peptides classified as biopharmaceuticals have gained attention as a new generation of cancer therapeutics with enhanced efficiency and diminished toxicity. They often fail to have sufficient effects due to their unsatisfactory pharmacokinetic profiles, which include poor bioavailability, low stability, short half-life, and poor penetration across the biological membrane. Elastin-like polypeptide (ELP)-based drug delivery has been utilized for various applications including cancer therapies for many years. Genetic incorporation of internalization ligands and cell targeting peptides along with ELP polymer enhanced tumor accumulation and retention time as well as stability and activities of the drug conjugates. Herein, we described a unique delivery system comprised of genetically engineered ELP incorporated with multiple copies of IL-4 receptor targeting peptide (AP1) periodically and proapoptotic peptide (KLAKLAK)2 referred to as AP1-ELP-KLAK. It triggered thermal responsive self-assembly into a nanoparticle-like structure at physiological body temperature and stabilized its helical conformation, which is critical for its membrane disrupting activities. Increased IL-4 receptor specific cellular internalization was associated with the enhanced cytotoxic effect of (KLAKLAK)2 peptide. Additionally, multivalent presentation of targeting ligands by AP1-ELP-KLAK significantly enhanced intratumoral localization and prolonged the retention time compared to ELP-KLAK, non-targeted control. Systemic administration of AP1-ELP-KLAK significantly inhibited tumor growth by provoking cell apoptosis in MDA-MB231 breast cancer and B16F10 melanoma tumor xenograft models without any specific organ toxicity. Thus, our newly designed AP1-ELP-KLAK polymer nanoparticle is a promising candidate for effective cancer therapy and due to the simple preparative procedures of ELPs, this platform can be used as a good carrier for tumor-specific delivery of other therapeutics.
Citation Format: Sarangthem Vijaya, Rang-Woon Park. Targeted delivery of pro-apoptotic peptide using ELP-based carrier for effective cancer therapy in various cancer model [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 2188. doi:10.1158/1538-7445.AM2017-2188