bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4658: Novel paclitaxel medical nanoparticle formulation for breast cancer
Authors: Chowdhury Pallabita , Chauhan Sumeet S. , Nagesh Prashanth K. , Hatami Elham , Hafeez Bilal B. , Khan Sheema , Jaggi Meena , Yallapu Murali M. 
Published: August 2018

Abstract
Objectives: Paclitaxel (Ptxl) is currently the most common first-line therapeutic option for breast cancer (BrCa). However, adverse side effects and problems associated with chemo-resistance, limits its use in clinical settings. Nanoparticle mediated delivery can improve Ptxl delivery and its activity at the tumor site, and considered to be an attractive strategy for BrCa therapy. Therefore, we aim to generate a novel Ptx medical nanoparticle formulation (PMNPs) using a polyphenol as a carrier, and evaluate its efficacy against BrCa cells. Methods: Physico-chemical characterization of this PMNPs was performed using TEM, DLS, FT-IR, TGA, X-RD, and SAXS methods. Its internalization and cellular availability was examined using HPLC method. Cell proliferation and colony formation assays were utilized to evaluate therapeutic efficacy of this unique nanoformulation in clinically relevant cell line models (MCF7 and MDA-MB-231). Additionally, molecular effects of this formulation on apoptosis, anti-apoptosis, and drug resistant associated proteins were evaluated using immunoblotting assays. A tubulin stabilization study was performed using confocal immunofluorescence microscopy analysis. Results: The PMNPs formulation showed optimal particle size and zeta potential, which can be efficiently internalized in BrCa cells. PMNPs exhibited potent anti-cancer efficacy via induction of the expression of apoptosis associated proteins (Bax and Bad, cleaved PARP, and caspase 3) and downregulation of anti-apoptotic proteins (Bcl-2 and Bcl-xL) in BrCa ell lines. Further, the expression of chemoresistance-associated proteins were also decreased with the treatment of PMNPs.
Conclusion: PMNPs formulation can efficiently be internalized in BrCa cells and induce enhanced therapeutic potential of Ptxl. Development of a targeted drug delivery system would not only reduce the dose of paclitaxel required to kill cancer cells but also minimize long-term paclitaxel associated systemic toxicity and drug-resistance.
Citation Format: Pallabita Chowdhury, Sumeet S. Chauhan, Prashanth K. Nagesh, Elham Hatami, Bilal B. Hafeez, Sheema Khan, Meena Jaggi, Murali M. Yallapu. Novel paclitaxel medical nanoparticle formulation for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4658.
Abstract 4660: Tumor multicomponent targeting nanoparticle library for personalized cancer therapy & imaging
Authors: Sau Samaresh , Alsaab Hashem , Tatiparti Katyayani , Bhise Ketki , Rishi Arun , Iyer Arun K. 
Published: August 2018

Abstract
The fundamental limitations of conventional cancer treatment have promoted the development and application of nanoengineering platforms for achieving effective patient outcomes. Over a time, considerable clinical success has been accomplished in nanotechnology field but there are many challenges limiting the progress of nanomedicine from bench to the beside. The highly heterogeneous tumor environment, an inadequate understanding of interactions between tumor biomarkers and nanomedicine, and reproducibility in synthesis required for clinical translation are some of the major challenges. Thus, there is an urgent need to redirect our focus of nano-drug carrier that can target multiple components of tumor including, tumor epithelial cells, tumor angiogenic vessels, tumor hypoxia and stromal cells. To achieve this, we developed a library of various tumor biomarker targeting ligands, and drug and imaging agents encapsulated in nanoparticles (NPs). Finally, the library of targeting ligands was conjugated with NPs using reagent free ‘click' chemistry. This strategy will serve as an “off-the-shelf ready to configure drug formulation" that can be engineered based on a mix-and-match strategy for individual patient needs. It is envisaged that the patient can walk in the clinic and be given the targeted drug that is personalized to their need. For the proof-of-concept, we evaluated tumor selectivity of multiple cancer biomarker targeting oligo-micelles (OMs), iron oxide and lipid NPs in various patient derived tumor xenograft (PDx) models, such as non-small cell lung and triple negative breast cancer. We observed that the dual tumor hypoxia and cancer stem cell (CSC) targeting rod shaped OM has 8-fold higher tumor core penetration compared to non-targeted OM in these PDx tumors, as obtained from NIR-fluorescence imaging. This OM has significantly higher tumor vs. liver ratio and they follow tumor specific receptor competition. The tumor growth inhibition of drug loaded OM is superior compared to free drug. This approach demonstrated significant improvement of tumor stroma penetration with low healthy organ uptake of NPs portending more promising potentials for selective cancer treatment.
Citation Format: Samaresh Sau, Hashem Alsaab, Katyayani Tatiparti, Ketki Bhise, Arun Rishi, Arun K. Iyer. Tumor multicomponent targeting nanoparticle library for personalized cancer therapy & imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4660.
Abstract 4721: Combining STING agonists with an anti-PD-1 antagonist results in marked antitumor activity in immune-excluded tumors
Authors: Perera Samanthi A. , Kopinja Johnny E. , Ma Yanhong , Laskey Jason , Chakravarthy Kalyan , Chen Yiping , Cui Long , Presland Jeremy , Zhao Shuxia , Minnihan Ellen , Ferguson Heidi , Piesvaux Jennifer , Pan Bo-Sheng , Woo Hyun Chong , Knemeyer Ian , Cemerski Saso , Cumming Jared , Trotter Wesley , Tse Archie , Addona George H. , Long Brian J. 
Published: August 2018

Abstract
The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I interferon production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent anti-tumor activity. To exploit this mechanism we synthesized a novel STING agonist, MSA-1, that activates both mouse and human STING with higher in vitro potency than cGAMP. MSA-1 was administered to immune-competent mice bearing MC38 syngeneic tumors to monitor pharmacodynamics, pharmacokinetics and in vivo efficacy. Intratumoral (IT) dosed MSA-1 demonstrated robust tumor and plasma cytokine upregulation and effective anti-tumor activity. The highest tolerated doses provided complete responses (CRs) in 100% of MC38 tumors. Tumor models such as CT26 and B16-F10 that are intrinsically resistant to single-agent therapy with a fully murinized mouse anti-PD-1 antibody (mDX400) also demonstrated long-term tumor regressions or CRs. Mechanistic studies in immune-deficient mice suggested that anti-tumor activity of IT dosed STING agonists are in part due to cytotoxicity and/or innate immune responses rather than development of robust adaptive anti-tumor immunity. To enhance the adaptive immune response, we combined MSA-1 with mDX400 in mouse syngeneic tumor models previously characterized to be unresponsive to anti-PD-1 blockade. This combination restored T-cell responses in both blood and tumors of the treated mice and provided long-lived immunologic memory in a majority of the animals. Taken together, these data strongly support the development of STING agonists in combination with Keytruda for patients with tumors that are partially responsive or non-responsive to single agent anti-PD-1 therapy.
Citation Format: Samanthi A. Perera, Johnny E. Kopinja, Yanhong Ma, Jason Laskey, Kalyan Chakravarthy, Yiping Chen, Long Cui, Jeremy Presland, Shuxia Zhao, Ellen Minnihan, Heidi Ferguson, Jennifer Piesvaux, Bo-Sheng Pan, Hyun Chong Woo, Ian Knemeyer, Saso Cemerski, Jared Cumming, Wesley Trotter, Archie Tse, George H. Addona, Brian J. Long. Combining STING agonists with an anti-PD-1 antagonist results in marked antitumor activity in immune-excluded tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4721.
Abstract 4761: Joint model of longitudinal tumor size and overall survival (OS) in non-small cell lung cancer (NSCLC): A Bayesian approach
Authors: Al-Huniti Nidal , Xu Hongmei , Zhou Diansong , Edlund Helena , Aksenov Sergey , Helmlinger Gabriel , Dunyak James 
Published: August 2018

Abstract
Objective: The methodology of joint modeling longitudinal tumor size and OS data is very promising and provides the opportunity of survival prediction in individual patients. However, current joint modeling software are restricted in terms of distributions/parameterizations available and non-linear mixed effects models are not supported. The objective of this work was to develop a joint model in Bayesian framework to relax these restrictions and enable investigation of additional (continuous and/or discrete) biomarkers. Methods: Longitudinal tumor size and OS data from gefitinib Phase 3 study in NSCLC (‘IPASS', NCT00322452) was used in the modeling analysis. Joint model was developed in JM package in R and the Bayesian formulation of the joint modeling was implemented in STAN. Different parametrizations were investigated for both sub-models and the impact of lag-times was explored. The parameter estimates and model fit were compared between models by JM package and STAN. The final Bayesian joint model was validated on an independent dataset from a Phase 4 study (‘IFUM', NCT01203917, EGFR positive patients only) by simulating individual survival based on their tumor size data and compared with observed survival. Results: The estimated parameter values were similar to those from the fit from JM package. The different parametrizations provided similar fits for the tumor size model, while the survival model was improved by using a b-spline model. The association parameters indicate a strong association between tumor size and survival and introduction of lag-times did not impact the association parameters to a great extent. Posterior predictive simulations of OS in phase 4 study were consistent with observed data. Conclusions: Bayesian formulation further improved the joint model of tumor size and OS which would enable investigation of additional biomarkers (e.g. new lesions).
Citation Format: Nidal Al-Huniti, Hongmei Xu, Diansong Zhou, Helena Edlund, Sergey Aksenov, Gabriel Helmlinger, James Dunyak. Joint model of longitudinal tumor size and overall survival (OS) in non-small cell lung cancer (NSCLC): A Bayesian approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4761.
Abstract 4798: Targeting hTERT for treatment of glioblastoma (GBM)
Authors: Bollam Saumya Reddy , Kang Hyun-Jin , Peng Sen , Gokhale Vijay , Hurley Laurence , Berens Michael , Dhruv Harshil 
Published: August 2018

Abstract
Approximately 86% of GBM tumors exhibit a mutation at -124 or -146 bp upstream from the ATG start site in the transcription activating promoter region of Human telomerase reverse transcriptase (hTERT). Mutations in the hTERT promoter are known to impair repression, leading to overexpression of hTERT and tumor maintenance. Yet, complete understanding of mechanistic implications is still necessary. While overexpressed hTERT is associated with oncogenesis and resistance to apoptosis, we also observe phenotypes unrelated to the reverse transcription function. We characterized long-term glioma cell lines and glioma PDX models by hTERT promoter mutation status, hTERT mRNA expression, and hTERT protein expression in subcellular fractions. The -124 and -146 mutations are located in the major 5-12 G-quadruplex and result in misfolding of the silencer element, thus causing over-expression of hTERT. Using a diverse small molecule library, we identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, TG-4260, which binds to the 26 mer base-pair heteroduplex loop, which is the nucleation site for cooperative folding of the major 5-12 G-quadruplex. The chaperone effect of TG-4260 corrects DNA hTERT G-quadruplex misfolding resulting from the promoter mutations and restores the silencer function of the G-quadruplex. TG-4260 directly decreases the transcription activity of the −124, −124/125, −138/139, and −146 mutants to a similar extent and suppresses the downstream gene BCL2, which activates caspase-3 and produces cell-cycle arrest, leading to cell death. This is the first example of the use of a pharmacoperone molecule to correct the misfolding of a DNA G-quadruplex element resulting from mutations in an early folding intermediate. We screened GBM cell models against this novel small molecule inhibitor that interferes with mutated hTERT promoter and demonstrated that TG-4260 selectively suppresses glioma cell viability without affecting non-transformed normal human astrocytes. Finally, telomere phenotypes from treated cells indicate non-canonical functions of telomerase may also contribute to glioma pathogenesis.
Citation Format: Saumya Reddy Bollam, Hyun-Jin Kang, Sen Peng, Vijay Gokhale, Laurence Hurley, Michael Berens, Harshil Dhruv. Targeting hTERT for treatment of glioblastoma (GBM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4798.
Abstract 4865: BI 907828: A highly potent MDM2 inhibitor with low human dose estimation, designed for high-dose intermittent schedules in the clinic
Authors: Rinnenthal Joerg , Rudolph Dorothea , Blake Sophia , Gollner Andreas , Wernitznig Andreas , Weyer-Czernilofsky Ulrike , Haslinger Christian , Garin-Chesa Pilar , Moll Jürgen , Kraut Norbert , McConnell Darryl , Quant Jens 
Published: August 2018

Abstract
MDM2 inhibitors block the interaction between the Tumor Protein p53 (TP53) and MDM2, its key negative regulator, and represent a new therapeutic concept for cancer therapy. MDM2 inhibitors are designed to restore p53 activity in TP53 wild-type tumors. Several MDM2 inhibitors are currently being evaluated in early clinical development with mainly daily dosing regimens. However, recent clinical data suggest myelosuppression as an on-target, dose-limiting toxicity for this class of inhibitors. Particularly thrombocytopenia could limit the clinical utility of MDM2 inhibitors. Hence there is a need to mitigate these side effects and to improve the therapeutic window. One approach is less frequent dosing to allow bone marrow recovery while still maintaining efficacious exposure levels and clinical activity. Here we present pharmacokinetic data on BI 907828, a novel and potent MDM2 inhibitor with optimized drug-like properties. Due to its high permeability, good physiological solubility and low systemic clearance, the compound shows a high bioavailability in mice, rats, dogs and minipigs. BI 907828 is not absorption-limited, even at multiples of the efficacious dose, and shows a reliable, dose-linear PK with low variability in AUC and Cmax across species. Based on a good PK-PD correlation with efficacy in preclinical models and a robust human PK prediction based on in vivo PK data across species, a low human efficacious dose is predicted. The PK properties of BI 907828 enable a variety of different clinical dosing schedules with the potential to improve the therapeutic index with respect to on-target safety. In summary, BI 907828 is a novel, potent, orally available MDM2 inhibitor with excellent PK properties and low estimated human dose suitable for high-dose intermittent dose schedules in the clinic.
Citation Format: Joerg Rinnenthal, Dorothea Rudolph, Sophia Blake, Andreas Gollner, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Christian Haslinger, Pilar Garin-Chesa, Jürgen Moll, Norbert Kraut, Darryl McConnell, Jens Quant. BI 907828: A highly potent MDM2 inhibitor with low human dose estimation, designed for high-dose intermittent schedules in the clinic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4865.
Abstract 5052: ID3 mediated vascular reprogramming of PCB exposed endothelial cells and its potential contribution to lung tumorigenicity
Authors: Doke Mayur , Das Jayanta , Felty Quentin 
Published: August 2018

Abstract
ID3, a transcription regulator, has been shown to contribute to the aggressive spread of certain cancers by facilitating the generation of tumor blood vessels. Tumor vascular cells characterized as CD133+ endothelial stem/progenitor cells are associated with poor prognosis in lung cancer. Previously, we have shown that ID3 overexpression reprograms adult endothelial cells to acquire vascular stem markers including CD133. However, little is known regarding the molecular contribution of ID3 to tumor vascular reprogramming and how this may impact the aggressive growth of lung cancer. In the current project, we evaluated ID3 mediated vascular reprogramming upon polychlorinated biphenyl (PCB) exposure. This idea is consistent with the literature, which shows that PCBs accumulate in the human lung; PCBs produce pathological vascular remodeling; high levels of PCBs are found in human lung tissue; and epidemiological studies associating lung toxicity with PCBs. Recent studies identify PCB153 as one of the largest contributors for total PCB body burden in humans. Using human lung endothelial and smooth muscle cells, we exposed ID3 overexpressing and vector control cells to PCB153. We observed a significant increase in cell proliferation as determined by the BrdU incorporation assay and FACS analysis. Similarly, a 3D HuBiogel model, which mimics in vivo conditions, showed a significant increase in size and number of vascular spheres upon PCB153 treatment. Pluripotent vascular stem cells showed the loss of VE-cadherin and gain of MMP9, N-cadherin, and vimentin, which are markers of endothelial-mesenchymal transition. RNA-seq analysis showed that PCB153 exposed vascular stem cells had a significant increase in lncRNAs MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) and HIF1A-AS2. A combination of ChIP-seq and transcriptome analysis identified significantly up-regulated genes (HES1, WEE1, E2F2) and down-regulated genes (SMURF2, CDKN2C, SH2B3). Our findings suggest that ID3 mediates vascular reprogramming through transcriptional regulation of pluripotency factors and epigenetic regulating lncRNAs. ID3 may also serve as a novel diagnostic/prognostic indicator for evaluating chemical-induced vascular reprogramming. Its potential application may be useful in identifying individuals who are susceptible to aggressive lung cancer from exposure to vascular toxicants.
Citation Format: Mayur Doke, Jayanta Das, Quentin Felty. ID3 mediated vascular reprogramming of PCB exposed endothelial cells and its potential contribution to lung tumorigenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5052.
Abstract 5117: A murine hematogenous bone metastatic cancer to model spontaneous metastasis of triple negative breast cancer
Authors: Lee Hye Jin 
Published: August 2018

Abstract
The development of bone metastasis in breast cancer and its pathologic progression are known to be clinically important problem. It is known that immunologic response in microenvironment is important as soil in the bone metastasis process and progression. Thus, immunologic modulation is expected to play a role in the prevention and treatment of the disease in bone metastasis. However, most studies to date; researches in bone metastasis were carried out using human breast cancer cell lines in xenograft model of immuno-deficient mouse or in vitro co-culture system. These approaches have limitations in regard to interaction among immune cells, cancer cells, and other stroma cells. To overcoming these limitation, we used the C3(1)Tag mouse model to establish a spontaneous bone metastasis model. First, a cell line (M6) obtained from a spontaneously occurring tumor in C3(1)Tag mice was infected with lentiviral-luciferase. M6 cells with lentiviral-luciferase were administered using intracardiac injection and C3(1) Tag mice were monitored until tumors are detected under bioluminescence imaging. In 3 weeks, metastatic bone lesions were apparent in 85.7% of mice. To understand biologic characteristics of in vivo selected bone metastatic subpopulation, metastatic cancer cells were harvested and were analyzed using immunohistochemical staing in comparison with parent cells. Tumor cells metastasized to bone showed differential expression in HIF1A, c-MET, and EMT markers. Unexpectedly, bone metastatic cancers showed better sensitivity to paclitaxel and cisplatin than parent cells in cell viability assay. In addition, immune microenvironment in bone metastatic foci was assessed using multiplex immunohistochemical staining and showed an immune suppressive MDSCs infiltration. Taken together, we established a murine hematogenous bone metastatic cancer and characterized biologic characteristics to model human triple negative breast cancer. The potential targets identified in this study might be a future immunologic target in patients with bone metastasis.
Citation Format: Hye Jin Lee. A murine hematogenous bone metastatic cancer to model spontaneous metastasis of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5117.
Abstract 512: miR-29 expression regulates B7-H3 mediated angiogenesis in medullablastoma
Authors: Purvis Ian , Guda Maheedhara R. , Venkataraman Sujatha , Vibhakar Rajeev , Velpula Kiran K. , Asuthkar Swapna 
Published: August 2018

Abstract
B7-H3 (CD276), an immune checkpoint member of the B7/CD28 family, plays a key role in the repression of the immune response by cancer cells. B7-H3 is overexpressed exclusively on tumor and tumor-associated cells, making it an interesting therapeutic target. B7-H3 also appears to play a role outside of immune evasion, contributing to the progression of cancer via invasion, migration, and angiogenesis. Our preliminary data have confirmed the presence of B7-H3 in highly aggressive MYC+ medulloblastoma (MB) tumors. Data-mining studies revealed that B7-H3 is highly expressed across the subgroups of MB, and is correlated with MYC expression in Group 3 and 4 MBs. Recently, miR-29, a tumor-suppressor miRNA, was shown downregulating B7-H3 expression by targeting the 3' UTR of B7-H3 mRNA. Immunoblot analysis of D283 and D458 cells demonstrated reduced expression of both cellular and soluble form of B7-H3 when transfected with miR-29 plasmid. Our preliminary data have shown a novel method of targeting B7-H3 expression by miR-29 in MB cells, inhibiting the ability of MB cells to induce angiogenesis. Because both miR-29 and B7-H3 form an inversely related axis that plays a role in tumor angiogenesis, inhibition of B7-H3 by miR-29 may have potential value in developing novel antiangiogenic treatments in MB.
Citation Format: Ian Purvis, Maheedhara R. Guda, Sujatha Venkataraman, Rajeev Vibhakar, Kiran K. Velpula, Swapna Asuthkar. miR-29 expression regulates B7-H3 mediated angiogenesis in medullablastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 512.