bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A065: Differential sensitivity of normal and tumor organoids to targeted therapies
Authors: Madej Mariusz , Zuvirie Cinthya Del Angel , Mateos Jara García , Price Leo , Daszkiewicz Lidia , Yan Kuan , Herpers Bram 
Published: March 2020

Abstract
Background: Advances in the culture of cells from human tissues have enabled the generation of normal and tumor organoid pairs derived from the same patient. These organoid cultures increase the scope for predicting responses to novel cancer therapeutics in patients. Here we present a high throughput 3D human intestinal organoid culture platform combined with high content image-based analysis. This platform allows visualization and quantification of responses beyond conventional cell viability measurements, including those associated with tumor killing, cell cycle arrest, toxicity and epithelial permeability and discriminates therapeutic and adverse responses in healthy tissue and tumor. Methods: Intestinal organoids, obtained from HUB Organoid Technology, cultured in natural extracellular matrix scaffolds show gene expression patterns, differentiation and functional characteristics that closely resemble the in vivo biology. To investigate the effect of standard-of-care (SoC) treatments, novel targeting antibodies and small molecules on tumor growth suppression and killing as well as function, formation and integrity of the gut epithelium, we tested a panel of normal and colorectal cancer organoids with a broad heterogeneity of mutations. 3D imaging and analysis was performed and responses in normal vs. tumor were compared. Results: High content 3D image analysis of the organoid enabled sensitive detection of treatment-induced and compound-specific morphological changes such as (inhibition of) growth, development, lumen formation, epithelial integrity and cell death. This enabled distinction between mechanisms of action and distinct effects and sensitivities in normal epithelium and tumor tissue from the same patient. Conclusion: 3D image analysis of in vitro cultured organoids represents a rapid and biologically relevant approach to test various anti-cancer-therapeutic modalities, including antibodies, antibody-drug conjugates and small molecules. Evaluating effects on healthy and tumor tissue from the same patient can give insight into potential toxicities and therapeutic window.
Citation Format: Mariusz Madej, Cinthya Del Angel Zuvirie, Jara García Mateos, Leo Price, Lidia Daszkiewicz, Kuan Yan, Bram Herpers. Differential sensitivity of normal and tumor organoids to targeted therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A065. doi:10.1158/1535-7163.TARG-19-A065
Abstract A066: Role of the NRF2 signaling pathway in sustaining chemoresistance in medulloblastoma
Authors: Rruga Fatlum , Mariotto Elena , Persano Luca , Rampazzo Elena , Luchini Alessandra , Liotta Lance A , Viola Giampietro , Bortolozzi Roberta 
Published: March 2020

Abstract
Nrf2, a key orchestrator of cell defense mechanisms against oxidative stress and xenobiotic insults, has been linked to chemotherapy resistance and recurrence in many human cancers. Through the establishment of an in vitro model of chemoresistance, we investigated the role of Nrf2 in sustaining resistance to chemotherapy in medulloblastoma (MB), a highly aggressive pediatric brain tumor intrinsically characterized by fast growth, high invasiveness and resistance to treatments. MB DAOY cells were weekly exposed to a cocktail of drugs commonly used in MB treatment, vincristine, etoposide, cisplatin and cyclophosphamide (VECC) inducing the emergence of a resistant phenotype. After 5 cycles of VECC treatment we obtained a culture of cells resistant to subsequent chemotherapy treatments. We observed increased Nrf2 levels and activity in therapy-exposed cells already from the first received dose of VECC. Nrf2 levels remained high throughout all the rest of chemotherapy cycles and interestingly, its transcriptional activity spiked up when resistance to chemotherapy emerged, as demonstrated by the increase of antioxidant response element (ARE)-driven luciferase activity and the expression of target genes. The knock down of Nrf2 in resistant cells, by the use of specific siRNA, was able to restore chemosensitivity, suggesting a role of Nrf2 signaling pathway in the onset of chemotherapy resistance in MB cells. Resistant cells showed a higher ROS (reactive oxygen species) scavenging capacity after stimulation with hydrogen peroxide. Nrf2 silencing partially reverts the ability of resistant cells to manage oxidative stress, supporting the hypothesis of Nrf2 involvement in the ROS scavenging potential of VECC resistant MB cells. In addition to directly regulate ROS-scavenging enzymes, Nrf2 has been described to control cell metabolism that maintain redox homeostasis in cancer stem cells. Among the Nrf2 target genes upregulated in DAOY resistant cells we found the upregulation of PFKFB-3, G6PD and TKT. The increased expression of this enzymes suggests a metabolic reprogramming in resistant cells. Our data support the involvement of Nrf2 pathway in MB response to VECC treatment and show that the upregulation of this detoxifying system sustains MB resistance to chemotherapy.
Citation Format: Fatlum Rruga, Elena Mariotto, Luca Persano, Elena Rampazzo, Alessandra Luchini, Lance A Liotta, Giampietro Viola, Roberta Bortolozzi. Role of the NRF2 signaling pathway in sustaining chemoresistance in medulloblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A066. doi:10.1158/1535-7163.TARG-19-A066
Abstract A100: Tumor-targeted and pH-shiftable nanoparticles to encapsulate oxaliplatin and microRNA for colorectal cancer therapy
Authors: Lo Yu-Li , Chen Y.C. , Chang C.H. , Tseng W.H. , Wang C.S. 
Published: March 2020

Abstract
Colorectal cancer is a popular cancer type all over the world. Among various treatment regimen, oxaliplatin (Oxa) is approved in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFOX) as the first-line therapy for colorectal cancer of metastatic or advanced stage. MicroRNAs (miRs) may target genes critical for regulating tumor proliferation and invasion. Among different miRs, miR-c has been proved to induce apoptosis, inhibit proliferation and epithelial-mesenchymal transition of cancer cells. Peptide-modified nanoparticles, which are capable of increasing cellular uptake and targeting to specific receptors, are well suitable for delivering Oxa and miR. Moreover, coating pH-sensitive polymers to the outer layer of peptide-modified nanoparticles may enhance specific targeting to the acidic tumor sites. Physicochemical characterization, cellular uptake, cytotoxicity, migration assay, and western blotting studies of these nanoparticle formulations have been performed. Our results indicated that these pH-sensitive and peptide-modified nanoparticles displayed a narrow size distribution. The cellular uptake of peptide-modified nanoparticles was found to be greater than that of naked nanoparticles. Besides, the cellular uptake of pH-sensitive nanoparticles was significantly increased at pH 6.0 compared to that at pH 7.4, suggesting the successful pH-responsive property of these delivery systems. Furthermore, the combined treatment of miR-c and Oxa by peptide-modified nanoparticles increased the cytotoxicity of Oxa to colorectal cancer cells. We demonstrated that the upregulation of apoptosis pathway and the downregulation of β-catenin pathway were accounted for the efficient antitumor effect. In conclusion, the delivery of miR-c and Oxa in pH-sensitive and peptide-modified nanoparticles may provide a novel and potential strategy for colorectal cancer treatment.
Citation Format: Yu-Li Lo, Y.C. Chen, C.H. Chang, W.H. Tseng, C.S. Wang. Tumor-targeted and pH-shiftable nanoparticles to encapsulate oxaliplatin and microRNA for colorectal cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A100. doi:10.1158/1535-7163.TARG-19-A100
Abstract A102: pHLIP technology for targeting acidity at surface of tumor cells and extracellular and intracellular delivery of imaging and therapeutic agents
Authors: Reshetnyak Yana K , Andreev Oleg A , Engelman Donald 
Published: March 2020

Abstract
pH-Low Insertion Peptides (pHLIP® peptides) are a platform technology for targeting of acidity at the surface of individual cells within tumors. Most proteins that are located across membranes have one or more helical segments that cross the lipid bilayer, and studies of these membrane proteins revealed pHLIPs, which could fold from disorganized (unstructured) states outside of a membrane to form a helix across the membrane in response to local acidity. Because tumor cell surfaces are acidic as a result of their active metabolism, versions of pHLIP® peptides were extensively investigated and tested as possible tumor targeting agents. Our studies showed that an extensive variety of cargoes can be targeted to cell surfaces and that a surprising range of cargoes can be delivered across membranes into cells if their surfaces are acidic, creating opportunities to detect and treat tumors. pHLIP® peptides can be used to target and tether cargo molecules to the surfaces of cells in low pH environments of acidic diseased tissues. The cargo can be an optical marker, a PET, a SPECT, or a MR imaging agent, or an antigen or a protein delivered to induce certain cellular or immune responses. We are translating pHLIP®-based imaging agents to the clinic for diagnostic PET imaging, fluorescence-guided surgical procedures and photo-acoustic pre-operative imaging. pHLIP® peptides can also be used for the intracellular delivery of payloads, facilitating the translocation of therapeutic cargoes across the membranes of cells with low extracellular pH, such as those cells found in acidic diseased tissue. These payloads are conjugated to the membrane-inserting end of pHLIP® peptide, typically via a link that is unstable inside the cell. Thus, pHLIP® peptide targets a payload to acidic diseased cells and flips the cargo across the plasma membrane, releasing it in the cytoplasm. Therapeutic cargoes may include toxins, metabolic activators/inhibitors, chemotherapeutic agents, or agents to alter gene expression. *YKR, OAA, and DME are founders of pHLIP, Inc. and have financial interests in the company.
Citation Format: Yana K Reshetnyak, Oleg A Andreev, Donald Engelman. pHLIP technology for targeting acidity at surface of tumor cells and extracellular and intracellular delivery of imaging and therapeutic agents [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A102. doi:10.1158/1535-7163.TARG-19-A102
Abstract A107: Small Molecule Degraders of the Estrogen Receptor (SERDs): Optimization of the tricyclic indole scaffold beyond AZD9496
Authors: Barlaam Bernard , Breed Jason , Carbajo Rodrigo J , Gangl Eric , Hughes Samantha , Morrow Christopher J , Moss Thomas A , Polanski Radoslaw , Nissink Willem M , O'Donovan Daniel , Varnes Jeffrey , Yang Bin , Scott James S 
Published: March 2020

Abstract
The estrogen receptor alpha (ERα) is expressed in &gt;70% of breast cancers and is a clinically validated target in oncology.1 Anti-hormonal therapies that directly block ER function (e.g., tamoxifen) or therapies that block the production of estrogen itself (e.g., aromatase inhibitors) have proven to be effective treatments of the disease. Further advances have been made with the development of SERDs (Selective Estrogen Receptor Degraders) such as fulvestrant which both antagonise ERα-driven tumor cell growth and cause degradation of the ERα receptor.2 We previously disclosed the identification of a tricyclic indole scaffold that led to the orally active clinical candidate AZD9496.3 Additional work to identify novel chemotypes including phenol 14 and indazole 25 was also disclosed together. The work previously disclosed relied on the presence of the acrylic acid for efficient degradation of the estrogen receptor. In this poster we will discuss the replacement of the acrylic acid on the tricyclic indole scaffold with amines (e.g. compound 3). Compound 3 is a degrader of the estrogen receptor in the MCF-7 cell line (pIC50 8.4). Further optimisation of lead structure 3 led to more potent selective degraders of the estrogen receptor in multiple cell lines (e.g. pIC50 &gt;10 in MCF-7) with suitable properties for oral absorption (e.g. oral AUC 44 μM.h in mice at 20 mg/kg). We will discuss some of the medicinal chemistry challenges that were faced along the way and the optimisation strategy (use of NMR derived solution phase conformations, understanding of the binding mode in the estrogen receptor by X-ray crystallography). ol&gt;
Citation Format: Bernard Barlaam, Jason Breed, Rodrigo J Carbajo, Eric Gangl, Samantha Hughes, Christopher J Morrow, Thomas A Moss, Radoslaw Polanski, Willem M Nissink, Daniel O'Donovan, Jeffrey Varnes, Bin Yang, James S Scott. Small Molecule Degraders of the Estrogen Receptor (SERDs): Optimization of the tricyclic indole scaffold beyond AZD9496 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A107. doi:10.1158/1535-7163.TARG-19-A107
Abstract A111: AF8c, a pan-ErbB family inhibitor induces apoptotic cell death by stimulating DR5/Nrf2 via ROS in colorectal cancer cells
Authors: Jeong Soyeon , Farag Ahmed Karam , Yun Hye Kyeong , Jeong Yoon A , Kim Dae Yeong , Jo Min Jee , Park Seong Hye , Kim Bo Ram , Kim Jung Lim , Lee Dae-Hee , Roh Eun Joo , Oh Sang Cheul 
Published: March 2020

Abstract
Multifunctional, antiproliferative small molecules are deemed to offer pharmacodynamic and pharmacokinetic benefits over combination therapy, in addition to reducing toxicity, cancer resistance, and therapy costs. In this study, we conducted an in vitro cellular screen of our recently reported series of EGFR/HER2 inhibitors. Due to its preferentially apoptosis triggering in colorectal cancer (CRC) cells compared to normal colon cells, the compound AF8c was selected for further evaluation. Analysis of the AF8c mode of action in CRC cells revealed that it mediates apoptosis via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as selective activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), but not DR4. Silencing of DR5 attenuated the expression levels of Nrf2 and partially inhibited AF8c-induced apoptosis. Additionally, upregulation of Nrf2 by AF8c evoked apoptosis through a decrease in antioxidant levels. Treatment of mice with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC. Moreover, it could also be a potential starting point for the understanding of the structural features of quinazoline-based ErbB family inhibitors targeting the TRAIL cascade.
Citation Format: Soyeon Jeong, Ahmed Karam Farag, Hye Kyeong Yun, Yoon A Jeong, Dae Yeong Kim, Min Jee Jo, Seong Hye Park, Bo Ram Kim, Jung Lim Kim, Dae-Hee Lee, Eun Joo Roh, Sang Cheul Oh. AF8c, a pan-ErbB family inhibitor induces apoptotic cell death by stimulating DR5/Nrf2 via ROS in colorectal cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A111. doi:10.1158/1535-7163.TARG-19-A111
Abstract B007: OKI-179 is a novel, oral, class I specific histone deacetylase inhibitor in phase 1 clinical trials
Authors: Diamond Jennifer R , Kagihara Jodi A , Liu Xuedong , Gordon Gilad , Heim Amy M , Winkler James , DeMattei John A , Piscopio Anthony D , Eckhardt S. Gail 
Published: March 2020

Abstract
Multiple histone deacetylase (HDAC) inhibitors are approved for use as single agents in hematological cancers, including T-cell lymphomas and multiple myeloma. However, these compounds have failed to address unmet needs in other hematological malignancies and solid tumors, due in part to the promiscuous inhibitory properties of pan inhibitors, a lack of suitable therapeutic indices for combination therapy, and, in some cases, a non-oral route of administration. Of the approved agents, romidepsin is the most potent and selective, but is limited by its need for IV infusion and therapeutic index. With these challenges in mind, our team designed OKI-179, a novel, oral pro-drug analog of largazole, a compound reminiscent of the romidepsin-depsipeptide class of natural products. OKI-179 demonstrates potent inhibition of the Class 1 HDACs, HDAC 1,2,3 (IC50 = 1.2, 2.4, 2.0 nM, respectively), with no significant inhibition of Class IIa HDACs. It shows potent antiproliferative and apoptotic effects against a wide range of cell lines, activity in xenograft cancer models, and good oral PK properties in mouse, rat and dog models. OKI-179 inhibits the growth in mice of colorectal (HCT-116) and triple negative breast (MDA-MB-231) xenograft models potently and dose-dependently as a single agent. OKI-179 potently and dose-dependently causes the upregulation of MHC Class 1 in B16F10 murine melanoma cells; patients with low MHC presentation respond poorly to checkpoint inhibitors. Importantly, the combination of OKI-179 and a murine anti-PD1 agent demonstrates significant synergistic tumor growth inhibition in the syngeneic CT26 murine CRC model and in a genetic model of DLBCL. OKI-179 is currently being investigated in a first-in-human phase 1 dose-escalation trial, with the goals of determining safety, MTD, RP2D, PK, PD, and preliminary efficacy signals. In the first dosing cohorts, the drug was well-tolerated, achieved good exposure following oral administration, and preliminary signs of on-target PD effects were observed. An update of the clinical experience will be presented and discussed, along with translational data that will guide subsequent clinical development.
Citation Format: Jennifer R Diamond, Jodi A Kagihara, Xuedong Liu, Gilad Gordon, Amy M Heim, James Winkler, John A DeMattei, Anthony D Piscopio, S. Gail Eckhardt. OKI-179 is a novel, oral, class I specific histone deacetylase inhibitor in phase 1 clinical trials [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B007. doi:10.1158/1535-7163.TARG-19-B007
Abstract B031: OneThree Biotech’s artificial intelligence platform for optimizing drug development
Authors: Gilvary Coryandar , Madhukar Neel , Elemento Olivier 
Published: March 2020

Abstract
Recently, it has been shown how artificial intelligence (AI) has the possibility to dramatically shorten the drug development pipeline by identifying insights that may have otherwise been missed. However, one major critique of these methods has been their black-box nature and the lack of mechanistic biology. To address these issues, OneThree Biotech has developed an extensive platform of biology-driven AI approaches that accelerate early stage drug development. Beginning with novel target identification, we present ECLIPSE, an AI approach that combines genomic, cell line and experimental design features to identify essential genes within cancer cell lines, based upon CRISPR and shRNA loss-of-function screenings. We demonstrated that ECLIPSE could accurately identify known and potential cancer targets, as well as be used to determine drug efficacy in the clinic. In cases where a compound’s target is unknown, we introduce BANDIT, a Bayesian model that combines divergent data sources to predict the targets and mechanisms for small molecules with unprecedented accuracy and versatility. Using BANDIT, we successfully identified a novel class of microtubule inhibitors and a previously unknown mechanism of ONC201, an anti-cancer small molecule, which led to a successful Phase 2 trial in a rare glioblastoma. Building on these approaches, we also introduce our suite of drug synergy prediction models. These models can not only predict the level of expected drug synergy in specific cancer types, but can also be used to pinpoint the specific mechanisms of actions that contribute to synergy. Altogether, OneThree’s platform is a comprehensive AI approach that combines high quality AI with mechanistic biology to optimize early-stage drug development.
Citation Format: Coryandar Gilvary, Neel Madhukar, Olivier Elemento. OneThree Biotech’s artificial intelligence platform for optimizing drug development [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B031. doi:10.1158/1535-7163.TARG-19-B031