bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B037: Potential next-generation androgen receptor-targeted therapeutic for enzalutamide-resistant prostate cancer; In vivo characterization in immune-compromised SRG rats
Authors: Ponnusamy Suriyan Udhayasuriyan , Noto Fallon K , Adedeji Bisoye Towobola , He Yali , Hwang Dong-Jin , Moody Sam , Thiyagarajan Thirumagal , Jamling Tseten Yeshi , Miller Duane D , Narayanan Ramesh 
Published: March 2020

Abstract
Current treatment options for advanced castration-resistant prostate cancers (CRPC) are effective for a brief period before becoming refractory. It is important to use relevant in vivo models for candidate selection in the development of next-generation mechanistically-distinct drugs to treat castration- and drug- resistant prostate cancers. Here, we describe a series of AR pan-antagonists (selective AR degraders (SARDs)) that degrade the AR and AR splice variants. SARDs inhibit the wild-type and LBD mutant ARs comparably and inhibit the in vitro proliferation and in vivo growth of enzalutamide-sensitive and resistant prostate cancer xenografts. Xenograft studies conducted in immune-compromised SRG rats (Sprague Dawley Rag2-/- Il2rg -/-; Hera Biolabs) with three lead SARDs demonstrated regression of enzalutamide-sensitive and -resistant VCaP tumors both in castrated and in intact rats. SRG rats provide the benefit of abundant blood samples for weekly evaluation of rising PSA, which also indicated that the SARDs inhibit the rising PSA, while enzalutamide was inactive in enzalutamide-resistant model. Drug metabolism and pharmacokinetic (DMPK) studies, also conducted with SRG and wild-type rats and in combination with efficacy, indicate that the molecules possess all the necessary drug-like properties. The molecules exhibit a broad safety margin with no cross-reactivity with G-Protein Coupled Receptor, kinase, and nuclear receptor family members. Collectively, the SARDs exhibit the properties necessary for a next-generation prostate cancer drug and that use of SRG rats facilitated thorough characterization of their in vivo properties.
Citation Format: Suriyan Udhayasuriyan Ponnusamy, Fallon K Noto, Bisoye Towobola Adedeji, Yali He, Dong-Jin Hwang, Sam Moody, Thirumagal Thiyagarajan, Tseten Yeshi Jamling, Duane D Miller, Ramesh Narayanan. Potential next-generation androgen receptor-targeted therapeutic for enzalutamide-resistant prostate cancer; In vivo characterization in immune-compromised SRG rats [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 B037. doi:10.1158/1535-7163.TARG-19-B037
Abstract B061: A novel cell-mediated immunotherapy for treatment of lung and breast cancer
Authors: Venugopal Indu , Gormley Claire , McGuire Michael J , Brown Kathlynn C 
Published: March 2020

Abstract
Cancer Immunotherapies designed to generate a cell-mediated immune response against tumors are emerging as frontline treatment options for cancer; however, concerns regarding efficacy, safety and cost efficacy have limited the use of these treatments. To address these weaknesses, we have developed a novel immunotherapy capable of delivering previously encountered antigenic peptides specifically to cancer cells and facilitating their presentation through the MHC class I pathway. Our therapy utilizes a modular synthetic nanoparticle delivery system comprising of three components: a neutral stealth liposome, encapsulated synthetic immunogenic HLA class I restricted peptides derived from measles virus (MV), and a tumor-targeting peptide on the external surface of the liposome. The targeting peptide results in accumulation of the liposomes specifically inside cancer cells and facilitates presentation of the MV-derived immunogenic peptides in HLA class I molecules. We refer to this system as TALL (Targeted Antigen Loaded Liposomes). Therefore, TALL can generate a secondary immune response specifically against the targeted tumor cells in a patient who has been previously vaccinated against or infected by MV. In short, we are attempting to trick the immune system into responding as though the cancer cell is infected with MV without the use of a viral particle. We have demonstrated that this approach leads to a cancer-specific CD8+ T cell response which requires all three components of the TALL system. The lead cancer-targeting peptide has been optimized for affinity, cellular uptake, hydrophobicity, and stability. The TALL liposomes home to tumors in vivo. We have demonstrated a significant reduction in subcutaneous tumor growth using P-TALL in aggressive LLC1 and 4T1 murine models.
Citation Format: Indu Venugopal, Claire Gormley, Michael J McGuire, Kathlynn C Brown. A novel cell-mediated immunotherapy for treatment of lung and breast cancer [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 B061. doi:10.1158/1535-7163.TARG-19-B061
Abstract B063: Role of HIPEC and its association with regulatory T cells in ovarian cancer: Preliminary experience from tertiary care center in India
Authors: Ray Mukurdipi , Rizwan Arshi 
Published: March 2020

Abstract
Introduction: Epithelial Ovarian cancer (EOC) is the most lethal Gynaecological Cancer and incidence is rapidly increasing in India and it is a leading cause of death due to its high relapse rate. Despite of multimodality treatment, the 5 years survival is dismal and for last three decades it is 15-30% and recurrence rate &gt;70%. The Hyperthermic intraperitoneal chemotherapy (HIPEC) is a highly concentrated, heated chemotherapy, delivered directly to the abdominal cavity at the end of complete Cytoreduction surgery aiming to destroy the microscopic cancer cells. Experimental Procedure: Regulatory T cells (Tregs) play a crucial role in ovarian cancer suppression and its recurrence. However changes in Tregs population in patients with ovarian cancer after HIPEC in not yet known. On occurrence of cancer, immunological imbalance between Tregs and Th17 cells leads to cancer suppression or inflammation. Our study aims to understand the expression pattern of Tregs (CD4+,CD25+, CD127- ,IL10+,Foxp3+) and Th17(CD4+, CCR6+, IL17+, RORγ) and intracellular cytokine profile in peripheral blood by flow cytometry before and after the HIPEC in 1st week and 4th week. Summary: We have observed that percentage of Tregs in Ovarian Cancer patients (n=24) were high as compared to healthy controls before HIPEC and were reduced remarkably after 4 weeks of operation. Th17 cells frequency was low before HIPEC but in patients with good recovery Th17 cells are relatively high after 4 weeks of HIPEC. The percentage of Tregs was very high in stage III/IV before HIPEC treatment whereas there is some change in Th17 cells observed before and after HIPEC. This is a preliminary data results will be further confirmed by having more number of patients and after statistical analysis. Further we are also looking forFOXP3expressionat tissue and gene level by Immunohistochemistry (IHC) and real time PCR to compare the difference in expression of FOXP3 Conclusion: Our work raises the possibility that the HIPEC procedure not only kills tumour cells but also induces an efficient anticancer immune response, therefore opening new therapeutic windows for the patients of EOC.
Citation Format: Mukurdipi Ray, Arshi Rizwan. Role of HIPEC and its association with regulatory T cells in ovarian cancer: Preliminary experience from tertiary care center in India [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 B063. doi:10.1158/1535-7163.TARG-19-B063
Abstract B073: Development of combination therapies to potentiate the impact of KRAS-G12C inhibitors in lung cancer
Authors: Molina-Arcas Miriam , Moore Christopher , Rana Sareena , Maldegem Febe Van , Mugarza Edurne , Romero-Clavijo Pablo , Horswell Stuart , Hancock David , Downward Julian 
Published: March 2020

Abstract
Oncogenic mutations in KRAS are frequent in non-small cell lung cancer (NSCLC) and have been associated with poor prognosis and resistance to existing therapies. We have previously shown that NSCLC cells harboring KRAS mutations are selectively sensitive to inhibition of MEK and IGF1R signaling. Using a whole-genome shRNA screen, we shown that this effect is markedly enhanced by simultaneous inhibition of mTOR, while maintaining selectivity for the KRAS mutant genotype. Mechanistic investigations demonstrated that IGF1R inhibitors block the reactivation of the PI3K pathway induced by mTOR inhibition, resulting in a robust suppression of PI3K and mTORC1 signalling. Addition of a MEK inhibitor to the combination results in simultaneous inhibition of the main nodes downstream of RAS. Notably, the inhibition of these signalling pathways is stronger in KRAS-mutant cells than in their wild-type counterparts. Combining MEK, IGF1R and mTOR inhibitors produces a profound and durable suppression of cell proliferation and a stronger induction of apoptosis, resulting in marked tumor regression in three different Kras-driven lung cancer mouse models. In order to achieve strong downstream pathway inhibition even more specifically in KRAS-mutant cells and reduce potential unwanted toxicities, we used KRAS-G12C mutant inhibitors. We show that the triple combination of mTOR, IGF1R and KRAS-G12C inhibitors causes a profound and durable inhibition of the main pathways downstream RAS and greatly improves the effectiveness of ARS-1620 on KRAS-G12C mutant lung cancer cells in vitro and in mouse models. This provides a clear rationale for the design of combination treatments to enhance and extend the response to KRAS-G12C inhibitors.
Citation Format: Miriam Molina-Arcas, Christopher Moore, Sareena Rana, Febe Van Maldegem, Edurne Mugarza, Pablo Romero-Clavijo, Stuart Horswell, David Hancock, Julian Downward. Development of combination therapies to potentiate the impact of KRAS-G12C inhibitors in lung cancer [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 B073. doi:10.1158/1535-7163.TARG-19-B073
Abstract B074: Sapanisertib in combination with trametinib in glioblastoma models enhances target inhibition and antitumor activity
Authors: Schreck Karisa C , Allen Amy , Wang Jiawan , Pratilas Christine A 
Published: March 2020

Abstract
Objective: To determine the biological and signaling effects of dual-pathway inhibition with mTORC1/2 and MEK inhibitors in glioblastoma neurosphere cell lines. Background: The PI3K/mTOR signaling pathway is frequently dysregulated in glioblastoma (GBM), making it the focus of active scientific and drug development efforts in brain tumors. Unfortunately, small molecule targeted therapies against EGFR and its downstream effector pathways, while promising in the pre-clinical setting, have been disappointing in glioma clinical trials. The mTOR pathway target ribosomal protein S6 (RPS6) can also be activated by the ERK pathway target p90-RSK. We therefore tested the hypothesis that small molecule inhibition of both ERK and mTOR signaling pathways would result in enhanced anti-tumor activity. Methods: Seven glioblastoma neurosphere lines were tested for sensitivity to the ATP-competitive mTORC1/2 inhibitor sapanisertib (MLN0128) alone or in combination with the allosteric MEK1/2 inhibitor trametinib (GSK1120212) using cell growth assays and immunoblots as indicated. Results: The dual mTORC1/2 inhibitor sapanisertib inhibits mTOR signaling and cell growth in all GBM neurosphere lines, but only partially inhibits phosphorylation of the downstream target ribosomal protein S6 (phospho-RPS6) in these models. The MEK inhibitor, trametinib, inhibited ERK phosphorylation in all neurosphere lines, though phosphorylation of downstream targets and cell growth were inhibited to varying degrees. Inhibition of RPS6 activation was dose-dependent and correlated with cell line sensitivity when treated with trametinib but not with sapanisertib. In combination, sapanisertib plus trametinib showed more profound inhibition of phospho-RPS6, as well as enhanced growth inhibition and induction of apoptosis in sensitive neurosphere lines. Conclusions: The combination of sapanisertib and trametinib may have significant antitumor activity in glioblastoma neurospheres by enhanced inhibition of S6, which serves as the convergence point between these effector pathways.
Citation Format: Karisa C Schreck, Amy Allen, Jiawan Wang, Christine A Pratilas. Sapanisertib in combination with trametinib in glioblastoma models enhances target inhibition and antitumor activity [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 B074. doi:10.1158/1535-7163.TARG-19-B074
Abstract B099: Characterization of monoclonal antibodies generated to the 287-302 amino acid loop of the human epidermal growth factor receptor
Authors: Ho Eric Chun Hei , Antignani Antonella , Sarnovsky Robert , FitzGerald David J 
Published: March 2020

Abstract
Dysregulation of the epidermal growth factor receptor (EGFR) has been implicated in the oncogenesis of malignancies including glioblastoma and various epithelial cancers. Oncogenesis occurs from overexpression of EGFR, often linked to gene amplification or receptor mutagenesis. The 287-302 loop from the extracellular domain is exposed completely on EGFRvIII (deletion of exons 2-7), partially exposed on some cancers but cryptic on normal cells expressing WT levels of EGFR. We report on the generation of antibodies to this loop. A peptide corresponding to amino acids 286-303 was synthesized and then coupled chemically to Keyhole Limpet Hemocyanin. After immunizations, sera were assayed for reactivity to the peptide. Mice with high titers were used for hybridoma production. Purified antibodies were isolated from hybridoma supernatants, while V-regions were cloned and sequenced. Receptor binding was characterized using ELISA and flow cytometry. Monoclonal antibodies (n=7) reactive for the 287-302 loop were characterized further. Each one reacted with EGFRvIII but not EGFR WT. Based on reactivity with the immunizing peptide, antibodies were mapped to one of three subgroups. One antibody, 40H3, also exhibited binding to MDA-468 and A431 cells but not to non-cancerous WI-38 cells. Because of its unusual binding characteristics, a recombinant immunotoxin was generated from 40H3, which proved to be potently cytotoxic for MDA-468, A431 and F98-EGFRvIII-expressing cells. We conclude that immunization with a peptide corresponding to a cryptic EGFR epitope can produce cancer-binding antibodies. By way of example, the 40H3 antibody was engineered as a cytotoxic recombinant immunotoxin and could be developed as a therapeutic agent for clinical use.
Citation Format: Eric Chun Hei Ho, Antonella Antignani, Robert Sarnovsky, David J FitzGerald. Characterization of monoclonal antibodies generated to the 287-302 amino acid loop of the human epidermal growth factor receptor [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 B099. doi:10.1158/1535-7163.TARG-19-B099
Abstract B121: An oncogene-linked prodrug strategy in lung cancer
Authors: Boudreau Aaron , Roth Jennifer , Rong James , Olsson Niclas , Mader Chris , Byran Jordan , Rossen Jordan , Wang Li , Larpenteur Kevin , Goodale Amy , Trepicchio Colin , Bender Samantha , Tsherniak Aviad , Subramanian Aravind , Kocak Mustafa , Piccioni Federica , Bittker Josh , Zhu Cong , Li Frank , Eriksson Nick , Koller Daphne , McAllister Fiona , Golub Todd , Settleman Jeff , Firestone Ari , Stokoe David 
Published: March 2020

Abstract
KEAP1-mutant non-small cell lung cancer is a high prevalence indication that responds poorly to conventional chemotherapy owing to constitutive activation of NRF2 and its associated drug metabolism target genes. Using an approach to identify compounds that selectively kill cancer cell lines in a biomarker-driven manner, we identify BRD-K19050021 (K1905), a compound displaying strong toxicity in cells expressing CYP4F11 - a cytochrome p450 family member and NRF2 transcriptional target. Using genome-wide pooled CRISPR screens, we show that CYP4F11 activity is necessary and sufficient for response to K1905, and in acquired resistance models developed from multiple cell lines, we show a minor subpopulation of cells mechanistically converge on suppressed CYP4F11 expression to bypass K1905 response. CYP4F11 converts K1905 from a prodrug into a covalent active metabolite that alkylates several cellular targets, triggering all three canonical arms of the unfolded protein response pathway and culminating in cell death. We propose that CYP4F11 and similar metabolic enzyme activities promoted by oncogenic drivers represent a unique opportunity to restrict prodrug activation within tumors, provided that normal tissue expression of such prodrug-converting enzymes do not diminish therapeutic index.
Citation Format: Aaron Boudreau, Jennifer Roth, James Rong, Niclas Olsson, Chris Mader, Jordan Byran, Jordan Rossen, Li Wang, Kevin Larpenteur, Amy Goodale, Colin Trepicchio, Samantha Bender, Aviad Tsherniak, Aravind Subramanian, Mustafa Kocak, Federica Piccioni, Josh Bittker, Cong Zhu, Frank Li, Nick Eriksson, Daphne Koller, Fiona McAllister, Todd Golub, Jeff Settleman, Ari Firestone, David Stokoe. An oncogene-linked prodrug strategy in lung cancer [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 B121. doi:10.1158/1535-7163.TARG-19-B121
Abstract B123: Full-length bio-active atypical protein kinase c ι expression and purification in a bacterial system
Authors: Smalley Tracess , Patel Rekha , Acevedo-Duncan Mildred 
Published: March 2020

Abstract
Background: Proteins are at the steering wheel in the route of cancer progression. Protein kinase C (PKC) is a contributor to malignant advancement and it pushes past some of the normal cell’s defenses. In particular, PKC-ι participates in oncogenesis at varying levels in signaling and tissue specificity. Around 70% of the selected chemical entities that are the result of in-silico investigations are found to be rejected in the final stages of drug development. Therefore, binding studies are essential to in-silico techniques and are pivotal for finding kinase inhibitors for overly active proteins like PKC-ι. Despite the fact that there are numerous binding studies involving PKC-ι, protein production remains tedious and expensive. Objective: In this investigation, we hope to produce large amounts of recombinant bio-active full-length PKC-ι in a bacterial system. The large quantity of PKC-ι can be used for future experiments such as Nuclear Magnetic Resonance (NMR), x-ray crystallography, isothermal titration calorimetry (ITC) and ligand binding studies. Methods: We used bacterial expression plasmids (pET-His) with full-length and catalytic domain only PKC-ι gene inserts (tagged and untagged with GST). We transformed the bacterial cells lines BL21(DE3), Tuner (DE3), and ArticExpress. Results and Discussion: So far we have successfully produced low amounts of the full-length PKC-ι and the catalytic domain of PKC-ι in Tuner (DE3) and BL21(DE3) bacterial cells, respectively. We have also isolated a small amount of the PKC-ι catalytic domain from BL21(DE3) using a nickel column. However, continued optimization of the bacterial environment is needed to increase the quantity and quality of our desired protein.
Citation Format: Tracess Smalley, Rekha Patel, Mildred Acevedo-Duncan. Full-length bio-active atypical protein kinase c ι expression and purification in a bacterial system [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 B123. doi:10.1158/1535-7163.TARG-19-B123
Abstract B125: Targeting translation for the treatment of pancreatic ductal adenocarcinoma
Authors: Safari Maryam , Kim Yu Ri , Mundi Prabhjot S. , Deng Changchun , Bates Susan E. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer deaths in the United States and is projected to be in second place by 2030. A key cellular aberration is the activating KRAS mutation (&gt;90%) which in turn leads to stabilizing the MYC oncoprotein and stimulating the growth of PDAC tumors. Dense stroma with elevated levels of hyaluronic acid is another characteristic of PDAC tumors contributing to poor therapeutic response. We describe a novel approach for the treatment of PDAC involving the targeting of thetranslation initiation factor 4A (eIF4A) with a new class of Pateamine A derivatives, DMDA PatA and MZ735.Our data show that nanomolar concentrations of these compounds inhibit cell proliferation and cause G0/G1 arrest in PDAC cell lines. We observed reduction of c-MYC, CyclinD1 and hyaluronic acid synthase HAS3 following treatment with eIF4A targeting compounds. RNA-seq analysis of Miapaca-2 cells treated with MZ735 using the Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER) algorithm revealed that loss of several MYC gene sets was among the most significantly altered compared to the control cells. We further performed proteomics to better define the consequences of MZ735-induced translation inhibition and observed that several key oncoproteins in PDAC were among the most depleted including MYC, CCND1, and EGFR. Finally, confocal imaging confirmed the reduction of hyaluronic acid in the eIF4A inhibitor-treated PDAC cells. We believe these small molecule compounds represent a new class of anticancer agents that have the potential to address both altered cellular and microenvironment components in PDAC.
Citation Format: Maryam Safari, Yu Ri Kim, Prabhjot S. Mundi, Changchun Deng, Susan E. Bates. Targeting translation for the treatment of pancreatic ductal adenocarcinoma [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 B125. doi:10.1158/1535-7163.TARG-19-B125