bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-A11: Quantitative and qualitative characterization of spontaneous resistance to targeted protein degradation
Authors: Brand Matthias , Winter Georg E. 
Published: March 2020

Abstract
Targeted protein degradation (TPD) by heterobifunctional small molecules commonly called PROTACs has recently emerged as a promising novel strategy in drug development. PROTACs hijack the endogenous cellular degradation machinery by recruiting E3 ubiquitin ligases to a protein of interest, resulting in its ubiquitination and degradation by the proteasome. The first two PROTACs have entered clinical investigation this year, but resistance mechanisms to this novel pharmacology are not yet thoroughly understood. Here, we set out to systematically quantify and characterize spontaneous resistance to TPD. For this, we made use of the well-characterized PROTACs dBET6 and ARV-771, that induce degradation of BET bromodomain proteins by recruitment of the E3 ligase CRBN or VHL, respectively. We estimated spontaneous resistance rates by exposing cells to lethal doses of drug and monitoring for the emergence of resistant clones. We detected important quantitative differences between the two PROTACs, with resistance rates to the VHL-based degrader ARV-771 being significantly lower than to dBET6. To characterize the mechanism of resistance, we implemented a customized hybrid-capture sequencing pipeline for known determinants of PROTAC sensitivity and applied it to drug-resistant cells, revealing several resistance-conferring mutations. Mapping of the mutations on crystal structures of the E3 ligase complexes highlighted their clustering at the drug binding pocket, as well as on important protein-protein interaction surfaces in the complex. The majority of identified mutations affected the hijiacked E3 ligase complex directly and not the general ubiquitination machinery, thereby not conferring cross-resistance to different PROTACS. This suggests combination treatment with degraders that exploit different E3 ligases as a viable strategy to limit emergence of PROTAC resistance.
Citation Format: Matthias Brand, Georg E. Winter. Quantitative and qualitative characterization of spontaneous resistance to targeted protein degradation [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 LB-A11. doi:10.1158/1535-7163.TARG-19-LB-A11
Abstract LB-B05: Characterization of a panel of 79 PDX-derived cell lines with a focus on the EGFR exon 20 insertion mutation-driven NSCLC model LXFE 2478
Authors: Kelter Gerhard , Peille Anne-Lise , Fehr Jutta , Klett Hagen , Maier Armin , Posch Markus , Metz Thomas M 
Published: March 2020

Abstract
Patient-derived tumor xenograft (PDX) models have become indispensable for the preclinical profiling of novel anti-cancer agents as they retain histological, molecular and pharmacological characteristics of the parental patient tumors and for many tumor types collectively replicate the diversity of patient tumors. To make PDX models available for in vitro assays, we have established a panel of 79 low passage cell lines derived from PDXs representing 15 different tumor histologies. Using, among others, the non-small cell lung cancer model LXFE_2478 which is driven by the exon 20 insertion EGFR mutation M766_A767insASV as an example, we demonstrate the following similarities of PDX models and the corresponding PDX-derived cell lines. (i) Subcutaneous xenografts established from PDX-derived cell lines mirror the histology of the corresponding PDX models and usually also patient tumors. (ii) For LXFE_2478 both the PDX model and the corresponding PDX-derived cell line express high levels of EGFR, suggesting that the oncogenic driver is still present. (iii) For LXFE_2478 the PDX and the PDX-derived cell line subcutaneously implanted in mice display comparable sensitivity to a variety of EGFR inhibitors and cytotoxics. (iv) For LXFE_2478 the sensitivity of the PDX-derived cell line to a variety of EGFR inhibitors in an in vitro 2D cell survival and proliferation assay in general corresponds to the EGFRi sensitivity of the corresponding PDX model in vivo. (v) For several additional PDX models representing various histotypes the sensitivity to first generation EGFR inhibitors of PDX-derived cell lines in the 2D assay is in line with the in vivo EGFR inhibitor sensitivity of the corresponding PDXs. In conclusion, at least for some mechanisms of action in vitro data obtained with PDX-derived cell lines can predict the in vivo behavior of the corresponding PDX model and can thereby accelerate, and reduce the costs of, the discovery of novel anticancer agents.
Citation Format: Gerhard Kelter, Anne-Lise Peille, Jutta Fehr, Hagen Klett, Armin Maier, Markus Posch, Thomas M Metz. Characterization of a panel of 79 PDX-derived cell lines with a focus on the EGFR exon 20 insertion mutation-driven NSCLC model LXFE 2478 [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 LB-B05. doi:10.1158/1535-7163.TARG-19-LB-B05
Abstract LB-B17: Uncovering novel cancer therapeutics using the Exoneural Medicines Platform: The role of innervation in cancer
Authors: Lou Shan , Fink Alexandria , Wang Jay , Turner Jesse , Thanawala Monica , Yuen Garmen , Lantermann Alexandra , Shu Jenny , Dai Hongyue , Huang Pearl , Hurov Jonathan 
Published: March 2020

Abstract
Peripheral nerves were first described as a component of tumors in the late 19th century. In the mid-20th century early preclinical studies indicated that tumor cells could recruit innervation from spinal cord ganglia and that stress promotes tumorigenesis. Within the last 10 years improvements in technologies allowing neuronal tracking and regulation of neuronal function have uncovered a role for both autonomic and sensory innervation in multiple tumor types. Initial studies have implicated this biology in prostate, pancreatic, gastric and breast cancer (among others) and point to a role for nerves in initiation, maintenance and metastasis of tumors. The stimulation of tumor cell growth by neural growth factors, the recruitment of neurites by tumor cells, the invasion and migration of tumor cells along nerves (perineural invasion), and the role of innervation in driving tumor angiogenesis are just a few examples of how peripheral nerves interact with the tumor microenvironment. Indeed, an argument could be made that innervation of tumors should be considered a hallmark of cancer. We describe here a biological platform that can define and decode the role of neural signaling in cancer. This platform, which we call Exoneural Medicines Platform ™, has 6 technical components: 1) co-culture models of primary neurons with both tumor and immune cells, 2) advanced imaging modalities to define the neural component of tumors, 3) AAV and transgenic tools that allow regulation of neurons proximal to tumors in vivo and in vitro, 4) neural-focused functional genomics, 5) neural-focused bioinformatics, and 6) a neuropharmacopeia compound library for probing relevant biological pathways and identification of advanced starting points for drug discovery. We show here how the platform is being employed to characterize this exciting new space in cancer biology and to identify new drivers of disease.
Citation Format: Shan Lou, Alexandria Fink, Jay Wang, Jesse Turner, Monica Thanawala, Garmen Yuen, Alexandra Lantermann, Jenny Shu, Hongyue Dai, Pearl Huang, Jonathan Hurov. Uncovering novel cancer therapeutics using the Exoneural Medicines Platform: The role of innervation in 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 LB-B17. doi:10.1158/1535-7163.TARG-19-LB-B17
Abstract LB-B19: Investigating the effect of pharmacogenetic variations on voriconazole levels in pediatric cancer patients
Authors: Saeed Dina , Shalaby Lobna , Nagy Mohamed , ElZeiny Ahmed , Mostafa Tarek M. , ElRakaiby Marwa T. , Nooh Mohammed M. , El-Haddad Alaa , Abbassi Maggie , Aziz Ramy K. 
Published: March 2020

Abstract
Background: Voriconazole is a second-generation triazole antifungal with broad-spectrum activity against Aspergillosis, metabolized mainly by CYP2C19 in the liver. Despite the use of weight-based dosing, plasma voriconazole blood levels show inter-individual variability, which is attributed to many factors such as weight, age, food, drug interactions, and CYP2C19 polymorphism. Voriconazole metabolism in pediatrics has been reported to be profoundly impacted by CYP2C19 genotypes. Aim: To evaluate the frequencies of CYP2C19 variant alleles (*2, *3, and *17), genotypes, and phenotypes in Egyptian pediatric cancer patients and to investigate the correlation between CYP2C19 genetic variability and other factors with voriconazole plasma levels. Methods: This study was conducted on 100 pediatric cancer patients with probable fungal infection treated with voriconazole. DNA was extracted from blood samples and analyzed by the TaqMan SNP genotyping assay. Identified genotypes were classified accordingly into various predicted phenotypes. Results: Voriconazole plasma levels widely varied, with only 49.5% reaching therapeutic levels. Frequencies of CYP2C19*2 and *17 allelic variants were 10.6 and 18.3%, respectively, while allele *3 was not detected in the study population. A significant correlation was found between plasma levels and CYP2C19 phenotypes: ultra-rapid metabolizers had significantly lower plasma levels (P=0.003) relative to the extensive metabolizer genotype. Conclusion: Determination of CYP2C19 genotype at initiation of therapy, followed by drug monitoring, would serve as a valuable tool for the optimization of voriconazole therapy for pediatric cancer patients. It would also be an essential step in the advancement of precision medicine to optimize therapeutic efficacy and minimize toxicity.
Citation Format: Dina Saeed, Lobna Shalaby, Mohamed Nagy, Ahmed ElZeiny, Tarek M. Mostafa, Marwa T. ElRakaiby, Mohammed M. Nooh, Alaa El-Haddad, Maggie Abbassi, Ramy K. Aziz. Investigating the effect of pharmacogenetic variations on voriconazole levels in pediatric cancer patients [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 LB-B19. doi:10.1158/1535-7163.TARG-19-LB-B19
Abstract LB-C10: Preclinical synergistic anti-tumor effect against multiple cancer types by EZH2 inhibitor EPZ-6438 plus imipridone ONC201 to mimic H3K27M mutation observed in DIPG tumors that respond to ONC201 in the clinic
Authors: Zhang Yiqun , Zhou Lanlan , Zhang Shengliang , Borsuk Robyn , Safran Howard P. , Seyhan Attila A. , El-Deiry Wafik S. 
Published: March 2020

Abstract
ONC201, the founding member of the imipridone class of small molecules, has broad spectrum anti-tumor activity and achieved tumor regressions and prolonged disease stability in clinical trials, especially in patients with histone H3 K27M mutated glioma. Levels of H3K27 dimethylation (H3K27me2) and trimethylation (H3K27me3) are reduced globally in H3 K27M patient samples. EZH2 is the catalytic component of the Polycomb Repressor Complex 2 (PRC2), a conserved multi-subunit that represses gene transcription by methylating lysine 27 on Histone H3 (H3K27). EZH2 is frequently overexpressed or mutated (activating) in numerous human malignancies and EZH2 inhibitors represent a promising therapeutic strategy. We hypothesized that cancer cells could be sensitized to ONC201 by EZH2 inhibition through suppression of H3K27 methylation that may mimic tumors such as DIPG with H3K27M mutations which are known to respond to ONC201 in the clinic and are defective in H3K27 methylation. We treated cancer cells from different tissue origins including breast cancer, pancreatic cancer, colorectal cancer, GBM, and DIPG with single agent ONC201, EZH2 inhibitor EPZ-6438 or the combination of ONC201 plus EPZ-6438. Cell viability was determined with the Cell Titer-Glo assay. Integrated stress response (ISR) activity widely observed in ONC201-treated tumor cells was evaluated using Western blot analysis of ATF4 and apoptosis by analysis of PARP cleavage. Our results demonstrate that ONC201 synergistically reduced cell viability, induced integrated stress response and apoptosis in combination with EZH2 inhibitor EPZ-6438. There was greater induction of ATF4 in combination therapy-treated tumor cells versus monotherapy. Intriguingly, U-251 GBM cells that were resistant to ONC201 under hypoxia could be sensitized to ONC201 by EZH2 inhibitor EPZ-6438. Our findings provide a preclinical rationale for developing ONC201 and EZH2 inhibitors as a novel synergistic combinatorial regimen with the potential for clinical translation in the treatment of several human malignancies including GBM, pancreatic cancer, colorectal cancer, and breast cancer.
Citation Format: Yiqun Zhang, Lanlan Zhou, Shengliang Zhang, Robyn Borsuk, Howard P. Safran, Attila A. Seyhan, Wafik S. El-Deiry. Preclinical synergistic anti-tumor effect against multiple cancer types by EZH2 inhibitor EPZ-6438 plus imipridone ONC201 to mimic H3K27M mutation observed in DIPG tumors that respond to ONC201 in the clinic [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 LB-C10. doi:10.1158/1535-7163.TARG-19-LB-C10
Abstract PL04-01: Background and use of circulating tumor-derived DNA and circulating tumor cells as biomarkers
Authors: Lolkema Martijn 
Published: March 2020

Abstract
The use of circulating biomarkers to assess malignant disease is an ever growing field of interest. Indeed, many studies have shown that mutations derived from tumors can be detected in plasma, and the use of novel sequencing techniques have given rise to many novel ways of probing blood samples for analytes that may reveal tumor characteristics. In my presentation I will present some crucial pieces of evidence that circulating tumor-derived DNA (ctDNA) may be used to detect minimal residual disease, track mutational evolution and may be used to monitor disease response to treatment. Indeed, ctDNA is one of the most promising analytes and has the potential to alter clinical practice in the foreseeable future. But to get there we need to have a basic understanding of the variables that determine the outcome of these tests. Pre-analytical conditions and proper controls for ctDNA quantification are crucial in the interpretation of the results. Seemingly trivial factors such as intrinsic variation of cfDNA may affect the way we can use this type of analyte. Moreover, I will give an overview of those tests that are about to become available in the coming years, including shallow whole genome sequencing, methylation specific sequencing and panel based sequencing of ctDNA. The second part of my presentation will deal with the first true circulating biomarker that has been the detection of Circulating Tumor Cells (CTCs) and still detecting CTCs is important for the oncology community. I will review the advances we made in this field and will dive a bit deeper into the reasons why we still should be looking at CTCs. In contrast to non-cellular analytes, CTCs can inform us on properties of cells as a whole. The technology development in this arena made enormous advances and the use of single cell sequencing techniques will revolutionize our understanding of intra-tumoral heterogeneity from relatively simple blood based tests. Moreover, the detection of CTCs has always been hampered by the relative low abundance of CTCs, however novel approaches such as leukapheresis to isolate CTCs may deliver on the promise characterization of CTCs holds to reveal the extent of tumor cell heterogeneity.
Citation Format: Martijn Lolkema. Background and use of circulating tumor-derived DNA and circulating tumor cells as biomarkers [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 PL04-01. doi:10.1158/1535-7163.TARG-19-PL04-01
Abstract A09: CD4 T cells mediated protumorigenic pathway in pancreatic cancer
Authors: Dey Prasenjit , Li Jun , Zhang Jianhua , Wang Huamin , Liao Wen-Ting , Bernard Vincent P , Genovese Giannicola , Maitra Anirban , Strom Anders , DePinho Ronald A. 
Published: March 2020

Abstract
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. This Kras*-driven heterotypic signaling circuit in the early and advance tumor microenvironment enables cooperative protumorigenic interactions in early steps of the neoplastic transformation process as well as in promoting growth of established tumors, providing novel therapeutic targets in the Kras* pathway for this intractable disease. Here, we explored the role of Kras* in protumorigenic signaling interactions between cancer cells and host cells in tumor microenvironment. Early-stage malignant lesions and advanced tumors show close proximity of Kras* expressing cancer cells and abundant invading TH2 (CD4+ Gata-3+) cells, which can produce IL-4 and IL-13. Single-cell analysis of low- and high-grade IPMN and PDAC patient samples revealed CD4+ T-cell infiltration and higher percentage of the CD4+ T cells are Gata3+ TH2 subtypes compared to T-bet+ TH1 cells. Similarly, imaging mass spectrometry analysis showed presence of CD4+ T cells in close proximity to cancer cells. Mechanistic studies identified Jak1-Stat6 as the primary signaling pathway downstream of IL-4/IL-13 activated IL-4 receptor complexes in cancer cells. Integrated transcriptomic and chromatin immunoprecipitation sequencing (ChIP-seq) profiling identified cMyc, specifically its upstream enhancer element, as a direct target of activated Stat6. Metabolomic analysis demonstrated that IL-4/13STAT6cMyc upregulation drives increased glycolysis along with upregulated expression of key glycolysis enzymes, forging a link between Kras*-driven glycolysis via paracrine activation of cMyc.
Citation Format: Prasenjit Dey, Jun Li, Jianhua Zhang, Huamin Wang, Wen-Ting Liao, Vincent P Bernard, Giannicola Genovese, Anirban Maitra, Anders Strom, Ronald A. DePinho. CD4 T cells mediated protumorigenic pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A09.
Abstract A16: A novel therapeutic approach to inhibit the bidirectional oncogenic crosstalk between pancreatic cancer cells and the surrounding stroma
Authors: Geleta Bekesho , Park Kyung Chan , Jansson Patric J. , Apte Minoti , Richardson Des R. , Kovacevic Zaklina 
Published: March 2020

Abstract
Background: Pancreatic cancer (PaCa) is a leading cause of cancer-related deaths and is projected to be the second most common cancer in a decade. It is characterized by a dense stroma surrounding tumor cells, known as desmoplasia that is stimulated by Sonic Hedgehog (SHH) released by PaCa cells. Stromal cells, in turn, release mitogenic substances such as hepatocyte growth factor (HGF) and Insulin-like growth factor receptor (IGF-1) by glioma-associated oncogene homolog 1 (GLI1) transcription factor that stimulate tumor growth, invasion, and resistance to therapy. We investigated the potential of targeting the metastasis suppressor gene N-myc downstream regulated gene 1 (NDRG1) to interrupt the oncogenic crosstalk between cancer associated human pancreatic stellate cells (PSCs) and PaCa cells.
Methods: We assessed novel thiosemicarbazone anti-cancer agents, Dp44mT and DpC, that upregulate NDRG1 and their effects on: (i) SHH production by PaCa cells and also HGF and IGF-1 production by PSCs; (ii) HGF and IGF-1 receptors and their downstream signaling in indirect 2D and direct 3D co-culture of PSCs and PaCa cells; (iii) GLI1 and its upstream mediators in PSCs; and (iv) proliferative and metastatic properties of PaCa cells co-cultured with PSCs.
Results: Dp44mT and DpC upregulated NDRG1 and reduced SHH production by PaCa. These agents also inhibited downstream HGF and IGF-1 signaling pathways in PaCa cells, leading to reduced metastatic potential in co-culture 2D and 3D models. Further, these agents also inhibited GLI1 levels and activation in PSCs, leading to reduced HGF and IGF-1 production by these stromal cells. NDRG1 overexpression alone had similar effects, while silencing NDRG1 further potentiated the oncogenic crosstalk between PaCa and PSC cells.
Conclusions: Novel agents targeting NDRG1 have the unique ability to block the oncogenic crosstalk between PaCa cells and the surrounding stroma. This presents a novel approach to PaCa treatment that can potentially overcome the major problems attributed to desmoplasia, including therapeutic resistance and metastasis.
Citation Format: Bekesho Geleta, Kyung Chan Park, Patric J. Jansson, Minoti Apte, Des R. Richardson, Zaklina Kovacevic. A novel therapeutic approach to inhibit the bidirectional oncogenic crosstalk between pancreatic cancer cells and the surrounding stroma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A16.