bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2805: Pharmacogenomic platform using patient-derived cells to delineate tumor heterogeneity and therapeutic response of refractory lung cancer
Authors: Park Charny , Hong Sehwa , Hwang Mihwa , Lee Youngjoo , Song Bo Ram , Kang Eun Hye , Sim Hanna , Ahn Beung-Chul , Hwang Kum Hui , Yu Namhee , Kim Sunshin , Han Ji-Youn 
Published: April 2023

Abstract
A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for advanced or refractory lung cancer patients. Drug sensitivity screening was acquired from short-term PDC culture and multi-omics datasets were acquired from lung cancer PDCs (n = 199). Integrative analysis was performed to explore susceptible drug candidates from genetic variants, gene expression, and clinical profiles. To demonstrate PDC heterogeneity and its therapeutic response, cellular subpopulation was identified from single cell transcriptome from the patients (n = 8) harboring EGFR mutations with poor response to EGFR-TKIs. Mutation and gene expression profile of our PDC samples conserved with lung cancer tissue. Poor survival mutations were observed in KRAS, PDGFA, KEAP1, and MET. EGFR rare variants facilitated fast progression as well as poor susceptibility in EGFR-TKIs. PDC therapeutic subtypes classified patients into five groups: (1) epithelial-to-mesenchymal transition (EMT)-like (30.6 %), (2) EGFR-dominant (21.4 %), (3) stemness (19.4 %), (4) angiogenesis (17.3 %), and (5) inflammatory (11.2 %). The subtypes implicated in distinct pathway regulation activation,
variant enrichment, pathologic type, and survival as well as therapeutic candidates. Meanwhile, single cell transcriptome uncovered IDO1 and MET activation of EGFR-TKI resistance cancer cells. Stromal cell clusters exhibited the variety according to combinatorial immunotherapy response. While VEGFA+, and TOP2A+ clusters exhibited well response to angiogenesis and DNA damage target drug combinations of patients, CALB2+ cluster was clearly abundant to non-responder patients. We could detect angiogenesis (dasatinib) and DNA damage (irinotecan) drug candidates according to stromal clusters’ scoring from bulk PDC samples. Our PDC platform recapitulated the molecular characteristics of solid lung tumor tissues including tumor microenvironment. Uncovered molecular mechanism implied drug candidates.
Citation Format: Charny Park, Sehwa Hong, Mihwa Hwang, Youngjoo Lee, Bo Ram Song, Eun Hye Kang, Hanna Sim, Beung-Chul Ahn, Kum Hui Hwang, Namhee Yu, Sunshin Kim, Ji-Youn Han. Pharmacogenomic platform using patient-derived cells to delineate tumor heterogeneity and therapeutic response of refractory lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2805.
Abstract 2814: The mutational basis of cancer's vulnerability to ionizing radiation
Authors: Gopal Priyanka , Abazeed Mohamed E. 
Published: April 2023

Abstract
Introduction: Large-scale sequencing efforts have established that cancer-associated genetic alterations are highly diverse, posing a challenge to the identification of variants that regulate complex phenotypes like radiation sensitivity. The impact of the vast majority of rare or common genetic variants on the sensitivity of cancers to radiotherapy remains largely unknown.
Methods: We developed a scalable gene editing and irradiation platform to assess the role of categories of variants in cells. Variants were prioritized based on genotype-phenotype associations from a previously completed large-scale cancer cell line radiation profiling study. Altogether, 488 alleles (396 unique SNVs) from 92 genes were generated and profiled in an immortalized lung cell line, BEAS-2B. We validated our results in other cell lines (TRT-HU1 and NCI-H520), in vivo via the use of both cell line and patient-derived murine xenografts, and in clinical cohorts.
Results: We show that resistance to radiation is characterized by substantial inter- and intra-gene allelic variation. Some genes (e.g. KEAP1) demonstrated significant intragenic allelic variation in the magnitude of conferred resistance and other genes (e.g. CTNNB1) displayed both resistance and sensitivity in a protein domain-dependent manner. We combined results from our platform with gene expression and metabolite features and identified the upregulation of amino acid transporters that facilitate oxidative reductive capacity and cell cycle deregulation as key regulators of radiation sensitivity.
Conclusions: Our results reveal new insights into the genetic determinants of tumor sensitivity to radiotherapy and nominate a multitude of cancer mutations that are predicted to impact treatment efficacy.
Citation Format: Priyanka Gopal, Mohamed E. Abazeed. The mutational basis of cancer's vulnerability to ionizing radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2814.
Abstract 2831: Enhanced efficacy of HDAC inhibitor panobinostat and ONC206 combined with radiation therapy against human glioblastoma cell lines without H3K27M mutation
Authors: Tajiknia Vida , Deiry Wafik El , Zhou Lanlan 
Published: April 2023

Abstract
Background: Glioblastoma multiforme (GBM) is the most common form of malignant brain tumor in adults. The prognosis of GBM is still poor despite first-line therapy, and the median overall survival (OS) is 12-15 months, while the 5-year survival does not exceed 5%. Despite aggressive initial treatment, most patients develop recurrent diseases. Novel drug combinations for malignant CNS tumors are under investigation. Panobinostat is a histone deacetylase inhibitor (HDACi) with antineoplastic and antiangiogenic effects in glioma, and we previously noted synergy with combination of panobinostat and imipridone ONC206. ONC206 is under clinical investigation for treating adult and pediatric brain tumor patients. We decided to investigate the triple combination of ONC206, Panobinostat and radiation against glioma cells.
Materials & Methods: We investigated cell viability and drug synergies of ONC206 plus Panobinostat with or without radiation in 4 human GBM cell lines at 72 hours.
Results: We identified synergy between impridone ONC206 and Panobinostat which improved with radiation therapy IC50 values of panobinostat and ONC206 against cell lines U138, U87, T98G & U251MG ranges from 29-85 nM & 0.8-1.2 μM, respectively. Synergies between ONC206 and Panobinostat were observed across cell lines with combination indices of &lt;0.5 indicating strong synergy. When treating with 4GY radiation after 48 h, combination index improved. documenting enhanced tumor cell killing of human glioma cells.
Conclusion: Our ongoing studies reveal synergy between ONC206, Panobinostat and radiation against GBM cell lines. The enhanced synergy with radiation provides an opportunity to develop a novel treatment combination for high grade glioma with a focus on recurrent GBM.
Citation Format: Vida Tajiknia, Wafik El Deiry, Lanlan Zhou. Enhanced efficacy of HDAC inhibitor panobinostat and ONC206 combined with radiation therapy against human glioblastoma cell lines without H3K27M mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2831.
Abstract 3011: Psychosocial stress, social support, and incident breast cancer by estrogen receptor status
Authors: Lawrence Wayne R. , McDonald Jasmine A. , Williams Faustine , Shiels Meredith S. , Freedman Neal D. , Lin Ziqiang , Magnani Jared W. 
Published: April 2023

Abstract
Introduction: Chronic stress affects immune function and hormonal signaling and has been hypothesized to be associated with breast cancer, although results from the few prior studies are mixed and have not examined potential differences by estrogen receptor (ER) status. We investigated the relationship between stressful life events and incident breast cancer by ER status among postmenopausal women. We further evaluated whether this association is modified by social support.
Methods: Our analysis included 76,951 postmenopausal women enrolled in the Women’s Health Initiative. Participants were followed for events for up to 26 years (median, 16.7). We generated Cox proportional hazards models adjusting for demographic, clinical, lifestyle/behavioral, and social factors to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for associations between baseline self-reported stressful life events and incident breast cancer by ER status.
Results: The mean age was 63 (SD 7.3), and majority of participants were White race (83.5%) and married or in a marriage-like relationship (63.0%). In analyses stratified by ER status, there was no relationship between stressful life events and ER-positive breast cancer. In contrast, compared to women in the lowest quartile, those in higher quartiles had an increased risk of ER-negative breast cancer, where those in quartile 4 had the highest risk (Quartile 4 vs Quartile 1; HR=1.30; 95%CI 1.01-1.68; Ptrend=0.050). Additionally, associations were stronger for the highest versus lowest quartile of stressful life events among widowed women (HR=2.39; 95%CI 1.29-4.44; Pinteraction&lt;0.001). Moreover, while the interaction was not statistically significant, we observed an elevated risk for ER-negative breast cancer among women in the highest quartile of stressful life events reporting lower social support.
Conclusion: In this cohort of postmenopausal women, higher experiences of pre-diagnostic stressful life events were associated with increased risk of ER-negative breast cancer.
Citation Format: Wayne R. Lawrence, Jasmine A. McDonald, Faustine Williams, Meredith S. Shiels, Neal D. Freedman, Ziqiang Lin, Jared W. Magnani. Psychosocial stress, social support, and incident breast cancer by estrogen receptor status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3011.
Abstract 3063: A novel mechanism for therapeutic targeting of the glucocorticoid receptor in triple negative breast cancer
Authors: Khan Shagufta H. , Carbe Christian , Ling Jun , Kumar Raj 
Published: April 2023

Abstract
Triple negative breast cancer (TNBC) is frequently diagnosed in younger women and is prevalent in African American women. Most TNBCs are highly aggressive with early pattern of metastasis, and with limited treatment options and poor prognosis. Finding effective therapeutic targets for TNBC has proven difficult so far. Therefore, there is an urgent need to develop new and novel therapeutic management of these patients. Recent studies have shown that glucocorticoid receptor (GR) is a mediator of pro-survival genes in TNBC cells, and its expression is predictive of increased risk of metastasis in TNBC tumors and decreased rate of patient survival. Therefore, blocking the effects of GR should be beneficial for TNBC patients. However, GR antagonists such as RU486 (mifepristone) targeting AF2/coactivators have shown only partial success in TNBC cell lines as well as in animal models. Based on our previous data we hypothesize that since in TNBC cells, the GR is constitutively active; therefore, attempts to block/inhibit GR activity through classic antagonists such as mifepristone that bind to ligand binding pocket of the receptor will have a limited clinical efficacy and higher side effects. To circumvent this problem, in this study, we propose a novel and innovative therapeutic approach to target constitutively active AF1 domain of the GR, which exists in an intrinsically disordered (ID) conformation. In this study, we tested our hypothesis that inhibiting/blocking TATA-box binding protein (TBP)-mediated GR’s AF1 activity by our newly identified molecule, PepT will attenuate TNBC cell survival via altering associated endogenous gene expressions. Our binding kinetics of AF1 showed that PepT binds to AF1 with about 10-fold higher affinity when compared with TBP’s binding to AF1. AF1 pre-bound with PepT fails to bind to TBP suggesting that PepT competes and blocks AF1-TBP interaction. We also found that treatment of MDA-MB-231 cells with PepT results in significant attenuation of cell viability and proliferation. Together, these results support our hypothesis that PepT has potential to kill TNBC cells by blocking GR AF1:co-regulator interactions.
Citation Format: Shagufta H. Khan, Christian Carbe, Jun Ling, Raj Kumar. A novel mechanism for therapeutic targeting of the glucocorticoid receptor in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3063.
Abstract 3071: Pituitary adenylate cyclase activating polypeptide stimulates NSCLC growth by increasing HER4 tyrosine phosphorylation in a neuregulin-1 dependent manner
Authors: Moody Terry W. , Alvarez Irene Ramos , Jensen Robert T. 
Published: April 2023

Abstract
Pituitary adenylate cyclase activating polypeptide [PACAP] is a 27 amino acid peptide which stimulates the growth of numerous cancers including non-small cell lung cancer (NSCLC). PACAP binds with high affinity to the type B G protein-coupled receptor [GPCR] PAC1 (Moody et al., Peptides 2021; 137: 170480). PAC1 activation causes phosphatidyl inositol [PI] turnover stimulating matrix metalloprotease [MMP]. By ELISA, PACAP increased secretion of neuregulin [NRG1] from NSCLC cells. NRG1 binds with high affinity to HER4. Here the ability of PAC1 to regulate transactivation of HER4 was investigated. By RT-PCR and Western blot, PAC1, NRG1 and HER4 but not HER3 or NRG2 were detected in NCI-H522 and H661 cells. Adding PACAP-27 (0.1 μM) or NRG1 (0.01 μg/ml) to NCI-H522 or H661 cells increased P-Tyr1284-HER4 3-fold after 5 min. Using immunoprecipitation techniques, adding PACAP TO NSCLC cells increased formation of HER4 homodimers and HER4-EGFR as well as HER4-HER2 heterodimers. The increase in P-HER4 caused by PACAP-27 was impaired by PACAP(6-38) [PAC1 antagonist], HER4 siRNA, NRG1 antibody [Ab] or ibrutinib [TKI]. The PAC1 regulation of HER4 transactivation is impaired by GM6001 [MMP inhibitor]. The clonal growth of NSCLC cells was stimulated by PACAP-27 or NRG1 but inhibited by PACAP(6-38) or ibrutinib. The results indicate that PACAP-27 stimulates the growth of NSCLC due to release of NRG1 which activates receptor tyrosine kinases such as HER4.
Citation Format: Terry W. Moody, Irene Ramos Alvarez, Robert T. Jensen. Pituitary adenylate cyclase activating polypeptide stimulates NSCLC growth by increasing HER4 tyrosine phosphorylation in a neuregulin-1 dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3071.
Abstract 3103: Dual targeting MYC G-quadruplex and topoisomerase I by indenoisoquinolines for cancer therapy
Authors: Yang Danzhou , Cushman Mark , Wang Kai-Bo , Elsayed Mohamed S. , Wu Guanhui , Buric Adam J. , DeMoss Mercedes 
Published: April 2023

Abstract
MYC is one of the most important oncogenes and is overexpressed in a number of human cancers. The G-quadruplex formed in the MYC oncogene promoter (MycG4) is a transcriptional silencer and amenable to small molecule targeting. G-quadruplexes are noncanonical four-stranded DNA or RNA secondary structures that have emerged as novel therapeutic targets. Indenoisoquinolines are human topoisomerase I inhibitors with improved physicochemical and biological properties as compared to the clinically used camptothecin anticancer drugs. Three indenoisoquinolines, indotecan (LMP400), indimitecan (LMP776), and LMP744, have entered phase I clinical trials in adults with relapsed solid tumors and lymphomas. However, some indenoisoquinolines showed potent anticancer activity without being strong topoisomerase I inhibitors, suggesting additional mechanisms of action. Herein, we demonstrate that a large number of anticancer indenoisoquinolines strongly bind and stabilize MycG4 in vitro, using fluorescence, nuclear magnetic resonance (NMR), and circular dichroism (CD) spectroscopy, as well as gel electromobility shift assay (EMSA). In addition, MycG4-interactive indenoisoquinolines lower MYC mRNA and protein levels in vivo, as shown by western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) experiments. Structure-activity-relationships of MycG4 recognition by indenoisoquinolines were investigated to understand structural requirements for binding. Systemic analysis of indenoisoquinoline derivatives led to the discovery of a synergistic effect of MYC inhibition and topoisomerase I inhibition on anticancer activity. Therefore, these results indicate that targeting the MYC promoter G-quadruplex to downregulate MYC is a new mechanism of action for anticancer indenoisoquinolines. Moreover, our data reveals dual targeting of MycG4 and topoisomerase I as a novel strategy for cancer therapy.
Citation Format: Danzhou Yang, Mark Cushman, Kai-Bo Wang, Mohamed S. Elsayed, Guanhui Wu, Adam J. Buric, Mercedes DeMoss. Dual targeting MYC G-quadruplex and topoisomerase I by indenoisoquinolines for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3103.
Abstract 3110: Design, synthesis, and biological evaluation of transducin β-like protein 1 (TBL1) degraders
Authors: Yang Rui , Alinari Lapo , Li Pui-kai (Tom) , Cheng Xiaolin 
Published: April 2023

Abstract
Transducin β-like protein 1 (TBL1) is an essential scaffold protein that participates in multiple critical signaling pathways, such as the Wnt/β-catenin pathway, where it protects β-catenin from ubiquitination and proteasomal degradation. Only one compound, BC-2059 (tegavivint, Iterion Therapeutics), has been reported to promote apoptosis by disrupting the TBL1/β-catenin interactions and show promising therapeutic effects in Wnt-driven cancers, such as colorectal cancer, breast cancer, and leukemia. However, recent studies showed that TBL1 modulates Wnt-regulated genes in a β-catenin-independent manner in diffuse large B-cell lymphoma (DLBCL). Although the involvement of β-catenin is still under debate, TBL1’s engagement in the antitumor effects of BC-2059 is certain and critical. In this study, we aimed to develop proof-of-concept BC-2059-based TBL1 selective degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy and use them as chemical probes to investigate TBL1-related pathways in DLBCL. Two series (N- and O-linked) of BC-2059-based PROTACs were synthesized, and their cytotoxicity and protein degradation profiles were tested in cellular assays. Several compounds showed low micromolar to nanomolar cytotoxic activity. The TBL1 degradation of these PROTACs is currently underway. In the meantime, we modeled the ternary complex formation by developing a workflow where two binary complexes and a library of PROTACs having varied linker lengths/chemical compositions were modeled by PRosettaC. The protein-protein interactions of the generated ternary complexes were analyzed by Rosetta and the interactions between the linkers and the protein were calculated by Autodock 4. The results suggested that short linkers (8-14 heavy atoms) are more suitable for N-linked series degraders in terms of PROTAC-induced ternary complex formation, while long linkers (&gt;18 heavy atoms) are preferable for O-linked series.
Citation Format: Rui Yang, Lapo Alinari, Pui-kai (Tom) Li, Xiaolin Cheng. Design, synthesis, and biological evaluation of transducin β-like protein 1 (TBL1) degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3110.
Abstract 3115: Predicting in-depth mechanism of action of cancer drugs
Authors: Sinha Sanju , Sinha Neelam , Ruppin Eytan 
Published: April 2023

Abstract
Knowing a drug’s mechanism of action (MOA) is essential for its clinical success by selecting the best indications, likely responders, and combinations. Yet knowledge of many drugs’ MOA remains lacking. Here we present DeepTarget, a computational tool for deep characterization of cancer drugs’ MOA by integrating existing large-scale genetic and drug screens. Spanning ∼1500 drugs across ∼18K possible target genes, DeepTarget predicts: (1) a drug’s primary target(s), (2) whether it specifically targets the wild-type or mutated target forms, and (3) the secondary target(s) that mediate its response when the primary target is not expressed. We first tested and successfully validated DeepTarget in a total of eleven unseen gold-standard datasets, with an average AUC of 0.82, 0.77, and 0.92 for the above three prediction abilities, respectively. We then proceed to use it in a wide range of applications: First, we find that DeepTarget’s predicted specificity of a drug to its target is strongly associated with its success in clinical trials and is higher in its FDA-approved indications. Second, DeepTarget predicts candidate drugs for targeting currently undruggable cancer oncogenes and their mutant forms. Finally, DeepTarget predicts new targets for drugs with unknown MOA and new secondary targets of approved drugs. Taken together, DeepTarget is a new computational framework for accelerating drug prioritization and its target discovery by leveraging large-scale genetic and drug screens.
Citation Format: Sanju Sinha, Neelam Sinha, Eytan Ruppin. Predicting in-depth mechanism of action of cancer drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3115.