bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB089: Effective in vivo treatment of endometrial tumor models with coexistent mutant PI3K and PTEN inactivation with a selective bi-steric mTORC1 kinase inhibitor
Authors: Solomon Hilla , Mukherjee Radha , Chen Xiaoping , Zhao HuiYong , de Stanchina Elisa , Weigelt Britta , Schram Alison M. , Aghajanian Carol , Singh Mallika , Smith Jan , Rosen Neal 
Published: June 2022

Abstract
Dysregulation of PI3K signaling is a common event in human cancer, but feedback inhibition of receptor kinase signaling and/or induction of PTEN translation by activated PI3K/AKT/mTOR signaling reduces pathway output and tumor dependency. In some cancers, including the majority of endometrial carcinomas, these lesions coexist and cause synergistic hyperactivation of pathway output, particularly mTORC1 kinase signaling. Although this suggests that PI3K signaling is a driver of these endometrial cancers, standard inhibitors have had only marginal activity in patients with advanced disease. We here show that, in experimental isogenic models and PDX models with PI3K and PTEN alterations, PI3K inhibitors and rapalogs are weak inhibitors of TORC1 targets and slow but do not suppress the in vivo growth of these tumors. Revolution Medicines has developed a series of bi-steric selective and potent mTORC1 inhibitors that inhibit the phosphorylation of 4EBP-1, S6K and other mTORC1 substrates at concentrations that do not affect TORC2 substrates and thus do not induce the hyperglycemia caused by downregulation of AKT signaling by pan-mTOR kinase inhibitors. We have explored the biologic and anti-tumor effects of these inhibitors in models of endometrial cancer with coexistent PI3K mutation and PTEN inactivation. The mTORC1 kinase selective bi-steric inhibitor RMC-6272 can potently suppress both mTORC1 activity and the growth of these tumor cells in vitro. Moreover, in contrast to PI3K inhibition, RMC-6272 effectively inhibited the phosphorylation of mTORC1 kinase substrates and completely suppressed the growth in vivo of multiple PDXs with this genotype without inducing hyperglycemia or causing weight loss in the mice. The results suggest that dysregulation of TORC1 activity is an important driver of endometrial carcinomas with coexistent PTEN inactivation and PI3K mutations and that selective TORC1 kinase inhibitors may prove to be useful therapeutics in this context. The bi-steric mTORC1 kinase inhibitor RMC-5552 is the first clinical candidate of this class and clinical testing is ongoing (NCT04774952).
Citation Format: Hilla Solomon, Radha Mukherjee, Xiaoping Chen, HuiYong Zhao, Elisa de Stanchina, Britta Weigelt, Alison M. Schram, Carol Aghajanian, Mallika Singh, Jan Smith, Neal Rosen. Effective in vivo treatment of endometrial tumor models with coexistent mutant PI3K and PTEN inactivation with a selective bi-steric mTORC1 kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB089.
Abstract LB098: Integrative approaches to modulate antigen presentation and boost cancer immune response
Authors: Gu Shengqing , Zhang Wubing , Wang Xiaoqing , Jiang Peng , Freeman Gordon J. , Rodig Scott J. , Long Henry , Gewurz Benjamin E. , Hodi F. Stephen , Liu X. Shirley , Brown Myles 
Published: June 2022

Abstract
Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but patients with impaired MHC-I and/or MHC-II expression show inferior response. We observed differential expression patterns for MHC-I and MHC-II in cancer cells and applied multiple approaches to examine their regulatory mechanisms. To identify the modulators of MHC-I, we combined FACS-based genome-wide CRISPR screens with data-mining from public data. We identified TRAF3, a suppressor of the NFkB pathway, as a negative regulator of MHC-I. The Traf3-knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell-dependent killing, and adds to ICB efficacy. In contrast to MHC-I, the expression of MHC-II shows dramatic intra- and inter-sample heterogeneity. To identify the regulators of MHC-II, we conducted data-mining of the transcriptomic and proteomic data from Cancer Cell Line Encyclopedia (CCLE) and multiple melanoma clinical cohorts. We found that a higher cancer-cell-intrinsic MHC-II level is significantly associated with better anti-PD-1 response, and that the Hippo signaling pathway can regulate MHC-II expression in melanoma cells. Our findings provide preclinical rationales for increasing cancer cell MHC-I/MHC-II expression to enhance sensitivity to immunotherapy.
Citation Format: Shengqing Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Gordon J. Freeman, Scott J. Rodig, Henry Long, Benjamin E. Gewurz, F. Stephen Hodi, X. Shirley Liu, Myles Brown. Integrative approaches to modulate antigen presentation and boost cancer immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB098.
Abstract LB116: CXCL8/Interleukin-8 orchestrates radiation-induced immune responses in pancreatic adenocarcinoma
Authors: Walle Thomas , Kraske Joscha A. , Liao Boyu , Timke Carmen , Lenoir Benedicte , Halama Niels , Huber Peter E. 
Published: June 2022

Abstract
The role of radiotherapy in the treatment of pancreatic adenocarcinoma (PDAC) is controversial. In many other tumor types, radiotherapy is a mainstay therapy whose anti-tumor effects have partially been ascribed to T cell responses. The role of Natural Killer (NK) cells in radiotherapy tumor responses remains unclear. Here, we focused on the role of NK cells in radiotherapy of pancreatic cancer.
In a randomized controlled pancreatic cancer trial, we found that CXCL8 serum levels increased under radiotherapy and NK cells positively correlated with prolonged overall patient survival. Accordingly, NK cells preferentially infiltrated irradiated tumors and exhibited CD56dim like cytotoxic transcriptomic states. In preclinical experimental systems in mice and tumor cells, NF-κB and mTOR signaling prompted radiation-induced CXCL8 secretion from senescent tumor cells causing directional migration of CD56dim NK cells into tumors. Thus, we link senescence-associated CXCL8 release to innate immune surveillance of human tumors. Moreover, combined radiotherapy and adoptive NK cell transfer improved tumor control over monotherapies in xenografted mice suggesting NK cells combined with radiotherapy as a rational cancer treatment strategy which may be integrated into PDAC treatment algorithms.
Citation Format: Thomas Walle, Joscha A. Kraske, Boyu Liao, Carmen Timke, Benedicte Lenoir, Niels Halama, Peter E. Huber. CXCL8/Interleukin-8 orchestrates radiation-induced immune responses in pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB116.
Abstract LB130: High-throughput RNA sequencing directly from cell lysates enables reproducible phenotypic profiling for assessing novel compounds and treatments in cancer research
Authors: O'Hara Andrea , Stephens Michael , DeVito Ilaria , Turner Laure , Mozdzierz Christopher , Latif Haythem , Zhou Ginger 
Published: June 2022

Abstract
New oncology therapies are driven by multiple approaches, with a heavy emphasis on small-molecule therapeutics to target cancer cells and provide a therapeutic benefit to cancer patients. These small-molecule compounds can be used as a stand-alone treatment approach or may be combined with other compounds to bring enhanced effects. Compound therapeutic discovery relies heavily on high-throughput screening assays for measurement of phenotypic responses following compound treatment of oncology cell cultures which can range from very targeted assays to wide-ranging unbiased approaches. Standard whole transcriptome RNA-seq is a preferred method for unbiased measurement of phenotypic responses but is often overlooked due to limited scalability and high sample screening costs.
To address these challenges, we have developed a high-throughput gene expression (HT-GEx) assay that combines a variety of strategies to enable a low-cost and high-throughput alternative to standard RNA-seq. First, a simplified workflow removes upstream RNA isolation steps and tags transcripts directly from cell lysate. This is achieved by incorporating both a sample barcode and a unique molecular index (UMI) during the reverse transcription reaction. Next, we leverage a 3’ end counting approach to enable a reduction in sequencing depth coverage (i.e. sample cost) without compromising gene detection sensitivity. With these key advances, a high-plex and high-throughput screening assay is achievable at a reduced cost by removing the need to purify RNA, tagging transcripts early in the workflow to allow pooling of samples and reducing sequencing depth. We have combined these high-throughput and cost-saving strategies and present results which confirm HT-GEx offers results on par with standard RNA-seq. Gene detection sensitivity based on number of genes detected per millions of reads is highly similar, with gene detection sensitivity saturated at approximately 2 million reads. Additionally, the number of genes detected between replicates for RNA samples and lysate samples demonstrate strong linear correlation, implying highly reproducible results. Thus, high-throughput gene expression is an ideal method for phenotypic screening in oncology cell lines following stand-alone or combined compound treatments.
Citation Format: Andrea O'Hara, Michael Stephens, Ilaria DeVito, Laure Turner, Christopher Mozdzierz, Haythem Latif, Ginger Zhou. High-throughput RNA sequencing directly from cell lysates enables reproducible phenotypic profiling for assessing novel compounds and treatments in cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB130.
Abstract LB159: Neighborhood obesogenic environment and risk of prostate cancer: The Multiethnic Cohort
Authors: Hebert-DeRouen Mindy C. , Tao Li , Shariff-Marco Salma , Yan Juan , Shvetsov Yurii B. , Park Song-Yi , Albright Cheryl L. , Monroe Kristine , Marchand Loic Le , Wilkens Lynne , Gomez Scarlett L. , Cheng Iona 
Published: June 2022

Abstract
Background: Obesity is associated with risk of aggressive prostate cancer. It is not known whether neighborhood obesogenic factors are associated with prostate cancer risk.
Methods: Neighborhood socioeconomic status (nSES) and four neighborhood obesogenic environment factors (urbanicity, mixed-land development, unhealthy food environment, and parks) were assessed for associations with prostate cancer risk among 41,563 African American, European American, Japanese American, and Latino males in the Multiethnic Cohort Study (MEC), California site. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for non-aggressive and aggressive prostate cancer, adjusting for individual-level sociodemographic, behavioral, and prostate cancer risk factors. Analyses were stratified by race, ethnicity, and, among Latino males, nativity.
Results: Males residing in low SES, compared to high SES, neighborhoods had lower risk of non-aggressive prostate cancer (lowest vs. highest quintile HR=0.81; 95% CI=0.68, 0.95, p-trend 0.024); driven by a similar trend among U.S.-born and foreign-born Latino males. Foreign-born Latino males in neighborhoods with low mixed-land development had increased risk (lowest vs. highest quintile HR=1.52; 95% CI=1.09, 2.12). African American males in neighborhoods with more unhealthy food environments had increased risk of aggressive disease (more vs. none, HR=1.35; 95% CI=1.02, 1.77).
Conclusions: Neighborhood SES and obesogenic factors were independently associated with prostate cancer risk; associations varied by race, ethnicity, nativity, and disease aggressiveness.
Impact: Upstream structural and social determinants of health that contribute to neighborhood obesogenic characteristics likely impact prostate cancer risk differently across groups defined by race, ethnicity, and nativity and by disease aggressiveness.
Citation Format: Mindy C. Hebert-DeRouen, Li Tao, Salma Shariff-Marco, Juan Yan, Yurii B. Shvetsov, Song-Yi Park, Cheryl L. Albright, Kristine Monroe, Loic Le Marchand, Lynne Wilkens, Scarlett L. Gomez, Iona Cheng. Neighborhood obesogenic environment and risk of prostate cancer: The Multiethnic Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB159.
Abstract LB506: Structure based small molecule drug design for targeting WNK1 in triple negative breast cancer
Authors: Kannangara Ashari Rashmi , Rodriguez Melanie , Chlebowicz Julita , Akella Radha , Cobb Melanie H. , Tambar Uttam , Goldsmith Elizabeth J. 
Published: June 2022

Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors lacking estrogen, progesterone, and HER-2 receptors. It accounts for 10-20% of breast cancers, appears in younger women, metastasizes fast, and is associated with poor prognosis and poor patient survival. There are no available tailored therapies for TNBC to date. One of the ways to treat TNBC is by targeting its metastasis feature. With-no-lysine kinase 1 (WNK1), which is known to interact with diverse signaling pathways including ion homeostasis, has been recently identified as one of 6 driver genes in a murine TNBC model. Published and preliminary data support the premise that WNK1 promotes epithelial-mesenchymal transition (EMT) and invasion in TNBC. Genetic and pharmacological inhibition of WNK1 blocks metastasis in a TNBC mouse model. Given the existence of four WNK isoforms in which kinase domains are 90% identical, developing a clinically available WNK1-specific inhibitor is an unmet need. We identified WNK1-selective inhibitors by a High Throughput Screen (HTS) of over 200,000 structurally diverse small molecules. A class of quinoline-derived compounds showed high specificity and potency for WNK1. A combination of molecular modeling, crystallography, and synthesis-based strategies were employed to improve the potency of compounds. Interestingly, the compound SC107-01 reported below 100 nM IC50 for WNK1 by in vitro assays. Also, it shows higher specificity for WNK1 over other kinases as evident by kinome-specificity profiling. We had previously crystallized the kinase domain of WNK1. The structure revealed its unique active site. Co-crystal structure of SC107-01 with WNK1 shows that the inhibitor binds to the WNKs’ specific active site and forms a unique set of interactions. Further modifications to the SC107-01 are underway to improve bioavailability and efficacy. In vivo toxicology and drug pharmacokinetics will be conducted in mouse models. We anticipate that this work will lay the foundation for developing a small molecule that inhibits WNK1 to combat metastasis in TNBC.
Citation Format: Ashari Rashmi Kannangara, Melanie Rodriguez, Julita Chlebowicz, Radha Akella, Melanie H. Cobb, Uttam Tambar, Elizabeth J. Goldsmith. Structure based small molecule drug design for targeting WNK1 in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB506.
Abstract LB513: In vivo efficacy screen of a CSF-1R inhibitor ABSK021 in mouse syngeneic tumor models reveals immune features that may predict its therapeutic response
Authors: Zhu Zhixuan , Peng Juan , Shi Wan , Chen Zhui , Yang Shuqun 
Published: June 2022

Abstract
Colony-stimulating factor 1 (CSF-1) and its receptor CSF-1R play critical roles in immune suppressive and tumor promoting characteristics of tumor-associated macrophages (TAM). ABSK021 is a highly potent and selective inhibitor of CSF-1R that is currently under investigation in phase 1b clinical trials of cancer patients. However, it remains to be elucidated what population might be sensitive to CSF-1R inhibitor. Syngeneic mouse models with complete and functional immune system are important for the translation of preclinical immuno-oncology research into clinical settings. Here, we performed an efficacy screen in ten syngeneic models to evaluate the response to CSF-1R inhibition by ASBK021, and profiled the transcriptomic features by RNA-sequencing in each model. In vivo efficacy studies showed that four models were sensitive to CSF-1R inhibition (tumor growth inhibition value (TGI) ≥ 35%) while six models were insensitive (TGI &lt; 35%). Differentially expressed gene (DEG) analysis and gene set enrichment analysis (GSEA) revealed that the MHC class II genes were down-regulated and immune-related pathways had lower enrichment level in the sensitive models, when compared with insensitive models. Further, the result of in silico immune cell deconvolution by CIBERSORT indicated that the activated CD8+ T cells had significantly negative correlation with TGI in this screen. Taken together, these observations suggested the predictive value of certain immune activation features for the sensitivity to the inhibition of CSF-1R signal.
Citation Format: Zhixuan Zhu, Juan Peng, Wan Shi, Zhui Chen, Shuqun Yang. In vivo efficacy screen of a CSF-1R inhibitor ABSK021 in mouse syngeneic tumor models reveals immune features that may predict its therapeutic response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB513.
Abstract LB526: HBI-2375, a selective inhibitor of MLL1-WDR5 interaction, possesses desirable preclinical characteristics to be pursued in IND enabling studies and future clinical investigations
Authors: Shojaei Farbod , Semple J E. , Fang Che , Ricono Jill M. , Kabbinavar Fairooz , Goodenow Bob , Gillings Mireille 
Published: June 2022

Abstract
92130MLL1 (mixed lineage leukemia1) interaction with WDR5 (WD repeat domain 5) is critical for MLL1 histone methyl transferase (H3K4me) activity leading to transcriptional regulation of gene expression. MLL1 dysregulation such as its translocation at chromosome 11q23 results in generation of MLL1 fusion genes and leukemia development. Additionally, recent studies indicated a role for MLL1-WDR5 interaction in solid tumors progression via directly affecting cancer cells or by suppression of tumor immunity. Therefore, MLL1-WDR5 interaction is an important target in cancer drug discovery, both in leukemia and in solid tumors. HUYABIO recently completed acquisition of a novel series of MLL1-WDR5 inhibitors and conducted an additional SAR campaign to identify a lead compound with greater efficacy and PK (pharmacokinetics)characteristics. Characterization of a series of analogs identified HBI-2375 as a selective inhibitor of MLL1-WDR5 interaction. TR-FRET peptide binding assay indicated potent binding of HBI-2375 to WDR5 (IC50=4.48 nM) and in vitro cell potency studies showed inhibition of proliferation in MV4;11 leukemia cells by HBI-2375 (IC50=3.17 µM).Furthermore, HBI-2375 was stable in liver S9 and whole blood and displayed reasonable PK properties (Cmax, T1/2, AUC and F%) in preclinical testing in mouse and dog. In vivo efficacy studies in MV4;11 model showed 86% and 77% tumor growth inhibition in HBI-2375 treated tumors when dosed at 80 mpk or 40 mpk (po, qd x 21) respectively. In addition, HBI-2375 was found to be well tolerated since body weight data in the recipients did not show a significant change throughout the treatment. Interestingly, ex vivo tumor analysis showed a reduction in H3K4me in both 40 and 80 mpk samples, further validating target-driven activity of HBI-2375. These data resulted in the nomination of HBI-2375 as the lead clinical candidate for the current IND enabling studies and future investigations in the clinic.
Citation Format: Farbod Shojaei, J E. Semple, Che Fang, Jill M. Ricono, Fairooz Kabbinavar, Bob Goodenow, Mireille Gillings. HBI-2375, a selective inhibitor of MLL1-WDR5 interaction, possesses desirable preclinical characteristics to be pursued in IND enabling studies and future clinical investigations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB526.
Abstract LB547: Ultra-deep targeted sequencing of circulating tumor DNA with colorectal cancer patients for prediction of treatment response and post-surgical follow-up
Authors: Lee Hyeonah , Kim Doo A , Seo Jieun , Shin Saeam , Kim Han Sang , Ahn Joong Bae , Lee Seung-Tae , Choi Jong Rak 
Published: June 2022

Abstract
Purpose: Colorectal cancer (CRC) patients require effective biomarkers to evaluate treatment efficacy and monitor minimal residual disease. However, current monitoring tools such as tumor markers and imaging methods have limited prognostic performance. Circulating-tumor DNA (ctDNA) could be a useful biomarker for monitoring patients with CRC. In this study, we evaluated the targeted next-generation sequencing (NGS) panel using ctDNA in monitoring clinical decision-making in CRC.
Experimental Design: We prospectively enrolled 100 CRC patients and collected 197_ plasma samples. Specimens were collected post-surgery from 74 patients, 42 of whom were also monitored during the immediate post-surgery and adjuvant therapy follow-up. Twenty-six patients’ bloods were received after adjuvant therapy without surgery. A total of patients performed ultra-deep sequencing of CRC-related 14 genes respectively and matched with tissue samples at the time of blood collection as possible. NGS results were assessed correlation with clinicopathologic characteristics and clinical outcome.
Results: Levels of ctDNA measurements were correlated with tumor stage. Stage IV patients had significantly higher ctDNA concentration than Stage I patients. ctDNA testing detected 112 alterations in 14 genes were identified in 69% of the patients (n=100). The results showed that APC (29%), TP53 (25%), KRAS (19%), and EGFR (5%) were the most frequently mutated genes. RAS family gene mutations were detected in 37 patients, yielding a concordance of 89% with tissue samples. Also, ctDNA detection was found to be a greater predictive performance when compared with CEA. Dynamics of ctDNA mutation levels reflected five follow-up patients’ clonal evolution and clinical outcomes. These data showed ctDNA is a sensitive monitoring biomarker for any clinical condition of the patients.
Conclusions: The present study suggests that the use of ctDNA in CRC patients can be a valuable non-invasive monitoring tool for monitoring disease states during or after treatment. Serial ctDNA testing can contribute to improving patient management through monitoring disease progression and clonal evolution.
Citation Format: Hyeonah Lee, Doo A Kim, Jieun Seo, Saeam Shin, Han Sang Kim, Joong Bae Ahn, Seung-Tae Lee, Jong Rak Choi. Ultra-deep targeted sequencing of circulating tumor DNA with colorectal cancer patients for prediction of treatment response and post-surgical follow-up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB547.