bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4044: Development of UCT-01-097, a novel orally available ERK1/2 inhibitor for the treatment of ERK1/2 dependent cancers
Authors: O'Brien Neil A. , McDermott Martina S. , O'Boyle Brendan M. , Reeves Corey M. , Bartberger Michael , Loson Oliver , Chau Kevin , Hong Jenny J. , Jia Weiping , Kamranpour Naeimeh , Luo Tong , Ayala Raul , Madrid Athena M. , Glaspy John A. , Stoltz Brian M. , Slamon Dennis J. 
Published: April 2023

Abstract
The MAPK signaling pathway is the most commonly mutated and/or dysregulated pathway in cancer. Strategies to target it have yielded some success with inhibitors against KRASG12C and BRAF, and to a lesser extent, MEK1/2. However, the impact of these molecules is often limited by toxicity and rapid and diverse mechanisms of resistance; both adaptive and/or acquired. For example, treatment with MAPK pathway targeting agents results in compensatory activation of the downstream mediator ERK1/2 and enables tumors to subvert the targeted therapy. Thus, targeting ERK1/2 provides promising potential advantages in overcoming and/or preventing adaptive and acquired resistance. We evaluated multiple preclinical and clinically staged ERK1/2 inhibitors—including ERAS-007 and BVD-523—in a 500+ cell line screening platform and identified cancers with subpopulations that are sensitive to this class of inhibitor. KiNativ analyses helped to inform the differences in sensitivity/selectivity that we observed between each ERK1/2 inhibitor. Comprehensive molecular profiling of the cell lines at baseline allowed us to screen for potential molecular markers of sensitivity/resistance to these compounds. Using this platform, we have developed a novel, potent ERK1/2 small molecule inhibitor, UCT-01-097, with improved selectivity over other clinically staged inhibitors. These data, coupled with the broad spectrum of in vitro responses, suggests an improved therapeutic index with this molecule. UCT-01-097 shows kinase selectivity in both cell free and in-cell assays and robust efficacy in panel of pancreatic PDX models. Inhibition of xenograft tumor growth was achieved using both daily dosing and intermittent dosing schedules. We have successfully submitted a regulatory IND and are currently enrolling a Phase 1 clinical trial in advanced solid tumors for treatment with UCT-01-097 (NCT04761601).
Citation Format: Neil A. O'Brien, Martina S. McDermott, Brendan M. O'Boyle, Corey M. Reeves, Michael Bartberger, Oliver Loson, Kevin Chau, Jenny J. Hong, Weiping Jia, Naeimeh Kamranpour, Tong Luo, Raul Ayala, Athena M. Madrid, John A. Glaspy, Brian M. Stoltz, Dennis J. Slamon. Development of UCT-01-097, a novel orally available ERK1/2 inhibitor for the treatment of ERK1/2 dependent cancers. [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 4044.
Abstract 410: Tumor heterogeneity via AXL activation on primary resistance to EGFR tyrosine kinase inhibitors in EGFR mutated lung cancer
Authors: Yamada Tadaaki , Nakamura Ryota , Fujii Hiroyuki , Yaoi Takeshi , Itoh Kyoko , Tokuda Shinsaku , Takayama Koichi 
Published: April 2023

Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatments for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, some patients show primary resistance to EGFR-TKIs at the first-line treatment setting. AXL, a member of the TAM family of receptor tyrosine kinase, was reported to be involved in primary resistance to EGFR-TKIs for EGFR mutated NSCLC patients. In the present study, we investigated spatial tumor heterogeneity using autopsy specimens from EGFR mutated NSCLC patients, showing primary resistance to erlotinib plus ramucirumab. qPCR analysis showed that the AXL mRNA expression levels differed in each metastatic site. In addition, the AXL expression levels were likely to negatively correlate with the efficacy of erlotinib plus ramucirumab therapy. The analysis of patient-derived cell lines, established from left pleural effusion before initiation of the treatment, showed that the combination of EGFR-TKIs and an AXL inhibitor remarkably inhibited cell viability compared with EGFR-TKI monotherapy or combination with ramucirumab. Our observations suggested that tumor AXL expression might play a critical role in progression of spatial tumor heterogeneity and primary resistance to EGFR-TKIs for EGFR mutated NSCLC patients.
Citation Format: Tadaaki Yamada, Ryota Nakamura, Hiroyuki Fujii, Takeshi Yaoi, Kyoko Itoh, Shinsaku Tokuda, Koichi Takayama. Tumor heterogeneity via AXL activation on primary resistance to EGFR tyrosine kinase inhibitors in EGFR mutated 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 410.
Abstract 4240: Tumor PD-L1 induction associated with dietary protein restriction is modulated by PERK activation
Authors: Cordova Ricardo , Colligan Sean , Rupert Chris , Wek Ronald , Staschke Kirk , Pili Roberto 
Published: April 2023

Abstract
Tumor cells rely on the Integrated Stress Response (ISR) to adapt to different environmental and physiological stresses. The ISR is comprised of four eIF2 kinases that sense different stresses and catalyze phosphorylation of the alpha subunit of eIF2. This results in inhibition of global translation initiation, but at the same time results in preferential translation of select mRNA transcripts in order to relieve stress. Recent work has suggested that programmed death-ligand 1 (PD-L1), a cell surface protein commonly upregulated by tumors to evade the immune system, may be translationally regulated by the ISR in cancer. PD-L1 interaction with immune-checkpoint receptor programmed death-1 (PD-1) leads to the negative regulation of T cell activation and inhibitors that block the PD-L1/PD-1 interaction are widely used to treat different cancers. The ISR may serve as a novel therapeutic target to modulate PD-L1 protein levels and treat immune-evasive cancers. Our group has previously reported that dietary protein restriction increases the anti-tumor effect of PD-1 inhibition in the RENCA kidney cancer mouse model. Here, we show that in the RENCA model, phospho-PERK and phospho-eIF2α protein levels correlate with PD-L1 induction associated with dietary protein restriction. This is supported by TCGA data that shows a correlation between PERK and PD-L1 mRNA levels in different genitourinary cancers. In vitro, activation of the eIF2 kinases PERK and GCN2 by ER stress and amino acid starvation, respectively, in both RENCA cells and prostate cancer cells, leads to induction of PD-L1 protein without changing mRNA levels, suggesting preferential translation under stress conditions. Inhibiting PERK using selective inhibitors blocked ER stress-induced induction of PD-L1. These data support the notion that PD-L1 is induced by dietary protein restriction and is translationally regulated by the ISR. Modulating PD-L1 protein levels in immune-evasive tumors by targeting the ISR in the context of dietary protein restriction may enhance the anti-tumor response to immune checkpoint inhibitors.
Citation Format: Ricardo Cordova, Sean Colligan, Chris Rupert, Ronald Wek, Kirk Staschke, Roberto Pili. Tumor PD-L1 induction associated with dietary protein restriction is modulated by PERK activation. [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 4240.
Abstract 4299: Gene expression based machine learning classifier to predict and validate cancer type in patient derived xenograft (PDX) models
Authors: Andrews Warren , Do Long , Nakashima Jonathan 
Published: April 2023

Abstract
Patient derived xenografts (PDX) are increasingly utilized in translational research and drug development. Characterizing the genomic features of PDX is essential to establishing reliable models for cancer research. Despite great interest, problems remain in PDX tumor data banks including improper cancer type diagnosis and sample mix-ups. In an effort to improve annotation and quality of PDX models, we developed a machine learning model trained on gene expression data from The Cancer Genome Atlas (TCGA). We then applied the model to corresponding data collected from nearly 300 Certis PDX models plus publicly available data from NCI’s Patient-Derived Models Repository (PDMR). The model shows high precision and variable recall and provides a fast and accurate method for cancer type diagnosis.
Citation Format: Warren Andrews, Long Do, Jonathan Nakashima. Gene expression based machine learning classifier to predict and validate cancer type in patient derived xenograft (PDX) models. [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 4299.
Abstract 4334: Clever-1/PD-L1 ratio predicts response to Bexmarilimab, a novel macrophage-guided immunotherapy, in immune deprived cancers
Authors: Björkman Mari L. , Vuorinen Elisa M. , Jalkanen Juho , Fjällskog Marie-Louise , Koivunen Jussi , Huttunen Teppo , Hollmén Maija , Bono Petri 
Published: April 2023

Abstract
Introduction: Clever-1 is an immunosuppressive scavenger receptor expressed on tumor associated macrophages. High levels of Clever-1 are associated with poor survival, T-cell exclusion and dysfunction, and immunotherapy resistance. Bexmarilimab (FP-1305) is a novel humanized anti-Clever-1 IgG4-antibody capable of promoting an immune switch, potentially leading to intratumoral proinflammatory responses in patients. In a first-in-human all-comer single agent Phase I/II study in advanced solid tumors (NCT03733990) approximately 30% of patients in hepatocellular carcinoma, cutaneous melanoma and cholangiocarcinoma achieved immune activation, characterized by an IFNg response, which led to a survival benefit (ASCO 2022). Here, we show that patients getting a therapy benefit have immunologically cold tumors with low PD-L1 staining and high Clever-1 staining.
Methods: Pre-treatment tumor samples were immunohistochemically stained for Clever-1 (4G9, Santa Cruz) using Ventana platform and scored by % of intratumoral positive cells out of all viable cells and PD-L1 (22C3, Agilent) with combined positivity scoring (CPS). Ratio (PD-L1/Clever-1) at baseline was compared using non-parametric Wilcoxon-test according to clinical benefit.
Results: 23 successful baseline biopsies and stainings were obtained, 6 per cutaneous melanoma, 11 per cholangiocarcinoma and 1 per hepatocellular carcinoma, from patients treated with bexmarilimab. Patients had received an average of three previous lines of therapy. At baseline, patients that saw a clinical benefit (CBR) from bexmarilimab had average PD-L1/Clever-1 ratio of 0.2 compared to 4.4 (p=0.042, Wilcoxon nonparametric test) in patients that did not respond to the treatment.
Conclusion: PD-L1/Clever-1 IHC staining ratio may be used to predict bexmarilimab responding patients. These patients have a low PD-L1 staining and low IFNg levels as reported previously, and are often refractory to checkpoint inhibitors and other T cell activating agents. Bexmarilimab provides a novel therapy option for a tumor group that is otherwise poorly responsive to immune therapies.
Citation Format: Mari L. Björkman, Elisa M. Vuorinen, Juho Jalkanen, Marie-Louise Fjällskog, Jussi Koivunen, Teppo Huttunen, Maija Hollmén, Petri Bono. Clever-1/PD-L1 ratio predicts response to Bexmarilimab, a novel macrophage-guided immunotherapy, in immune deprived cancers. [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 4334.
Abstract 4344: Consensus genomic subtypes of gastric adenocarcinoma and their therapeutic implication
Authors: Jeong Yun Seong , Eun Young-Gyu , Lee Sung Hwan , Kang Sang-Hee , Yim Sun Young , Kim Eui Hyun , Noh Joo Kyung , Sohn Bo Hwa , Lee Ju-Seog 
Published: April 2023

Abstract
Background: Gastric adenocarcinoma (GAC) is heterogeneous lethal disease in genomic and clinical level. Although the clinical relevance of genomic and molecular subtypes of GAC has been demonstrated, their translation to the clinic has been hindered by discrepancies in classification methods. We aim to examine a consensus of genomic subtypes and correlate them with clinical outcomes.
Method: We collected genomic data from 2527 GAC tumors and divided the data into discovery (n = 1427) and validation sets (n = 1100). By integrating 8 previously established genomic subtype algorithms, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs) in discovery set. For validation of clinical significance of new subtypes, we constructed GAC predictor of integrated consensus subtype with 120 genes (GPICS120) and applied it to validation data set. In systematic analysis of genomic and proteomic data, we estimated potential response rate of each subtype to standard and experimental treatments such as radiation therapy, target therapy, and immunotherapy and further validated their functional significance in cell line models.
Results: Among identified 6 subtypes. CGS1 is characterized by poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 showed canonical epithelial gene expression patterns. CGS3 and CGS4 are characterized by high copy number alterations and low immune activity. However, CGS3 and CGS4 are different in high HER2 activation (CGS3) and SALL4 and KRAS activation (CSG4). CGS5 has highest mutation burden and moderately high immune activity that is characteristics of MSI-high tumors. Most of CGS6 tumors are EBV-positive and shows extremely high methylation and high immune activity. Most interestingly, CSG1 is most responsive to immunotherapy while CGS3 is significantly associated with benefit of chemoradiation therapy due to high basal level ferroptosis. In addition, we also identified potential therapeutic targets for each subtype.
Conclusion: Consensus subtype is robust classification system and can be the basis for pre-clinical investigation of subtype-based targeted interventions and future clinical trials.
Citation Format: Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Ju-Seog Lee. Consensus genomic subtypes of gastric adenocarcinoma and their therapeutic implication. [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 4344.
Abstract 4349: C-C chemokine receptor 2-positive monocytic myeloid-derived suppressor cells predicts chemotherapeutic responses of the metastatic lesions in breast cancer patients
Authors: Kim Ju Won , Sa Jason K. , Jung Seung Pil , Park Kyong Hwa , Park Serk In 
Published: April 2023

Abstract
Anti-tumoral T cell immunity is counterbalanced by several types of immunosuppressive cells such as Myeloid-Derived Suppressor Cells (MDSC). Circulating MDSC levels correlate with poor prognosis and metastatic progression of breast cancer patients. However, the value of MDSC in predicting chemotherapeutic treatment responses in the metastatic lesions is not clearly understood. We performed a prospective cohort clinical study to measure MDSC before and after chemotherapy in metastatic breast cancer patients (N=64). Multicolor flow cytometry was used to quantitate two major subtypes, i.e. monocytic (M-) and polymorphonuclear (PMN-) MDSC, and one additional subtype, C-C chemokine receptor 2 (CCR2)-positive M-MDSC in the fresh peripheral blood mononuclear cells. M-MDSC were defined as HLA-DRlow/−CD45+CD11b+CD15−CD14+ PBMC, and PMN-MDSC were defined as CD45+CD11b+CD33+CD15+ CD14− PBMC. PMN-MDSC and CCR2+ M-MDSC, but not M-MDSC, were significantly increased after chemotherapy. Subsequently, we divided the patients by two groups (therapy-sensitive vs. -resistant groups) by treatment responses. Treatment-resistant patients had significantly increased CCR2+ M-MDSC. Unsupervised clustering of patients based on MDSCs populations dichotomized patients PMN-MDSC high or M-MDSC high groups. M-MDSC high patients had increased bone and lymph node metastasis. In addition, CCR2+ M-MDSC levels correlated with the progression-free survival (P&lt;0.05). Altogether, our results showed that CCR2+ M-MDSC levels potentially predict the therapeutic responses in the metastatic lesions of breast cancer patients.
Citation Format: Ju Won Kim, Jason K. Sa, Seung Pil Jung, Kyong Hwa Park, Serk In Park. C-C chemokine receptor 2-positive monocytic myeloid-derived suppressor cells predicts chemotherapeutic responses of the metastatic lesions in breast cancer patients. [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 4349.
Abstract 4359: Interventions to improve pathologic nodal staging of curatively resected lung cancer: A population-based implementation study
Authors: Ray Meredith A. , Fehnel Carrie , Akinbobola Olawale , Saulsberry Andrea , Dortch Kourtney , Matthews Anberitha , Anga Amal , Giampapa Christopher , Sales Elizabeth , Okun Sherry , Robbins Edward T. , Wolf Bradley , Levy Paul , Wiggins Horace L. , Ng Thomas , Sachdev Vishal , Valaulikar Ganpat , Patel Hetal D. , Faris Nicholas R. , Smeltzer Matthew , Osarogiagbon Raymond U. 
Published: April 2023

Abstract
Introduction. Despite its importance, pathologic nodal (pN) staging of lung cancer remains poor. We evaluated the quality and survival impact of two interventions to improve pN staging.
Methods. Using a non-randomized stepped-wedge design, we implemented use of a lymph node (LN) specimen collection kit to improve intraoperative LN collection (surgical intervention) and a novel gross dissection method for intrapulmonary LN retrieval (pathology intervention) in 12 hospitals in five contiguous Hospital Referral Regions in AR, MS and TN (2009-2021). With appropriate statistical methods we compared surgical quality and survival of patients among: neither (Group 1), pathology only (Group 2), surgical only (Group 3), and both (Group 4) interventions.
Results. Of 4,019 patients, 50%, 5%, 21% and 24%, were in Groups 1-4 respectively. Rates of non-examination of LNs and non-examination of mediastinal LNs: 11%, 9%, 0% and 0%; 29%, 35%, 2% and 2% respectively in Groups 1-4 (p&lt;0.0001). Attainment of American College of Surgeons Operative Standard 5.8: 22%, 29%, 72%, 85%; International Association for the Study of Lung Cancer’s stringent definition of ‘complete resection’: 14%, 21%, 53%, 61% (p&lt;0.0001). Compared to Group 1, adjusted hazard ratios, aHR (95% CI), were: Group 2, 0.93 (0.76-1.15); Group 3, 0.91 (0.78-1.03); Group 4, 0.75 (0.64-0.87). Compared to Group 2, Group 4 aHR- 0.72 (0.57-0.91); compared to Group 3, was 0.83 (0.69-0.99). These relationships remained after excluding wedge resections.
Discussion. Combining a LN collection kit and novel gross dissection method significantly improved pN evaluation and survival in a population-based cohort.
Citation Format: Meredith A. Ray, Carrie Fehnel, Olawale Akinbobola, Andrea Saulsberry, Kourtney Dortch, Anberitha Matthews, Amal Anga, Christopher Giampapa, Elizabeth Sales, Sherry Okun, Edward T. Robbins, Bradley Wolf, Paul Levy, Horace L. Wiggins, Thomas Ng, Vishal Sachdev, Ganpat Valaulikar, Hetal D. Patel, Nicholas R. Faris, Matthew Smeltzer, Raymond U. Osarogiagbon. Interventions to improve pathologic nodal staging of curatively resected lung cancer: A population-based implementation study. [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 4359.
Abstract 4417: Activity of novel RNA therapeutics to overcome resistance to immune checkpoint blockade
Authors: O'Ketch Marvin , Kiefer Jeffrey A. , Rasale Dnyanesh , Weiner Warren S. , Castaño Lizette A. , Azorsa Nathalie A. , Lee David W. , Barnhart Kerry M. , Mousses Spyro , Azorsa David O. 
Published: April 2023

Abstract
T-cells in the tumor microenvironment can often become exhausted and dysfunctional due to chronic and prolonged exposure to antigen. The resulting condition of T cell exhaustion represents an important mechanism of clinical resistance to immune checkpoint blockade. The transcription factor NR4A1 is known to be upregulated in tumor-specific T-cells and is a mediator of T cell dysfunction including driving exhaustion during chronic antigen stimulation of T-cells. Pro-oncogenic activities of NR4A1 have been observed in various solid tumors, including colorectal and breast cancers, and co-expression of NR4A1 with known immune checkpoint markers such as PD-L1 and B7 family members has also been observed in various cancer cell lines. These findings have identified NR4A1 as an important target for overcoming resistance to cancer immunotherapy. We hypothesize that targeted silencing of the NR4A1 and other immunomodulatory genes can reverse T-cell exhaustion and expand the clinical benefit of immune checkpoint blockade in solid tumors resistant to immune therapy. To reverse T-cell exhaustion with a targeted approach, we developed T cell targeting SeekRsTM, which are chimeric RNA therapeutics containing dual-flanking aptamer binders connected by a double-stranded bridge containing siRNA silencers that can target multiple immunomodulatory genes. First-generation aptamer-siRNA chimeras designed with a CTLA-4 targeting aptamer containing a STAT3 siRNA demonstrated effectiveness in silencing its target. Modifications to the structure included the addition of chemically modified nucleotides to improve serum stability. Additionally, dimerization of the structure to form a SeekR dimer molecule greatly improved internalization and target silencing compared to the monomeric chimera. Newly developed SeekRs targeting T cells and designed to silence NR4A1 have effectively downregulated NR4A1 in model cell lines and activated T cells. These results demonstrate that dual targeting SeekRs can be used to specifically deliver siRNA to T cells for targeted silencing that can reverse exhaustion and potentially overcome resistance to cancer immunotherapy in the clinic.
Citation Format: Marvin O'Ketch, Jeffrey A. Kiefer, Dnyanesh Rasale, Warren S. Weiner, Lizette A. Castaño, Nathalie A. Azorsa, David W. Lee, Kerry M. Barnhart, Spyro Mousses, David O. Azorsa. Activity of novel RNA therapeutics to overcome resistance to immune checkpoint blockade. [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 4417.