bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4923: A systematic framework for predicting adverse drug reaction signals using medical data
Authors: Jeon Junhyeok , Hong Eujin , Kim Hyun Uk
Published: March 2024

Prescribing a combination of medications is a common strategy to enhance the effectiveness of disease treatment. While this approach aims to improve therapeutic outcomes, it may lead to unintended adverse drug reactions (ADRs) due to interactions between prescribed drugs and individual factors. Recognizing the importance of ADRs, various machine learning models have been developed. However, these models face limitations, particularly in predicting reactions induced by three or more drugs and in accounting for individual patient factors, such as age and medical history. To address these limitations, we propose a systematic framework that leverages medical data for predicting ADR signals. In the framework, the MIMIC-IV database was systematically preprocessed, and a series of machine learning models were developed that predict the ADR signals. The model predictions were validated using the eICU collaborative research database. The machine learning models process multiple inputs, including information on administered drugs, age, gender, ethnicity, and underlying medical conditions to predict ADR signals. The ADR signals are determined by classifying abnormalities in 20 specific laboratory test values, such as hematocrit, creatinine, and hemoglobin. The machine learning models developed in this study hold promise as a valuable tool for assessing potential risks, such as ADRs, associated with the concurrent use of multiple drugs.

Citation Format: Junhyeok Jeon, Eujin Hong, Hyun Uk Kim. A systematic framework for predicting adverse drug reaction signals using medical data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4923.
Abstract 4931: The Cancer Proteome Atlas: Expanded datasets and empowered with an AI-driven chatbot
Authors: Liang Han , Liu Wei , Li Jun , Tang Yitao
Published: March 2024

Reverse-phase protein arrays (RPPAs) represent a powerful functional proteomic approach to elucidate cancer-related molecular mechanisms and develop novel cancer therapies. To facilitate community-based investigation of the large-scale protein expression data generated by this platform, we have developed a user-friendly, open-access bioinformatic resource, The Cancer Proteome Atlas (TCPA, http://tcpaportal.org), which contains several applications. The first one focuses on RPPA data of patient tumors, which contains >8,000 samples of 32 cancer types from The Cancer Genome Atlas (TCGA) and other independent patient cohorts. The second application focuses on the RPPA data of >1,500 cancer cell lines with publicly available, high-quality DNA, RNA and drug screening data. The third one focuses on perturbed RPPA profiles of >14,000 samples given drug treatments. We recently expanded our RPPA protein set from 200 to 500 proteins Importantly, this highly selected set is enriched in therapeutic targets and biomarkers and covers key oncogenic pathways such as PI3K/AKT, RAS/MAPK, Src/FAK, TGFβ/SMAD, JAK/STAT, epithelial-mesenchymal transition, DNA damage repair, Hippo, Notch, cell cycle, apoptosis, and immune-oncology. Using this upgraded RPPA platform, we generated an harmonized, expanded RPPA dataset of 8000 TCGA patient samples and 1000 CCLE cell line samples. To further address the informatic challenges of analyzing such large, diverse datasets, in addition to the GUI interfaces, we recently developed a chatbot through which users can analyze the RPPA data through human nature languages and obtain the results and related analytic reports without a learning curve. Such a chatbot empowers a broad research community to explore high-quality RPPA datasets and generate testable hypotheses in an effective and intuitive manner, representing the direction of next-generation data analytics.

Citation Format: Han Liang, Wei Liu, Jun Li, Yitao Tang. The Cancer Proteome Atlas: Expanded datasets and empowered with an AI-driven chatbot [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4931.
Abstract 4966: Machine learning and large language model approach to pancancer data elements
Authors: Niederhausern Andrew , Bahadur Nadia S. , Wallace Gary , Saadawi Gilan E. , Philip John
Published: March 2024

Introductory Statement: The goal is to use machine learning (ML) and large language model (LLM) to augment the manual curation of cancer data elements.

Introduction: Memorial Sloan Kettering Cancer Center (MSKCC) has ~100,000 cancer patients and counting with genomic testing. Clinicians use genomic data for research but lack clinical data to analyze together. We use a vendor, VASTA Global to hire curators to manually curate cancer patient’s core clinical data elements (CCDE) within unstructured/paragraph text in electronic medical record (EMR) notes.

CCDE encompasses 122 data elements that include a patient’s full cancer history that can take up to 1 working day to curate. We collaborated with the Realyze Intelligence Healthcare Solutions vendor to use their AI pipeline to generate the manual curated dataset.

Realyze generated the CCDE data elements such as histology, pathology site, MMR, TNM staging, ECOG, and KPS for a pilot lung cancer cohort of 150 patients. We manually validated the generated data for 74 out of 150 patients.

Methods:The Realyze platform uses a combination of LLMs, ML algorithms and standard terminologies to create a cancer patient model. These models are flexible enough to address the unique needs and challenges of a pan-cancer oncology model. By using standardized FHIR export, results were delivered to a data lake solution and written into a REDCap database to enable human review.

Summary:We manually assessed 74 patients. The NLP gave concordant values for MMR, KPS and TNM staging for 100% of the instances. For MMR these were all null values with false negative (FN) of 100% accuracy. Pathology site had 92.15% accuracy while histology has 97.5% accuracy.

Conclusion:Will work on refining pathology site and histology’s ICDO3 list to increase the percentage of accuracy. Once Realyze refines their model for these data elements we will re-run it on a larger cohort of cancer patients and calculate the accuracy.

Accuracy Results Clinical data elements 74 patients assessed: Accuracy % ECOG 98.6 KPS 100 T (path) 100 T (clinical) 100 N (path) 100 N (clinical) 100 M (path) 100 M(clinical) 100 MMR 100 Histology (path) 97.5 Path site 92.15

Citation Format: Andrew Niederhausern, Nadia S. Bahadur, Gary Wallace, Gilan E. Saadawi, John Philip. Machine learning and large language model approach to pancancer data elements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4966.
Abstract 4968: Discovery of cancer-associated factors in 293.5 million diagnosis records using statistical machine learning analysis
Authors: Alam Md Ashad , Duesbery Nick , Fort Daniel Daniel
Published: March 2024

Cancer, a leading global public health issue, ranks as the second leading cause of death in the United States, with projections indicating 1,958,310 new cases and 609,820 deaths in 2023. Accurately quantifying specific pre-disease diagnosis factors associated with cancer, as well as predicting cancer through disease trajectories and imaging modalities, presents a complex and formidable challenge. A comprehensive temporal trajectory analysis of cancer diseases, using disease trajectories as an insight within large cohorts in the USA, has not yet been developed. Our analysis used a comprehensive EHR dataset stretching back to 1999, encompassing 293,501,891 records and involving 3,019,978 patients within Ochsner Health, a large integrated health system across the State of Louisiana. According to our investigation, those diagnosed at the ICD chapter level with diseases of the genitourinary system (genitourinary diseases, ICD-10 Chapter 14, relative risk (RR=1.65)) or endocrine nutritional and metabolic diseases (obesity, ICD-10 Chapter 4, RR=1.35) have an elevated risk of being diagnosed with cancer in the subsequent five years. The top four individual diagnosis ICD-10 codes associated with increased risk are N60 (Benign Mammary dysplasia, RR=7.80), M34 (Systemic sclerosis, RR=7.72), R43 (Disturbances of smell and taste, RR=6.93), and R92 (Abnormal and inconclusive findings on diagnostic imaging of the breast, RR=6.59). Furthermore, in our investigation of specific types of cancer risk across 17 cancer types (Breast, Skin, Prostate, Lung, Pancreatic, etc.), we observed that the most common diseases associated with breast and skin cancer involved immune mechanisms (RR=8.35 and 8.68), genitourinary issues (RR=4.13 and 2.48), obesity (RR=3.42 , 3.35), and cardiovascular conditions (ICD-10 Chapter 9, RR=1.73 and 2.19). For prostate cancer, associations were found with obesity (RR=3.50), human immunodeficiency virus (HIV, ICD-10 Chapter 1, RR=2.39). Across lung cancer, involvement with chronic viral hepatitis (ICD-10 Chapter 1, RR=4.00), cardiovascular issues (RR=3.52), genitourinary problems (RR=4.13), and obesity (RR=3.42) were indicated. Our comprehensive analysis has the potential to contribute to the early detection, diagnosis trajectories, and improved understanding of the pathological processes underlying cancer in patients worldwide.

Citation Format: Md Ashad Alam, Nick Duesbery, Daniel Daniel Fort. Discovery of cancer-associated factors in 293.5 million diagnosis records using statistical machine learning analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4968.
Abstract 5015: Genomic profiling of colorectal cancer - insights from liquid biopsy comparisons between U.S. and China cohorts
Authors: Tang Haoran , Jia Cancan , Xie Feng , Zhang Yue , Dong Xiaoxi , Huang Yong , Jia Shidong
Published: March 2024

Background: Molecular characteristics play a pivotal role in cancer diagnosis, treatment selection, and disease monitoring across various tumor types. While previous research has elucidated the molecular classification of colorectal cancer using tissue NGS, limited investigation has explored the molecular profile of colorectal cancer through liquid biopsy, especially across diverse human races. This study presents a comprehensive genomic profiling analysis of colorectal cancer patients, using a globally harmonized liquid biopsy assay to compare patient cohorts from both the U.S. and China.

Methods: The prospective study is part of Predicine’s Phoenix Program, a global molecular biomarker screening initiative across multiple solid tumors. At present, the study has enrolled 57 patients in the U.S. and 62 patients in China, all presenting with advanced colorectal cancer. A 10ml blood sample was collected from each patient and tested using PredicineCARE, an NGS-based liquid biopsy assay, to profile somatic mutations, copy number variations, and gene fusions among these patients.

Results: The assay, validated in both the U.S. and China using the same reference materials, achieved a LOD of 0.25% mutation allele frequency, with a positive predictive value exceeding 99%. Subsequently, the assay was applied to profile molecular aberrations in colorectal patients in both the U.S. and China. Among U.S. patients, the most commonly altered genes were APC (60%), KRAS (56%), TP53 (54%), MYC (25%), PIK3CA (16%), and EGFR (14%). In Chinese patients, the predominant altered genes were TP53 (48%), APC (42%), KRAS (32%), GNAS (21%), EGFR (16%), and PIK3CA (11%). The prevalence of GNAS variations was significantly higher in China than in the U.S. (p < 0.05), while the prevalence of APC (p < 0.05), KRAS (p < 0.01), and MYC (p < 0.001) variations was significantly higher in the U.S. than in China.

Conclusions: This study reveals the extensive mutational landscape in advanced colorectal cancer patients through liquid biopsy. Distinct prevalence patterns in certain genes between the U.S. and China cohorts offer novel biomarkers for clinical diagnosis and provide insights for targeted therapy mechanism studies.

Citation Format: Haoran Tang, Cancan Jia, Feng Xie, Yue Zhang, Xiaoxi Dong, Yong Huang, Shidong Jia. Genomic profiling of colorectal cancer - insights from liquid biopsy comparisons between U.S. and China cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5015.
Abstract 5034: Analytic validation of an ultra-sensitive tumor-informed circulating tumor DNA assay based on whole genome sequencing
Authors: Northcott Josette , Bartha Gabor , Harris Jason , Ma Shuyuan , Hong Manqing , Zhang Qi , Chen Richard , Lyle John
Published: March 2024

Monitoring of circulating tumor DNA (ctDNA) levels has demonstrated utility in the detection of residual and recurrent disease after tumor resection, and as a prognostic indicator of patient outcome following initial therapy, in a wide range of cancers. Here we describe the analytic validation of the NeXT Personal® assay, an ultra-sensitive, quantitative, tumor-informed ctDNA assay for use in patients diagnosed with solid tumors. NeXT Personal utilizes whole genome sequencing (WGS) of tumor and normal samples and advanced noise suppression to accurately identify somatic variants and generate a patient-specific diagnostic panel based on up to ~1,800 single nucleotide variants. This personalized panel is used to test for the presence of ctDNA in the patient’s blood samples. The NeXT Personal validation was performed using 123 matched tumor, normal and plasma clinical sample sets representing 9 cancer types. The assay achieved 100% specificity on donor normal plasma samples with an in silico approach giving us a confidence interval of 99.87% to 100%. The analytical range measurements were performed using two paired tumor and normal cell lines, one of which is a commercially available MRD control. The detection threshold for the analytical range measurement was 1.68 parts per million (PPM) with a limit of detection at 95% (LOD95) of 3.52 PPM. Furthermore, NeXT Personal showed linearity over a range of 0.8 PPM to 300,000 PPM (Pearson correlation coefficient= 0.9998) with a limit of quant (LOQ) of 10 PPM. The assay also demonstrated strong performance across varying cfDNA input amounts from 2 ng to 30 ng. These studies demonstrate that NeXT Personal is an ultra-sensitive, highly specific, quantitative and robust assay, giving it the potential to detect residual disease and recurrence earlier than less sensitive assays.

Citation Format: Josette Northcott, Gabor Bartha, Jason Harris, Shuyuan Ma, Manqing Hong, Qi Zhang, Richard Chen, John Lyle. Analytic validation of an ultra-sensitive tumor-informed circulating tumor DNA assay based on whole genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5034.
Abstract 5067: Exploring the genomic landscape of de novo neuroendocrine prostate cancer: Insights for innovative therapies from spatial gene expression analysis
Authors: Watanabe Ryuta , Miura Noriyoshi , Kurata Mie , Kitazawa Riko , Kikugawa Tadahiko , Saika Takashi
Published: March 2024

Introduction & Objectives Neuroendocrine prostate cancer (NEPC) accounts for less than 1% of all prostate cancers but has a worse prognosis than androgen receptor-positive prostate adenocarcinoma (ARPC). Rare cases exist where both de novo NEPC and ARPC are found in the same tissue sample. Our study examines one such unique case: a 78-year-old male treated at Ehime University Hospital who was diagnosed with both ARPC and adjacent de novo metastatic NEPC. This case provides an excellent opportunity for studying gene expression in these two types of prostate cancer. Materials & Methods We used Visium CytAssist Spatial Gene Expression technology from 10x Genomics to analyze formalin-fixed, paraffin-embedded (FFPE) tissue samples from this unique patient. Results We observed elevated expression levels of specific neuroendocrine markers like PEG10, DLL3, NCAM1, SYP, and CHGA in de novo NEPC regions. In contrast, androgen receptor markers such as KLK3, ACPP, TMPRSS2, and NKX3.1 were more prevalent in ARPC areas. Furthermore, genes like Chek1, BRCA1/2, TOP2A, and FANCA were also elevated in NEPC, suggesting that PARP and TOP2 inhibitors could be effective. Expression levels of Rbfox3 and SFRTM2 were lower in NEPC areas, implying possible roles in epithelial-mesenchymal transition (EMT) and Wnt signaling pathways. Additionally, fibrotic markers like HGF, HMOX1, ELN, and GREM1 were upregulated, suggesting that de novo NEPC tumors might be 'immune cold,' thus requiring treatments to boost the effectiveness of immune checkpoint inhibitors. Conclusion The data from additional cases could open the door for new treatment options for NEPC and improve survival rates for castration-resistant prostate cancer patients. Our research serves as a pioneering application of Visium CytAssist on FFPE samples and is the first to examine gene expression in both ARPC and de novo NEPC. A subset of these findings was published in the International Journal of Molecular Science (IJMS) in May 2023.

Citation Format: Ryuta Watanabe, Noriyoshi Miura, Mie Kurata, Riko Kitazawa, Tadahiko Kikugawa, Takashi Saika. Exploring the genomic landscape of de novo neuroendocrine prostate cancer: Insights for innovative therapies from spatial gene expression analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5067.
Abstract 5073: Advancing precision oncology: Insights from pan-cancer proteogenomic signatures
Authors: Li Yize , Terekhanova Nadezhda V. , Wendl Michael C. , Chen Feng , Ding Li
Published: March 2024

Somatic mutations in cancer genomes arise from diverse mutational processes, leaving distinct mutational signatures. However, the proteogenomic implications of these signatures and their connections to environmental influences and immune interactions remain largely unexplored. In this study, we comprehensively investigated these signatures from a broader proteogenomic perspective to further discern their genetic, proteomic, phosphoproteomic, and environmental ramifications. The harmonized dataset of 1064 samples across ten cancer types from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) pan-cancer resource was utilized for this investigation. Beyond genetic alterations and mutational signatures, we harnessed high-throughput multi-omics data to detect critical changes and infer expression signatures associated with the transitions to seven tumor-linked phenotypes: aging, Apolipoprotein B mRNA Editing Catalytic Polypeptide (APOBEC), Homologous Recombination Deficiency (HRD), Microsatellite Instability (MSI), Polymerase Epsilon (POLE), smoking, and ultraviolet (UV) light exposure at the pan-cancer level. We prioritized the top differentially expressed markers uniquely found at the protein and phosphoprotein levels and developed a quantitative score predicting each phenotype status, such as MSI. Respectively, we pinpointed potential candidates as actionable therapeutic targets by linking the identified markers to druggable databases. This offers additional cues to optimize therapeutic options for patients. Specifically, directing attention to genes up-regulated in HRD tumors treated with PARP1 inhibitors shows potential promise in overcoming resistance. Moreover, we explored environmental exposure-related tumor proteogenomic signatures and their association with immune infiltration levels and phenotypes. Notably, smoking strongly influenced the tumor microenvironment (TME) and prognosis in lung cancer. In summary, our identification of expression signatures facilitates phenotype prediction and unveils their molecular mechanisms. We anticipate clinical utility in classifying samples using proteogenomics, particularly in cases where a solely genomic assessment is inconclusive.

Citation Format: Yize Li, Nadezhda V. Terekhanova, Michael C. Wendl, Feng Chen, Li Ding. Advancing precision oncology: Insights from pan-cancer proteogenomic signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5073.
Abstract 5092: Development of a priming approach to enhance antigen-directed therapies in hematological malignancies and solid tumors
Authors: Vanderlaag Kathryn E. , Dhar Anukriti , Volkman Molly , Werner Erik , Nguyen Transon , Ali Kamran
Published: March 2024

Clinical success of antigen-directed therapies in cancer has been limited by heterogeneous antigen expression and a narrow therapeutic window. In many patients, failure of antigen-directed therapies such as CAR T-cell therapies, antibody-drug conjugates (ADC) or radioligand therapies (RLT) has less to do with a lack of potency or specificity of the agent and more to do with variable and suboptimal antigen expression in the patient. We are developing combination therapies that introduce a priming agent designed to optimize antigen expression in the patient and improve the therapeutic window of existing antigen-directed therapies. Our high-throughput platform utilizes machine learning and automation to scale functional combinatorial screening for small molecule priming agents using cell lines and patient samples. Using this platform, we are identifying priming therapies for CD123, CD33, CD22, and CD19 in hematological malignancies including acute myeloid leukemia (AML), and HER2, HER3, and TROP2 in solid tumors including breast cancer.For our CD123 program, we have identified priming agents that selectively upregulate CD123 expression ≥2-fold on AML cells without increasing expression on normal myeloid progenitor cells, which also express CD123. AML cells treated with a CD123 priming agent in combination with a CD123 ADC showed greater tumor-cell killing compared to the ADC alone. In comparison, normal myeloid progenitor cells from healthy bone marrow treated with the same CD123 priming-ADC combination treatment did not show an increase in ADC-mediated cell killing. From our mechanistic studies, we have identified a somatic mutation associated with CD123 upregulation that may lead to selective upregulation on cancer cells and not on normal cells. Additionally, this marker can be used for patient selection. We have also observed CD123 upregulation in vivo using mouse models of AML and are currently conducting additional in vivo proof of concept studies to demonstrate that CD123 priming therapy enhances efficacy.There are two distinct advantages of a priming approach paired with an antigen-directed therapy, which include: (1) improving the durability of patient responses and (2) expanding the patient population. Our priming combination approach has the potential to overcome antigen heterogeneity and thereby improve the clinical success of antigen-directed therapies.

Citation Format: Kathryn E. Vanderlaag, Anukriti Dhar, Molly Volkman, Erik Werner, Transon Nguyen, Kamran Ali. Development of a priming approach to enhance antigen-directed therapies in hematological malignancies and solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5092.
Abstract 5093: Analysis of protein expression in head and neck cancers as therapeutic targets for antibody drug conjugates
Authors: Moyers Justin Tyler , Smith Seth L. , Mora Miranda M. , Pestana Roberto Carmagnani
Published: March 2024

Introduction: Antibody Drug Conjugates (ADCs) represent a new category of therapeutic molecular targeting for solid tumors. To date 6 ADCs have been approved in solid tumors against 5 targets (HER2/ERBB2, Folate alpha, Tissue Factor, Nectin-4, and Trop-2). Thus far, no ADCs have been approved for head and neck cancers.

Methods: We queried protein expression data from a publically available consortium of datasets (TNMPlot.com) containing protein expression data from over 56,000 tumor and normal samples from GEO, GTex, TCGA, and TARGET databases. Genes examined for protein targets, included those with ADC targets of both presently approved and investigational drugs from clinical trials.The level of overexpression was determined as the percent of tumors over the 75th percentile of expression in normal tissue.

Results: Protein expression data were available for 99 HNSCC samples. Among targets with ADCs available, increased protein expression was seen in HNSCC for 0% of ERBB2 (n=0/99), 38% of FOLR1 (n=38/99), 0% of TACSTD2 (n=0/99), and 42% of F2 (n=42/99) genes.Among gene targets with investigational ADCs, increased protein expression was seen in HNSCC for 35% of of AXL (n=35/99), 13% of B7H3/CD27 (n=12/99), 50% of EGFR (n=50/99), 63% of VTCN1 (n=63/99), 10% of MSLN (n=10/99), 77% of CDH3 (n=76/99), and 39% of PDGFRA (n=39/99).

Conclusion: Increased protein expression for approved ADC targets were infrequent in HNSCC. However, increased protein expression is seen for several ADCs under clinical investigation supporting the potential therapeutic approaches for investigational ADC targets.

Citation Format: Justin Tyler Moyers, Seth L. Smith, Miranda M. Mora, Roberto Carmagnani Pestana. Analysis of protein expression in head and neck cancers as therapeutic targets for antibody drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5093.
Abstract 5109: Novel acylfulvene LP184 shows single agent and combinatorial efficacy with PARP inhibitors in atypical teratoid rhabdoid tumors
Authors: Tindall Abigail , Kwon Hyuk J. , Musa Istabraq , Findlay Tyler , Lee Su Chan , Eberhart Charles , Raabe Eric
Published: March 2024

Atypical Teratoid Rhabdoid Tumor (AT/RT) is an aggressive form of pediatric brain cancer that spreads quickly and leads to survival rates of less than 40%. Current treatments are insufficient at reducing this poor prognosis. A hallmark feature of ATRT is a SMARCB1 mutation. Illudins are a class of cytotoxic compounds with activity against pediatric solid tumors, including AT/RT. LP-184 is a novel synthetic illudin with improved brain penetration and activity against adult high-grade glioma orthotopic xenografts. We tested LP-184 against a battery of AT/RT cell lines including BT37, CHLA06, CHLA05, and CHLA266. LP-184 decreases viability at nanomolar concentrations with IC50s ranging from 9.91nM - 23.92nM. LP-184 decreased proliferation as measured by immunofluorescence and confirmed by western blots (BT37 p=0.0001, CHLA06 =0.0001, CHLA05=0.033). LP-184 also induced apoptosis as demonstrated in immunofluorescent images and western blots (BT37 p=0.0001, CHLA06 =0.0001, CHLA05=0.0015, CHLA266 p=0.002). Furthermore, LP-184 shows strong synergy with the PARP inhibitor Rucaparib, suggesting that inhibition of DNA repair potentiates LP-184 activity. LP-184 reduces viable cell count by as much as 50% and combination with Rucaparib further decreases viability by 75% (BT37=0.0001, CHLA06=0.0002, CHLA05=0.0077). The dual therapy also demonstrates cytostatic and cytotoxic effects as confirmed by immunofluorescence and western blots (BT37 BrdU = 0.0004, BT37 CC3 = 0.0002, CHLA06 BrdU = 0.0033, CHLA06 CC3 = 0.0117 compared to control). Further studies in vivo are being conducted to test single agent and combination therapies of LP-184 and Rucaparib in ATRT, as our data indicates that the two could provide a compelling treatment option for patients with this poor prognosis brain tumor.

Citation Format: Abigail Tindall, Hyuk J. Kwon, Istabraq Musa, Tyler Findlay, Su Chan Lee, Charles Eberhart, Eric Raabe. Novel acylfulvene LP184 shows single agent and combinatorial efficacy with PARP inhibitors in atypical teratoid rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5109.
Abstract 5146: Clinical significance of inter-assay discrepancy in PD-L1 expression evaluation for the efficacy of pembrolizumab in advanced NSCLC patients with high PD-L1 expression
Authors: Miyakoshi Jun , Kashima Jumpei , Shirasawa Masayuki , Torasawa Masahiro , Matsumoto Yuji , Masuda Ken , Shinno Yuki , Okuma Yusuke , Yoshida Tatsuya , Goto Yasushi , Horinouchi Hidehito , Shiraishi Kouya , Kohno Takashi , Yamamoto Noboru , Yatabe Yasushi , Ohe Yuichiro
Published: March 2024

Introduction: The expression of programmed cell death ligand-1 (PD-L1) is a predictive biomarker for the efficacy of pembrolizumab in advanced non-small cell lung cancer (NSCLC). While several assays have been approved for evaluating PD-L1 expression status, the inter-assay discordances are observed. The clinical significance of these discrepancies is still unclear.

Methods: We retrospectively reviewed treatment-naïve NSCLC patients with available PD-L1 expression status by both 22C3 and SP142 assays. Among these patients, efficacy analysis was performed in those with PD-L1 tumor proportion score (TPS) ≥ 50% (22C3) who received the first-line pembrolizumab monotherapy. Additionally, we conducted RNA-sequence analysis in the patients with TPS ≥ 50% to investigate the distinct immune profiles with the inter-assay discordance.

Results: A total of 611 patients were evaluated for PD-L1 expression status by both assays. Of 198 patients with TPS ≥ 50%, 91 (46%) had TC score ≤ 1 (SP142, i.e., inter-assay discrepancy). In 52 patients who received the first-line pembrolizumab monotherapy, the efficacy in patients with the inter-assay discrepancy was significantly lower than those without the discrepancy (shown in Table). While there was no difference in tumor microenvironments such as the tumor-infiltrating lymphocytes, the transcriptome analysis revealed significantly more CD274 splicing variants with aberrant 3’-terminal sequences in tumors with the inter-assay discrepancy than those without discrepancy, leading to the suppressed PD-1/PD-L1 pathway in those with the discrepancy.

Conclusion: The inter-assay discrepancy in the PD-L1 expression status on tumor cells between the 22C3 and SP142 assays, reflecting an imbalance of the CD274 splicing variants, could be a primary-resistance mechanism to the pembrolizumab monotherapy in highly PD-L1-expressing NSCLCs.

PD-L1(22C3) Discrepancy Pts. ORR(%) p value Median PFS(months) 95%CI p value TPS ≥ 50% yes 17 18 < 0.001 3.2 0.8–5.5 < 0.001 no 35 83 8.3 5.7–24.2

Citation Format: Jun Miyakoshi, Jumpei Kashima, Masayuki Shirasawa, Masahiro Torasawa, Yuji Matsumoto, Ken Masuda, Yuki Shinno, Yusuke Okuma, Tatsuya Yoshida, Yasushi Goto, Hidehito Horinouchi, Kouya Shiraishi, Takashi Kohno, Noboru Yamamoto, Yasushi Yatabe, Yuichiro Ohe. Clinical significance of inter-assay discrepancy in PD-L1 expression evaluation for the efficacy of pembrolizumab in advanced NSCLC patients with high PD-L1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5146.
Abstract 5210: The Prognostic value of serum TK1 protein determinations using AroCell TK210 ELISA in DLBCL patients treated with R CHOP
Authors: Jagarlamudi Kiran , Hedström Gustaf , Venge Per , Eriksson Staffan , Molin Daniel , Enblad Gunilla
Published: March 2024

Background: Diffuse large-cell B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin’s lymphomas (NHL) that accounts for approximately 25% of the patients. Earlier studies demonstrated the prognostic value of serum thymidine kinase 1 (STK1) activity determinations in different hematological malignancies. To date, the prognostic value of STK1 protein concentration in patients with DLBCL treated with R-CHOP has not been investigated. The purpose of this retrospective study was to determine the value of high TK levels on Overall survival among DLBCL patients treated with R-CHOP as first-line treatment.

Materials and Methods: The study included 146 patients diagnosed with DLBCL between 2010 and 2016 from the Uppsala-Umeå Comprehensive Cancer Consortium (U-CAN). All patients included were treated using the standard chemotherapy regimen R-CHOP. Serum samples were collected at the time of diagnosis, during the treatment, 1 year after treatment, and after relapse. Non-infected and apparently healthy persons, matched to the DLBCL patients (57 males and 88 females), served as controls. The TK1 protein levels in all serum samples were determined by using AroCell TK 210 ELISA (AroCell AB, Sweden). The TK1 protein concentration was expressed as μg/L.

Results: The TK1 concentrations in sera from DLBCL patients before treatment were significantly higher compared to the concentrations in healthy individuals, median 0.44 μg/L (IQ range 0.22 to 1.06 μg/L) vs. median 0.22 μg/L (IQ range 0.18 to 0.29 μg/L, P<0.00001). Serum TK1 was also significantly higher in patients with more advanced stages (P<0.00001), higher IPI (P<0.00001), and in patients with B-symptoms (P<0.0001). Patients with STK1 protein levels below the cut-off value (0.45 μg/L) had significantly better OS and DFS (P=0.04 and P=0.0006, respectively) compared to patients with STK1 concentration above the cut-off. In multivariate analyses, dichotomized S-TK1 measurements before treatment were found to be significant for the risk of relapse in combination with either aaIPI or IPI (p<0.01).

Conclusions: These results confirmed that STK1 concentration correlates with risk factors such as tumor burden, Ann Arbor stage, and IPI. In conclusion, patients with high TK1 concentrations at the time of diagnosis have short overall survival and STK1 concentrations are apparently a prognostic indicator for survival in patients treated with modern chemo-immunotherapy.

Citation Format: Kiran Jagarlamudi, Gustaf Hedström, Per Venge, Staffan Eriksson, Daniel Molin, Gunilla Enblad. The Prognostic value of serum TK1 protein determinations using AroCell TK210 ELISA in DLBCL patients treated with R CHOP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5210.
Abstract 5234: TGFbeta-conditioned K-NK cells are able to counter immune suppression in the tumor micro-environment
Authors: Kunert Andre , Oja Anna , Cesonyte Ieva , Franciszkiewicz Katarzyna , Sidhu Sukhvinder , Jetani Hardik , Bocconcelli Giulio , Igarashi Robert , Fantin Valeria R.
Published: March 2024

Recent advances have enabled the use of autologous K-NK cells to treat patients suffering from hematological malignancies. When aiming to treat patients suffering from solid tumors however, the suppressive effects of the tumor microenvironment (TME) and the involvement of other immune cells need to be considered to make a cell therapeutic potentially more effective.

TGFβ-conditioning (TGFβ-c), the co-culture of K-NK cells with low-dose TGFβ while undergoing cytokine-mediated expansion, imbues these cells with unique qualities suitable to mitigate immuno-suppressive effects of the TME, making them more efficacious toward solid tumors. The exposure to TGFβ during expansion results in significant downregulation of SMAD3, rendering these cells insensitive to TGFβ-mediated down-regulation of NK cell receptors. TGFβ-c K-NK cells display enhanced in vitro cytotoxicity towards 2D, 3D cultured cell lines as well as against organoid models derived of various indications. These cells infiltrate into patient-derived tumor organoids at higher frequency and have increased IFNγ secretion upon target-specific activation. The effect of the higher IFNγ output on a complementary anti-tumor immune subset was investigated in complex immune cell cultures and was indeed shown to enhance DC maturation.

In vivo studies revealed prolonged persistence of TGFβ-c K-NK cells in mice while retaining both altered gene-expression and functional hallmarks for up to 28 days, indicating that the conditioning results in a stable phenotype.

In summary, TGFβ-c K-NKs are a platform with enhanced potency to transition cell therapy from treating hematological to solid tumor malignancies.

Citation Format: Andre Kunert, Anna Oja, Ieva Cesonyte, Katarzyna Franciszkiewicz, Sukhvinder Sidhu, Hardik Jetani, Giulio Bocconcelli, Robert Igarashi, Valeria R. Fantin. TGFbeta-conditioned K-NK cells are able to counter immune suppression in the tumor micro-environment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5234.
Abstract 5251: RNA primed SMAR-T cells against multiple driver mutations, all HLA's designed for first line therapy
Authors: Slanetz Alfred E. , Srivatsa Sriram , Muzaffar Farzona , Barry Walter , Ryan David , Metri Salim , Slanetz Michael
Published: March 2024

Success of immune checkpoint inhibitors (e.g., anti-PD1 antibodies) have revolutionized cancer immunotherapy by demonstrating that a patient’s own T-cells recognize and treat cancer. The efficacy of PD-1 blockade is driven by recruitment of new T-cells from blood rather than via activation of pre-existing tumor infiltrating lymphocytes (Yost K.E., et al. Nat. Med. 2019). However, anti-PD1 therapy is most effective in ~5% of malignancies i.e., cancers with high mutational burden. Hence, the challenge of addressing most lower mutational burden cancers (the ~95%) needs an alternate treatment strategy. We address this challenge by using RNA to prime and expand peripheral T-cells to cancer-specific mutations ex-vivo. Using our proprietary, patented, and robust manufacturing method, we can generate T-cell populations reactive to as low as 8 and as high as 40 cancer-specific mutant proteins. In-vitro, these T-cells have cancer mutation-specific cytotoxicity and do not kill the normal cells. Further, the T-cells express homing receptors enabling them to infiltrate tumors and express high levels of TNFα and IFNγ, which are associated with effective tumor cytotoxicity and pro-inflammatory modification of tumor microenvironment (TME). Additional characterization shows these cells to be predominantly CD4+ and CD8+ T-cells bearing central and effector memory phenotypic with negligible regulatory or exhausted T-cells. We believe our T-cells can be used for cellular therapy in conjunction with, or as an alternative to, immune checkpoint inhibitors to treat lower mutational burden cancers present in most patients.

Citation Format: Alfred E. Slanetz, Sriram Srivatsa, Farzona Muzaffar, Walter Barry, David Ryan, Salim Metri, Michael Slanetz. RNA primed SMAR-T cells against multiple driver mutations, all HLA's designed for first line therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5251.
Abstract 5253: Epigenetic drugs partially restored anti-cholangiocarcinoma activity of dysfunctional CD3+CD56+ cells
Authors: Wongkajornsilp Adisak , Chusorn Porncheera , Phongkitkarun Kriengkrai , Htwe Khin Su Su , Duangsa-ard Sunisa , Kasetsinsombat Kanda , Sawatpiboon Nathawadee
Published: March 2024

The cholangiocarcinoma cell-exposed cytokine-induced killer (CIK) cells or their most efficacious CD3+CD56+ subset displayed weaken anti-tumor cytotoxicity upon subsequent exposure. RNAseq analysis of the resistant phenotype gave rise to a list of drugs that could potentially counter the activity of genes associated with resistance to the anti-tumor activity of CIK cells. The top-ranking drugs appeared to be epigenetic drugs. Sublethal concentration of these drugs were assayed for their synergistic activity with CIK cell or the CD3+CD56+ subset for cytolysis of resistant CCA cells in tissue culture model. These drugs, although in low concentration, contained anti-tumor activity. The tumor cytolysis was greater after the combination with either CIK cells or the CD3+CD56+ subset. An in vivo model of CCA-implanted mice exhibited the synergistic activity of subtherapeutic dose of these drugs and CD3+CD56+ subset in suppressing tumor growth. It is concluded that epigenetic drugs in subtherapeutic dose could prevent the dysfunction of CCA-exposed CIK cells.

Citation Format: Adisak Wongkajornsilp, Porncheera Chusorn, Kriengkrai Phongkitkarun, Khin Su Su Htwe, Sunisa Duangsa-ard, Kanda Kasetsinsombat, Nathawadee Sawatpiboon. Epigenetic drugs partially restored anti-cholangiocarcinoma activity of dysfunctional CD3+CD56+ cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5253.
Abstract 5352: SOX9-dependent immune microenvironment remodeling drives KRAS-induced lung adenocarcinoma progression
Authors: Menon Dinoop Ravindran , Zhong Hua , Ganesan Shridar , Sabaawy Hatim , Pine Sharon
Published: March 2024

Interactions between tumor intrinsic factors and tumor microenvironment play a vital role in disease progression and treatment response. SOX9, a transcription factor crucial for tissue development and homeostasis, has been linked to the advancement of tumor growth. However, its specific role as a driver in lung adenocarcinoma (LUAD) is not well-defined. Additionally, the impact of SOX9 on the tumor microenvironment has not been previously explored. We here identify SOX9 transcription factor to play a critical role in defining tumor immune microenvironment and driving disease progression. We employed CRISPR/Cas9 and Cre-LoxP gene knockout methods within the Kras G12D-induced mouse model of lung adenocarcinoma (LUAD). Our objective was to investigate the mechanisms through which SOX9 contributes to the development and advancement of lung adenocarcinoma. To substantiate our findings, we conducted immune profiling, gene expression analyses, RT-qPCR, and immunohistochemistry assessments in the Kras G12D-driven murine LUAD. These results were subsequently validated by examining bulk and single-cell gene expression profiles, as well as immunohistochemistry, in human lung adenocarcinoma. Our studies indicated that SOX9 played a very important role by enhancing lung tumor development, burden, and progression, leading to lower overall survival. SOX9. SOX9 consistently facilitated the growth of organoids in vitro. However, the promotion of tumor growth by SOX9 was notably reduced in immunocompromised mice compared to syngeneic mice. SOX9 demonstrated a suppressive effect on immune cell infiltration, particularly affecting the functionality of tumor-associated CD8+ T cells, natural killer cells, and dendritic cells. CD8+ T cells in the SOX9 overexpressing tumors showed upregulation of exhaustion markers. SOX9-mediated tumor growth advantage could not be observed in the CD8 knockout mice model, suggesting a CD8+ T cell-dependent role. In addition, SOX9 significantly upregulated collagen-related gene expression, leading to a substantial increase in collagen fibers possibly affecting the migration of immune cells into the tumor microenvironment. Together, our studies indicate that SOX9 plays a very critical role in modulating tumor microenvironment by controlling immune cell infiltration and CD8+ T cell exhaustion driving Kras G12D- driven lung tumor progression.

Citation Format: Dinoop Ravindran Menon, Hua Zhong, Shridar Ganesan, Hatim Sabaawy, Sharon Pine. SOX9-dependent immune microenvironment remodeling drives KRAS-induced lung adenocarcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5352.
Abstract 5362: Targeting IRE1α alleviates the immunosuppressive tumor microenvironment in prostate cancer
Authors: Unal Bilal , Kuzu Omer Faruk , Jin Yang , Hurtado Daniel Camilo , Kuijjer Marieke Lydia , Daugaard Mads , Oo Htoo Zarni , Patterson John B. , Saatcioglu Fahri
Published: March 2024

Unfolded protein response (UPR) is a central stress response pathway in normal cells that is hijacked by tumor cells for their survival. However, how activation of UPR in cancer cells shapes the tumor microenvironment (TME) remain largely unexplored. Here, we investigated the role of IRE1α-XBP1s pathway on modulation of TME dynamics in prostate cancer (PCa). We found that IRE1α is increased in PCa patients and genetic or pharmacological inhibition of IRE1α signaling in the immunocompetent syngeneic mouse PCa model dramatically reduced tumor growth. Multiomics analysis of tumor samples upon IRE1α deletion in cancer cells showed significantly potentiated interferon (IFN) response and activation of immune system related pathways in the TME. Single-cell RNA sequencing (scRNA-seq) analysis revealed that the abundance of immunosuppressive cells, such as tumor-associated macrophages (TAMs) and T regulatory cells were markedly reduced in the IRE1α deficient tumors. Analysis of differentially expressed genes in the annotated cell types in the TME demonstrated that expression signatures associated with IFN responses were significantly enriched in TAMs, cancer cells, and dendritic cells. In addition, a novel scRNA-seq derived TAM gene signature is strongly associated with poor PCa survival. Furthermore, IRE1α inhibition by the small molecule MKC8866 (ORIN1001) that is in clinical trials significantly enhanced anti-PD-1 checkpoint inhibitor therapy in mice. Our findings indicate that IRE1α not only promotes cancer cell growth and survival, but it also strongly inhibits anti-tumor immunity in the PCa TME.

Citation Format: Bilal Unal, Omer Faruk Kuzu, Yang Jin, Daniel Camilo Hurtado, Marieke Lydia Kuijjer, Mads Daugaard, Htoo Zarni Oo, John B. Patterson, Fahri Saatcioglu. Targeting IRE1α alleviates the immunosuppressive tumor microenvironment in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5362.