bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 7452: ApoE genotype influences susceptibility to doxorubicin-induced cognitive impairment in juvenile rats
Authors: Patel Chadni , Willekens Jeremy , Diglio Frank , Cole Peter
Published: March 2024

Many pediatric cancer survivors experience chemotherapy-induced cognitive impairment (CICI), which negatively impacts the quality of life. Despite extensive research into the multifactorial causes of CICI, there are no FDA approved drugs available to prevent it and the interpatient variability in susceptibility to CICI is not well understood. Among pediatric cancer survivors, those with the E4 allele of Apolipoprotein E (ApoE) are more likely to exhibit cognitive dysfunction than those with the more prevalent ApoE3 allele, suggesting the ApoE4 allele increases susceptibility to CICI. To mimic a curative pediatric treatment regimen, in our experimental model, five-week-old rats homozygous for either human ApoE3 or ApoE4 allele were treated with doxorubicin (DOXO) (2mg/kg/week for 4 weeks) or saline. ApoE4 rats were more likely than ApoE3 rats to exhibit DOXO-induced impairments in visual memory. However, there was no difference between ApoE3 and ApoE4 rats in sensitivity to DOXO-induced spatial memory impairments. Contrast-enhanced magnetic resonance imaging (MRI) was done to evaluate the blood-brain barrier (BBB) integrity because of literature suggesting that the ApoE4 allele contributes to BBB weakness. However, no significant difference was observed in the BBB integrity between ApoE3 and ApoE4 rats. To delve deeper into the neuropathological basis of DOXO-induced cognitive impairment on the ApoE4 allele, ongoing experiments involve immunohistochemical analyses targeting neurogenic changes in neural stem cell proliferation (DCX), neuronal maturation (Syn and PSD95), as well as glial differentiation (Iba1 and GFAP) in brain regions including hippocampus (dentate gyrus) and cortex. Additionally, to determine the effect of DOXO treatment on ApoE4, we are investigating the role of mitogen-activated protein kinase (MAPK) signaling pathways within brain regions pertinent to memory and recognition. In summary, ApoE genotype contributes to differential susceptibility to CICI.

Citation Format: Chadni Patel, Jeremy Willekens, Frank Diglio, Peter Cole. ApoE genotype influences susceptibility to doxorubicin-induced cognitive impairment in juvenile rats [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 7452.
Abstract 7476: Obtusifolin attenuates LPS-induced inflammation and NLRP3 inflammasome activation by suppressing the MAPK/NF-κB signaling pathway and ROS production in BV2 cells
Authors: Lin Hsin Yi , Lee Che-Hsin , Li Chia-Yang
Published: March 2024

Neuroinflammation, along with activation of microglia and oxidative stress, plays an important role in the development and progression of neurodegenerative diseases. During the inflammation process, immune cells release inflammatory mediators such as cytokines and chemicals that may promote the formation and growth of cancer cells. Obtusifolin, an anthraquinone extracted from the seeds of Senna obtusifolin, has anti-inflammatory properties. However, the effect of obtusifolin on neuroinflammation and its regulatory mechanism have not been yet investigated. In the present study, BV2 microglial cells were used to investigate the effects of obtusifolin on LPS-induced inflammatory responses, NLRP3 inflammasome activation, and reactive oxygen species (ROS) production. The secretion of nitric oxide (NO) was analyzed by Griess reagent assay, and the cell viability was detected by the CCK-8 assay. The expressions of iNOS, COX-2, STAT3, ERK, JNK, and p38 were examined using Western blotting, and the production of IL-6 and TNF-α was measured by ELISA. To examine whether obtusifolin affected NLRP3 inflammasome activation, BV2 cells were pretreated with LPS and then stimulated with ATP or nigericin. The secretion of IL-1β was measured by ELISA, whereas the expression of NLRP3 inflammasome-related proteins was detected using Western blotting. The production of ROS was analyzed by flow cytometry. Our experimental results showed that obtusifolin suppressed the production of NO and the secretion of proinflammatory cytokines by LPS-induced BV2 cells under noncytotoxic concentrations. In addition, obtusifolin decreased the expression of iNOS, COX-2, phospho-STAT3, phospho-ERK, phosphor-JNK and phospho-p38, and also attenuated the expression of NLRP3 and ASC, cleaved caspase-1 and cleaved IL-1β by LPS- induced BV2 cells. Moreover, obtusifolin reduced the production of both intracellular and mitochondrial ROS by LPS-induced BV2 cells. Overall, these results demonstrated that obtusifolin attenuated LPS-induced inflammation by suppressing the activation of MAPK and NF-κB signaling pathways, inhibiting NLRP3 inflammasome activation, and reducing the production of ROS in microglia, suggesting that obtusifolin might have benefits in the treatment of neurodegenerative diseases.

Citation Format: Hsin Yi Lin, Che-Hsin Lee, Chia-Yang Li. Obtusifolin attenuates LPS-induced inflammation and NLRP3 inflammasome activation by suppressing the MAPK/NF-κB signaling pathway and ROS production in BV2 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 7476.
Abstract 7497: Advancing multi-biomarker CTC assay and CDx development through the automated GenoCTC system
Authors: Chelakkot Chaithanya , Park Jieun , Kim Chae Rin , Lee Yeonu , Lee Yu Rim , Lee Saehyung , Choi Jun Young , Moon Young Ho , Choi Yoon-La , Shin Young Kee , Lee Hun Seok
Published: March 2024

Introduction: The successful outcomes observed in clinical trials emphasize the effectiveness of therapeutic approaches relying on biomarker tests, particularly in the development of cancer drugs. The parallel development of a drug and its associated predictive biomarker is considered an ideal strategy for achieving rapid and successful drug development in precision medicine. In this context, we employ an automated circulating tumor cell (CTC) isolation platform, known as GenoCTC, to facilitate the development of biomarker-driven CTC assays, with the ultimate goal of developing companion diagnostic (CDx) tests. Method: This study employed the 5th generation GenoCTC device, a fully automated system designed for marker-based CTC enrichment using immune magnetophoresis. We confirmed the isolation of CTCs through spiking tests, utilizing cancer biomarkers such as cMET, Mesothelin (MSLN), and Claudin 3 (CLDN3). cMET is a biomarker extensively studied in various cancers, particularly non-small cell lung cancer. We previously showed the prognostic significance of cMET expressing CTCs in HR+ and HER2- metastatic breast cancer patients. MSLN and CLDN3 are tumor-associated proteins showing overexpression across diverse cancer types, with a potential for the development of antibody-based cytotoxic drugs. The GenoCTC device allows efficient separation of CTCs expressing these biomarkers, ensuring high accuracy, precision, specificity, and sensitivity. Simultaneously, therapeutic drugs directed at these markers are progressing through phase trials or preclinical studies. Conclusion: Our results show that cMET, MSLN, and CLDN3 are potential markers for the development of biomarker tests, that can improve the patient selection process for personalized therapy targeting these biomarkers.

Citation Format: Chaithanya Chelakkot, Jieun Park, Chae Rin Kim, Yeonu Lee, Yu Rim Lee, Saehyung Lee, Jun Young Choi, Young Ho Moon, Yoon-La Choi, Young Kee Shin, Hun Seok Lee. Advancing multi-biomarker CTC assay and CDx development through the automated GenoCTC system [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 7497.
Abstract 7520: NRT-YHD_001, targeting CD47 for liver cancer immunotherapy
Authors: Nam Suk Woo , Kim Sangyean , Na Minjeong , Shin Eunbi , Ha Jin Woong , Jeon Soyoung , Yoon Sungpil
Published: March 2024

Previously, we demonstrated that recovery of histone deacetylase 6 (HDAC6) suppressed let-7i-5p expression to de-repress the thrombospondin-1 (TSP1) expression, and thereby it occupied CD47 receptor to block CD47-SIRPα mediated anti-phagocytosis of macrophage in liver cancer. NRT-YHD_001 is a modified antisense miRNA of let-7i-5p for liver cancer treatment. In addition, N-acetylgalactosamine was attached to NRT-YHD_001 for specific delivery to the liver. In vitro phagocytosis assay showed better macrophage phagocytosis activity than non-modified antisense let-7i-5p. To investigate the in vivo efficacy of NRT-YHD_001, spontaneous (Ras-transgenic) mouse liver cancer model was used and compared with that of sorafenib treatment. This mouse liver cancer model usually develops spontaneous liver cancer mass after 15 ~ 20 weeks of birth. We confirmed that both weekly i.v. injection of 1mg/kg and biweekly i.v. injection of 2mg/kg NRT-YHD_001 showed more significant therapeutic efficacy than the sorafenib-treated group. Furthermore, xenograft assay with Hep3B human liver cancer cells in athymic-nude mouse also showed that weekly i.v. injection of 1mg/kg NRT-YHD_001 exhibited better survival and tumor growth inhibition compared to non-treated group. In mouse and cynomolgus monkey maximum tolerated dose (MTD) studies, no toxicity of NRT-YHD_001 was found at doses up to 500 mg/kg intravenously. These results showed that NRT-YHD_001 had a robust anticancer effect by converting the macrophage of “don't eat me” into “eat me signal” in the tumor microenvironment of liver cancer, thereby removing or inhibiting liver cancer cells.

Keywords: let-7i-5p, macrophage, phagocytosis, liver cancer, CD47

Citation Format: Suk Woo Nam, Sangyean Kim, Minjeong Na, Eunbi Shin, Jin Woong Ha, Soyoung Jeon, Sungpil Yoon. NRT-YHD_001, targeting CD47 for liver cancer immunotherapy [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 7520.
Abstract 7546: Targeting NSD2 to reverse lineage plasticity and drug resistance in neuroendocrine prostate cancer and subtypes of mCRPC
Authors: Li Jia J. , Vasciaveo Alessandro , Karagiannis Dimitrios , Chen Xiao , Yu Chen , Califano Andrea , Lu Chao , Shen Michael M.
Published: March 2024

Treatment with highly potent anti-androgens, such as enzalutamide and abiraterone promotes lineage plasticity in metastatic castration-resistant prostate cancer (mCRPC), which results in intra-tumor heterogeneity and emergence of mCRPC subtypes. The histological transformation from adenocarcinoma to aggressive neuroendocrine prostate cancer (CRPC-NE) has been associated with a loss of dependency on lineage-survival signals, leading to targeted drug resistance. Epigenomic reprogramming might be a fundamental driver of lineage plasticity. To determine CRPC-NE vulnerabilities, we have performed image-based screening using a small library of antibodies targeting different histone marks on CRPC-NE organoids derived from genetically engineered mice. We find that the histone mark H3K36me2 and the histone methyltransferase NSD2 play important roles in maintain the CRPC-NE epigenetic state. Knockout of NSD2 or ablation of H3K36me2 using an oncohistone mutant H3.3K36M reverted CRPC-NE to an adenocarcinoma phenotype. Simultaneous profiling of the transcriptome and epigenome from single cells verified this lineage conversion and the generation of cell states with canonical AR signaling. Moreover, H3K36me2 or NSD2 depleted mouse and human CRPC-NE organoids responded to enzalutamide treatment in vitro and in vivo, suggesting a reversal of castration-resistance. Most importantly, a small molecule inhibitor of NSD2 in combination with enzalutamide leads to growth suppression or apoptosis of mouse and human CRPC-NE organoids, as well as organoids of other CRPC subtypes. In conclusion, inhibition of NSD2 reverts the epigenomic state of CRPC-NE, reversing lineage plasticity and restoring anti-androgen sensitivity. Thus, we suggest that the combination of NSD2 inhibition with AR inhibition may represent a novel therapeutic approach for patients with CRPC-NE or even other CRPC subtypes.

Citation Format: Jia J. Li, Alessandro Vasciaveo, Dimitrios Karagiannis, Xiao Chen, Chen Yu, Andrea Califano, Chao Lu, Michael M. Shen. Targeting NSD2 to reverse lineage plasticity and drug resistance in neuroendocrine prostate cancer and subtypes of mCRPC [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 7546.
Abstract 755: Fecal microbial dysbiosis is associated with colorectal cancer risk
Authors: Kim Jeongseon , Gunathilake Madhawa , Yeo Hyun Yang , Oh Jae Hwan , Kim Byung Chang , Han Nayoung , Kim Bun , Pyun Hyojin , Lim Mi Young , Nam Young-Do , Chang Hee Jin
Published: March 2024

Although there is evidence of an association between the fecal microbiota and colorectal cancer (CRC) risk in epidemiologic studies, there is a lack of data from large-scale population-based studies. To address this gap, we assessed the dysbiosis of the fecal microbiome in a large-scale study in Korea. We recruited 287 CRC patients from the Center for Colorectal Cancer, National Cancer Center Hospital, Korea to perform 16S rRNA gene sequencing of fecal samples. A total of 287 age- and sex-matched healthy participants were selected from 890 cohort of healthy Koreans that are publicly available (PRJEB33905). The microbial dysbiosis index (MDI) was calculated based on the differentially abundant species. The association between MDI and CRC risk was observed using conditional logistic regression. Alpha-diversity indices were not significantly different between CRC cases and controls. The first three principal coordinates derived by a principal coordinate analysis (PCoA) based on weighted UniFrac distance explained 41.24% of the overall microbial diversity, with a significant divergence of the microbial composition between CRC patients and controls (PERMANOVA p=0.001). Three enterotypes were found based on CRC patients’ microbial composition. Those who were in the third tertile of the MDI showed a significantly increased risk of CRC in the total population (OR: 6.59, 95% CI: 3.83-11.33, p-trend<0.001) compared to those in the lowest tertile. Similar results were found for men (OR: 6.58, 95% CI: 3.17-13.63, p-trend<0.001) and women (OR: 6.69, 95% CI: 2.91-15.37, p-trend<0.001). Dysbiosis in the fecal microbiota may be associated with an increased risk of CRC. Due to the potentially modifiable nature of the gut microbiota, our findings may have implications for CRC prevention among Koreans.

Key words: Fecal microbiome, 16S rRNA gene sequencing, Microbial dysbiosis, Colorectal cancer

Citation Format: Jeongseon Kim, Madhawa Gunathilake, Hyun Yang Yeo, Jae Hwan Oh, Byung Chang Kim, Nayoung Han, Bun Kim, Hyojin Pyun, Mi Young Lim, Young-Do Nam, Hee Jin Chang. Fecal microbial dysbiosis is associated with colorectal cancer risk [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 755.
Abstract 7659: AI-driven hypothesis-free analysis for biomarker discovery: Introducing the Biomarkers Navigator Framework
Authors: Kagiampakis Ioannis , Gidwani Mishka , Korkodinov Iaroslav , Ponomarev Georgiy , Jacob Etai
Published: March 2024

The pivotal role of biomarkers in personalizing patient treatment and guiding drug development is well-recognized, with the ultimate goal of enhancing therapeutic efficacy and patient quality of life by minimizing adverse events. Their development, however, is challenged by strict regulations and high costs, leading to sparse and varied data collected over extended periods and through diverse technologies. These variations complicate the harmonization and analysis of the data. Traditional methods struggle to navigate these complexities, further obscuring biomarker identification. For instance, PDL-1, approved as a biomarker by the FDA, has its effectiveness debated in several studies. To address these issues, we introduce Biomarkers Navigator, a flexible and automated analysis framework engineered explicitly for the robust identification of biomarkers. This framework is designed to aggregate, standardize, and store expansive biomarker information, ensuring efficient and traceable knowledge retrieval. By pre-calculating each potential biomarker, Biomarkers Navigator enables immediate and comprehensive meta-analyses, facilitating rapid decision-making tailored to the level of risk acceptance. Large Language Models (LLMs) further enhance the framework's capability to uncover signatures of response and resistance. LLM integration has accelerated the discovery of new potential biomarkers for hematological malignancies by combining prior knowledge and previously obscured associations. Our approach demonstrates the feasibility of large-scale hypothesis-free analysis and substantiates the utility of AI in unveiling hidden biological connections within clinical data. Our findings underscore the potential of AI-augmented frameworks in revolutionizing biomarker discovery and advancing personalized medicine.

Citation Format: Ioannis Kagiampakis, Mishka Gidwani, Iaroslav Korkodinov, Georgiy Ponomarev, Etai Jacob. AI-driven hypothesis-free analysis for biomarker discovery: Introducing the Biomarkers Navigator Framework [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 7659.
Abstract 7663: Identification of high-risk patients in multiple myeloma using a clonal gene signature
Authors: Li Jian-Rong , Wang Christiana , Cheng Chao
Published: March 2024

Introduction: Multiple myeloma (MM) is a heterogeneous disease with a small subset of high-risk patients associated with poor prognosis. The identification of these patients is crucial for treatment management and strategic decisions.

Methods: We developed a novel computational framework that only requires gene expression profiles to define prognostic gene signatures by selecting genes with expression driven by inferred clonal copy number alterations. We applied this framework to MM and developed a clonal gene signature (CGS) consisting of only 22 genes. This prognostic signature was evaluated in 5 independent datasets with gene expression data of a total of 2,155 MM samples. For each patient, we calculated a prognostic score based on the expression of the signature genes. Multivariate Cox regression analyses were performed to investigate the association of these signature scores with patient prognosis after adjusting established clinical factors. The performances of CGS and the only commercialized MM gene signatures, GEP70 and SKY92, in identifying high-risk patients were carefully compared by multiple different approaches.

Results: Our results indicated that CGS provided significant prognostic values after adjusting for well-established prognostic factors including cytogenetic abnormalities, International Staging System (ISS), and Revised ISS (R-ISS). In addition, it showed significant prognostic associations in patient subsets stratified by these conventional prognostic factors. Importantly, CGS demonstrated a better performance in identifying high-risk patients compared to the GEP70 and SKY92 signatures, which have been recommended for prognostic stratification in MM. Moreover, CGS can further stratify patients into subgroups with significantly differential prognoses when applied to the high-risk and low-risk groups already identified by GEP70 and SKY92. The higher CGS score of patients is significantly associated with poor response to dexamethasone, a commonly used drug for MM treatment.

Conclusions: In summary, we proposed a computational framework that only requires gene expression data to identify clonal gene signatures for prognosis prediction. The CGS provides a useful biomarker for improving prognostic stratification in MM, especially for the identification of patients with the highest risk. The computational framework used for defining this signature provides a useful tool, which can be readily applied to many other cancer types.

Citation Format: Jian-Rong Li, Christiana Wang, Chao Cheng. Identification of high-risk patients in multiple myeloma using a clonal gene signature [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 7663.
Abstract 767: The role of abdominal obesity in the association between obesity and prostate cancer: A U.S. population-based cross-sectional study NHANES 2001-2020
Authors: Ahmed Anwar E. , Martin Callista B. , Dahman Bassam , Kern Sean Q. , Chesnut Gregory T.
Published: March 2024

Background: Research suggests inconsistent evidence regarding the association between general obesity and prostate cancer among men in the United States. This study aimed to examine whether the association between general obesity and prostate cancer is influenced by abdominal obesity.

Methods: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), 2001-2020, a nationally representative survey. The analysis was restricted to 16,703 non-Hispanic men (10,683 White and 6,020 Black). General obesity was defined by a body mass index of 30 kg/m2 or greater and abdominal obesity was defined by a waist circumference of 102 cm or greater. Respondents were classified into four mutually exclusive groups according to the body fat indicators: 1) presence of both general and abdominal obesity, 2) abdominal obesity without general obesity, 3) general obesity without abdominal obesity, and 4) none of the two (the reference group).

Results: The overall prevalence of prostate cancer was 2.25% (95% CI: 2.0-2.5%). Men with abdominal obesity without general obesity have significantly higher prevalence of prostate cancer (4.28%) compared to men with both abdominal obesity and general obesity (2.23%), men with neither abdominal obesity or general obesity (1.70%), and men with general obesity without abdominal obesity (0.18%), P <.0001. Black men with abdominal obesity without general obesity have the highest prevalence of prostate cancer (7.21%), followed by White men with abdominal obesity without general obesity (4.10%). With and without adjusting for age and education, men with abdominal obesity without general obesity had significantly higher odds of prostate cancer, regardless of ethnicity. Black men with both abdominal obesity and general obesity had significantly higher odds of prostate cancer. General obesity without abdominal obesity was inversely associated with prostate cancer in White men but not in Black men.

Conclusions: This study illustrates that waist circumference is a potential classifier of prostate cancer as it shows variation in prevalence of prostate cancer by general obesity within the same and different racial and ethnic groups.

Citation Format: Anwar E. Ahmed, Callista B. Martin, Bassam Dahman, Sean Q. Kern, Gregory T. Chesnut. The role of abdominal obesity in the association between obesity and prostate cancer: A U.S. population-based cross-sectional study NHANES 2001-2020 [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 767.
Abstract 770: The innate immune system response to malignancy- under the radar
Authors: Tobi Martin , Talwar Harvinder , McVicker Benita
Published: March 2024

It has become clear that many cancers evade detection by, for example, silencing of immune checkpoints. Re-activation of the immune armamentarium by checkpoint inhibitors has improved survival in many types of cancer. However, we still are unable to gauge the response of the innate immune system (InImS) to incipient malignancy. The InImS is likely both a sentient early warning system and an immediately deployed cancer combatant. We describe a potential marker that quantifies the innate immune system response to multiple deadly tumors. Methods: We obtained a database of patients at high risk of colorectal neoplasia and prospectively noted those who contracted cancer on follow up. We contrasted the historic, premorbid biomarker response from the time of enrolment, primarily using the FERAD ratio. This was obtained by dividing the ferritin blood concentration by the denominator of fecal shedding of a Paneth cell marker, p87. We also compared the FERAD response to the absolute neutrophil:lymphocyte ratio (NLR), a known prognostic biomarker, and also the available, known PDL-1 response for each group of cancers. Results: We found that certain groups of cancers historically had very low FERAD ratios while others were high. Using FERAD ratios for lung, gastric, non-Hodgkin’s lymphoma, melanoma, thyroid, renal, and head and neck cancers, there is a significant inverse correlation between survival and FERAD (r=-0.8;p<0.025) which is similar to that of NLR (r=-0.7;p<0.035). For prostate cancer, breast, colorectal cancer (CRC), leukemia/MDS, there is a direct correlation between survival and FERAD (r=0.99;p<0.002). There is also an inverse relationship between NLR and PDL-1 response rates (r=-0.8;p<0.04). An observed mild positive trend for FERAD PDL-1 response rates may bode well for melanoma, lung, head and neck and renal cancers. Conclusions: Since p87 could be manipulated by dietary means to affect the FERAD ratio favorably, this could be incorporated into more effective chemotherapy regimens and result in better cancer treatment outcomes. Hepatocellular cancer (HCC) and CRC-liver metastasis appear to be immunological outliers. This will need an additional unique approach such as TIGIT intervention therapy (Zheng et al.. Immune checkpoint targeting TIGIT in HCC. Am J Transl Res. 2020). This may allow modulation of the immune response based on FERAD, NLR ratios, and other considerations of mutational burden and genetic mutations, in patients with selected cancers.

Citation Format: Martin Tobi, Harvinder Talwar, Benita McVicker. The innate immune system response to malignancy- under the radar [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 770.
Abstract 777: Notch signaling dependent chemoresistance in racial disparity in ER+ breast cancer
Authors: Singh Shailesh , Das Megha , Chakrabarti Rumela
Published: March 2024

Breast cancer (BCa) is the leading cause of cancer related death in women worldwide. The most common BCa subtype is the Estrogen/Progesterone receptor (ER+/PR+) luminal subtype, comprising up to 75% of all newly diagnosed BCa. Although these patients show initial benefit with chemotherapy and endocrine therapy, however, 40-50% of them eventually don’t respond to treatment due to resistance. Thus, the need for additional targeted therapies for this large subset of ER+ BCa patients is critical. Based on recent studies, it is observed that Afro-American (AA) patients experience substantially higher BCa mortality (40% more) than White American (WA) women in ER+ breast cancer. Unfortunately, the cause behind this difference in mortality in AA patients is not well understood. Notch signaling is a highly conserved intercellular communication mechanism critical for many cellular processes and is composed of several receptors and ligands. Recent data show that Notch receptors are overexpressed in hormone treatment refractory ER− patients of (Afro-American) AA origin, hinting connection of Notch signaling to racial disparity in breast cancer. Notch signaling is also identified in several metabolic disorders involving fatty acids and other lipids. However, function of Notch signaling in context of chemoresistance in AA ER+ breast cancer is still unknown. Using single cell sequencing, we found that chemo-resistant AA ER+ breast cancer patient samples have a distinct Notch signature enriched subpopulations in tumor cells, which was missing in WA patients. Notch signaling happens through juxtacrine signaling of ligand/receptor signaling. Further analysis in tumor microenvironment shows lipid enriched tumor associated macrophages, which are Notch dependent, suggesting potential crosstalk between lipid heavy tumor-macrophages and tumor cells, which may drive the chemoresistance in AA patients. Further analysis using patient derived explants, an attractive new tool for drug efficacy testing in ex vivo, we found that chemotherapy itself increases Notch signaling in the tumors. Ongoing studies involving scRNAseq, untargeted lipidomics and chemo-resistant PDE will delineate the precise mechanism of action between tumor cells and tumor associated lipid heavy macrophages in context of Notch signaling in chemo-resistant AA ER+ breast cancer.

Citation Format: Shailesh Singh, Megha Das, Rumela Chakrabarti. Notch signaling dependent chemoresistance in racial disparity in ER+ breast 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 777.
Abstract 842: Maize consumption and circulating aflatoxin B1 levels in Mexican adults
Authors: Lajous Martin , Solis-Martinez Obed , Monge Adriana , Groopman John , McGlynn Katherine A. , Romero Martin , Batis Carolina , Lamadrid-Figeuroa Hector , Riojas-Rodriguez Horacio
Published: March 2024

Objective: To estimate the impact of maize consumption on aflatoxin B1 [AFB1] levels, a potent carcinogen, in Mexican adults living in south and eastern Mexico.

Methods: Study participants were women and men ≥40 years of age living in five high hepatocellular carcinoma burden states who participated in Mexico’s 2018 National Health and Nutrition Survey, a stratified, multi-stage, and cluster survey probability sampling household survey that is representative of the Mexican population. We estimated the consumption of maize intake in grams per day using a previously validated semi-quantitative food frequency questionnaire with a time reference of the previous seven days. We determined circulating AFB1-albumin lysine adduct [AFB1-lys] levels in serum using liquid chromatography. Guided by subject-matter knowledge we fit multivariable linear regression models that considered the survey design and included age, sex, residence, ethnicity, education, socioeconomic status, and foods known to be contaminated with aflatoxins including peanuts, rice, dried chili, milk, and cheese.

Results: Among the 915 participants, median maize consumption was 307 grams per day [Q1-Q3: 165 - 554]. Maize tortillas contributed 80% of the total maize consumption. The median maize tortillas consumption was 252 grams per day [Q1-Q3: 120 - 462], approximately 8 tortillas per day. Prevalence of AFB1-lys detection was 92% and median levels were 0.127 pg/µL [Q1-Q3: 0.052 - 0.449]. After adjusting for factors that may affect aflatoxin levels, for every 100 grams of maize consumption AFB1-lys levels were 7.4% [β: 0.071, 95% CI: 0.030 - 0.112] higher. And for every tortilla consumed [30 g of maize], we observed a 2.0% [β: 0.020, 95% CI: 0.006 - 0.034] higher level of circulating AFB1-lys.

Conclusion: These findings indicate that maize and maize tortillas may be an important source of AFB1 exposure in the Mexican population. Mexico requires effective public health interventions to mitigate exposure to AFB1.

Citation Format: Martin Lajous, Obed Solis-Martinez, Adriana Monge, John Groopman, Katherine A. McGlynn, Martin Romero, Carolina Batis, Hector Lamadrid-Figeuroa, Horacio Riojas-Rodriguez. Maize consumption and circulating aflatoxin B1 levels in Mexican adults [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 842.
Abstract 85: Immunomics of immune-deficient mouse models before and after CD34 humanization
Authors: Luche Hervé , Hadjem Lilia , Mello Marielle , Canavese Priscilla , Angelis Fabien , Joachim Anais , Bouilly Sylvie , Guinut Frédéric , Fiore Frederic , Malissen Bernard , Zarubica Ana , Corcuff Erwan
Published: March 2024

Preclinical tumor oncology research relies historically on the analysis of mouse or human tumor cell lines implanted onto severely immune-deficient mouse models carrying nude, SCID or Rag mutations on different genetical background (C57Bl/6N, BalbC, NMRI, CB17 or NOD). These lines harbor defects in several leukocyte lineages among which Tc, Bc and NKc might be affected. Humanized mice are emerging models that have been transplanted with human cells or tissues (and/or equipped with human transgenes). Currently, the most advanced strains are the nonobese diabetic, severe combined immunodeficiency (NOD-SCID) mouse with complete disruptions in the interleukin-2 (IL-2) common γ-chain (IL2R γ null) receptor (NSG) and BALB/c Rag2−/− IL2R γ null SirpaNOD mice (BRGS).1 Neonate or juvenile chimera are reconstituted in NSG, BRGS or B6 RGS with CD34+ hematopoietic progenitor cell (HPCs) from human cord blood yielding robust engraftment of a human immune system (HIS).. We genetically modified the mouse genome introducing mutations involved in Tc, Bc and NKc development. We then immuno-phenotyped over 23 lines of mouse mutants produced from the same animal house to minimize the impact of microbiota on innate immune cell populations. High content cytometry analysis of several organs was performed in a standardized manner before and after humanization. The resource obtained of these immunotypes was used to highlight similarities and differences among these lines across several genetical background and will help in selecting the most appropriate model to use for tumor implantation and CD34 or PBMC humanization.

Citation Format: Hervé Luche, Lilia Hadjem, Marielle Mello, Priscilla Canavese, Fabien Angelis, Anais Joachim, Sylvie Bouilly, Frédéric Guinut, Frederic Fiore, Bernard Malissen, Ana Zarubica, Erwan Corcuff. Immunomics of immune-deficient mouse models before and after CD34 humanization [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 85.
Abstract 852: Measuring the level of knowledge and awareness about radon in Northeast Tennessee
Authors: Al ksir Kawther , Stanifer Stacy , Quinn Megan , Mamudu Hadii , Slawson Deborah
Published: March 2024

Introduction: Radon, a radioactive gas found in soil and rocks, is the second leading cause of lung cancer in the United States (1). Despite its significant health risks, radon awareness and knowledge remain low (2). In Tennessee, where geological factors contribute to elevated radon levels, understanding the levels of awareness and knowledge about radon is crucial (3). This study focuses on Northeast Tennessee, an area known for its high radon concentrations.

Methods: This cross-sectional study, conducted from September to November 2023, aims to assess radon awareness and knowledge among participants from seven Northeast Tennessee health councils. These councils play a critical role in public health initiatives and provide access to individuals actively involved in health-related discussions. A convenience sample of 150 participants was chosen from an email listserv of 650 health council members. Participants, aged 18 or older, affiliated with the health councils in the study area, and physically present in the US, were eligible to participate. Demographic data, radon knowledge and awareness were assessed. Additional questions evaluated information sources, concern levels, and willingness to inform the community about radon.

Conclusion: This research addresses a significant knowledge gap regarding radon awareness and knowledge in Northeast Tennessee, an area with unique geological factors that elevate radon exposure risks. The study's findings will contribute to the development of targeted educational campaigns and interventions, ultimately promoting awareness and proactive measures to mitigate radon exposure in the region. With the potential to inform policy and public health efforts, this study holds the promise of reducing the health risks associated with radon in Northeast Tennessee.

Citation Format: Kawther Al ksir, Stacy Stanifer, Megan Quinn, Hadii Mamudu, Deborah Slawson. Measuring the level of knowledge and awareness about radon in Northeast Tennessee [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 852.
Abstract 858: A functional atlas of cancer mutation-rewired protein interactome networks
Authors: Agrawal Anjali , McGrail Daniel , Sahni Nidhi , Yi S. Stephen
Published: March 2024

Somatic mutations in cancer can exert effects on protein-protein interactions (PPIs), leaving some wild-type (WT) interactions perturbed while others unperturbed. The type of PPI perturbations can be used to link the mutation to its phenotypic effects. Here, we apply a technique known as functional variomics to characterize PPI profile changes for around 1,000 cancer missense mutations. Remarkably, our results reveal 5 distinct classes (edgotypes) of mutations: mutations losing PPIs compared to WT (edgetic), gaining PPIs (gain), gaining & losing PPIs (gain/loss), losing all PPIs (quasi-null), and those that do not perturb PPIs (quasi-WT). Notably, gastroenterological cancers have a greater proportion of edgetic mutations, whereas reproductive cancers have a greater proportion of gain edgotype mutations, demonstrating the link between edgotype and cancer type. We further show that more severe cancer stages are associated with interaction-perturbing mutation edgotypes, and the gain/loss edgotype is the most deleterious of all. In addition, pathway enrichment analysis suggests that the edgotypes are predictive of biological effects. For example, mutation edgotypes with loss of interactions are involved in apoptotic process and DNA damage repair, consistent with the expected loss of such functions in cancer. Meanwhile, gain edgotype is linked with cell division and G2/M transition. To our knowledge, this represents the first attempt to perform systematic interactome profiling for cancer mutations. As our results can reveal specific phenotypic attributes and biological functions that are altered for different PPI profiles, our functional platform is important for cancer precision medicine. Our study strengthens the link between genotypes and phenotypes while illustrating the significance of edgotypes in complex disease modeling.

Citation Format: Anjali Agrawal, Daniel McGrail, Nidhi Sahni, S. Stephen Yi. A functional atlas of cancer mutation-rewired protein interactome networks [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 858.
Abstract 897: Synthetic lethality screening with Recursive Feature Machines
Authors: Radhakrishnan Adityanarayanan , Cai Cathy , Weir Barbara A. , Moy Christopher , Uhler Caroline
Published: March 2024

Synthetic lethality refers to the concept that simultaneous perturbation of gene pairs leads to cell death but individual perturbation does not. Synthetically lethal gene pairs (SL pairs) provide a potential avenue for selective targeting of cancer cells based on underlying genetic vulnerabilities. The rise of large scale gene perturbation screens such as the Cancer Dependency Map (DepMap) offers the opportunity to identify SL pairs automatically using machine learning. Yet, a key difficulty in using machine learning models for this task is the lack of labeled data in the form of known SL pairs. Thus, prior approaches framed SL pair identification as a feature learning problem where the goal is to identify the genomic features most influential for predicting low cellular viability under a gene knockout. These prior approaches have primarily utilized random forests since these machine learning models are one of the only nonlinear models for which feature importances are provided explicitly. On the other hand, if we could identify features learned by state-of-the-art models on screening tasks such as kernel machines, we would be better powered in finding SL pairs. In this work, we present a computationally efficient and effective pipeline for SL pair screening built on a recently developed class of feature learning kernel machines known as Recursive Feature Machines (RFMs). We show that our pipeline more accurately recovers experimentally verified SL pairs than prior work including the best model from the DepMap portal and previous random forest based approaches (see the table below). Moreover, our pipeline identifies several new candidate SL pairs for further analysis, opening new avenues for targeting genetic vulnerabilities in cancer.

Rank of verified SL pairs across unsupervised methods (lower is better with a minimum value of 1). Experimentally Verified SL Pairs Pearson Correlation PARIS DepMap RFMs (Ours) SMARCA2/SMARCA4 1 1 1 1 ARID1A/ARID1B 1 1 1 1 STAG1/STAG2 1 1 1 1 CREBBP/EP300 1 1 1 1 VPS4A/VPS4B 7 > 10 5 1 DDX17/DDX5 4 1 1 1 ENO1/ENO2 > 10 1 1 1 SMARCC1/SMARCC2 > 10 1 1 1 UBB/UBC > 10 1 > 10 1 MAGOH/MAGOHB 1 1 1 1 FAM50A/FAM50B 1 1 1 1

Citation Format: Adityanarayanan Radhakrishnan, Cathy Cai, Barbara A. Weir, Christopher Moy, Caroline Uhler. Synthetic lethality screening with Recursive Feature Machines [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 897.
Abstract 90: In vitro functional evaluation of immuno-oncology drug candidates in customized bioassays
Authors: Vlaming Martijn , Sidot Emmanuelle , Lefèvre Jezabel , Boelen Ellen , Pattyn Sofie
Published: March 2024

Increased understanding of the complex tumor microenvironment and its interactors has boosted therapeutic interest and highlighted the importance of the development of innovative in vitro bioassays to represent all the players of the cancer immune response and thereby potentially provide pivotal information on the functional dynamics of candidate therapeutics. Regulatory T cells play an important role by downregulating the anti-tumor response. Their regulation mechanisms constitute an important target for new therapeutics. To study these mechanisms in a human model, suppressive Treg bioassays, mimicking the suppressive action of these cells, were developed and optimized. We further highlight the study of neutrophil function in vitro using flow-cytometry or the Incucyte® live imaging system to monitor neutrophil functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), Neutrophil Extracellular Traps (NETs) formation and the release of Reactive Oxygen Species (ROS). Additionally, multiplex cytokine and peroxidase enzyme analysis after activation and stimulation of neutrophils can be evaluated using ELISA or Luminex technology. Moreover, to refine/reduce non-human primate (NHP) usage, we aimed to develop cost-effective NHP in vitro assays with predictive value for in vivo studies. We isolated Cynomolgus Macaque monocytes and successfully differentiated/polarized them into M0- and M2-like macrophages with a cell surface phenotype comparable to that of their human counterparts. We further developed a Cynomolgus Macaque PBMC x human dendritic cell (DC) mixed lymphocyte reaction (MLR) assay for functional evaluation of test compounds, effectively generated Cynomolgus Macaque immature DCs and implemented Cynomolgus Macaque cytokine release assays.Using high quality primary human immune cells from our own biobank, in vitro bioassays have been developed with superior robustness and reproducibility to screen candidate Immuno-Oncology therapeutics.

Citation Format: Martijn Vlaming, Emmanuelle Sidot, Jezabel Lefèvre, Ellen Boelen, Sofie Pattyn. In vitro functional evaluation of immuno-oncology drug candidates in customized bioassays [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 90.
Abstract 91: Comprehensive 27-marker standard panel for immune monitoring of pre-clinical tumor mouse models using spectral analyzer technology
Authors: Hummel Jonas F. , Metzger Philipp , Sonntag Roland , Borrero-Wolff Dennis , Obodozie Cynthia , Weber Holger
Published: March 2024

Within the last decade, major technological advances in flow cytometry and (single cell) RNA-sequencing have deepened our understanding of complex anti-tumoral immune responses. This allows a comprehensive immune monitoring of novel therapies in pre-clinical models.

Conventional flow cytometry is reaching its technical limitation. The emitted fluorescence signal of the target population stained with antibodies is evaluated with simple bandpass filters, which leads to spectral overlap and thus the number of parameters that can be analyzed simultaneously is limited. The spectral analyzer technology combines both methods, providing great flexibility in evaluating different immune cell populations. This provides the opportunity to obtain target information by measuring the entire fluorescence spectrum measuring each wavelength individually and thus evaluating the true signal of each fluorochrome unaffected by autofluorescence or spillover.

Our standard all-in-one flow cytometry panel uses the full capacity of a conventional BD Fortessa flow cytometer and enables the differentiation of important immune cell populations in tumors, such as T cells (CD4+, CD8+, regulatory T cells), B and NK cells as well as macrophages (M1/M2), MDSCs (granulocytes and monocytes) and dendritic cells. However, it would be of great advantage to gain further insights into activation and effector functions of the immune cells using markers like CD44 & CD62L, CD69, PD-1, Lag-3, Tim-3 and PDL-1, CD80, CD86, CD40 and Ki-67. The Sony ID7000 spectral analyzer enables the simultaneous assessment of 27 markers to evaluate immune phenotypes, with the ability to include up to 4 individual target antibodies.

Flow cytometry data from various tumor models are presented, demonstrating the enormous utility and potential of the spectral analyzer, especially with limited and precious tumor sample material, by evaluating different immune cell populations simultaneously without reaching its technical limits. The spectral analyzer technology enables us to mechanistically investigate differences in tumor therapies such as PD-1 treatment or other immune cell modulators not only phenotypically but also with regard to activation and differentiation of immune cell populations.

Citation Format: Jonas F. Hummel, Philipp Metzger, Roland Sonntag, Dennis Borrero-Wolff, Cynthia Obodozie, Holger Weber. Comprehensive 27-marker standard panel for immune monitoring of pre-clinical tumor mouse models using spectral analyzer technology [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 91.