bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 6082: Rapid on-site nucleic acid detection using CRISPR and digital signal processing for portable and integrated cervical cancer screening in low resource settings
Authors: Lee Chang Yeol , Kim Hyunho , Lee Hanna , Randall Thomas , Ly Amy , Lee Hakho , Castro Cesar M.
Published: March 2024

Addressing the global disparity in cancer care necessitates the development of rapid and affordable nucleic acid (NA) testing technologies. This need is particularly critical for cervical cancer. Molecular detection of human papillomavirus (HPV) has emerged as a highly accurate screening method, surpassing traditional Pap smears. However, implementing this transition in low- and middle-income countries has been challenging due to the high costs and centralized facilities required for current NA tests. Here, we present CreDiT (CRISPR Enhanced Digital Testing), an advanced diagnostic system for rapid, on-site NA detection. CreDiT integrates two major technical breakthroughs: i) a one-pot CRISPR strategy that simultaneously amplifies both target NAs and analytical signals, and ii) a robust fluorescent detection method based on digital communication (encoding/decoding) technology. These innovations enhance CreDiT's practical utility, offering a rapid assay (<35 minutes) that integrates NA extraction and detection in a single streamlined workflow. Furthermore, CreDiT's straightforward probe design enables easy incorporation of new NA targets, while its compact device provides robust signal detection. We adapted CreDiT for point-of-care HPV screening by designing probes for high-risk HPV genes (HPV16, HPV18, HPV45, HPV31, HPV33, HPV58) and oncoprotein mRNAs (E6, E7, p16INK4a) and developing a portable CreDiT device capable of processing 12 samples. CreDiT demonstrated sensitive detection of cell-derived HPV DNA targets down to single copies and accurately identified HPV types in every clinical cervical brushing specimen (n = 121) we tested. This technology has the potential to facilitate prompt and reliable triaging of high-risk HPV, overcoming pathology bottlenecks and circumventing geographical and socioeconomic barriers to effective cervical cancer screening in resource-limited regions. This work has spearheaded recent screening research efforts in Uganda and Ghana.

Citation Format: Chang Yeol Lee, Hyunho Kim, Hanna Lee, Thomas Randall, Amy Ly, Hakho Lee, Cesar M. Castro. Rapid on-site nucleic acid detection using CRISPR and digital signal processing for portable and integrated cervical cancer screening in low resource settings [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 6082.
Abstract 6096: Targeting premalignant lung cancer to intercept progression to invasive disease
Authors: Martin Mitchell , He Yongfeng , Bhinder Bhavneet , Yoffe Liron , Zhong Sijin Luo , Singh Arshdeep , Elemento Olivier , Jiang Shaoyi , Altorki Nasser , Mittal Vivek
Published: March 2024

Increased implementation of low dose CT-guided screens in the clinic has led to the identification of premalignant lung nodules (ground glass opacity, GGO) which progress to invasive adenocarcinoma1,2. Using integrated genomic analysis of a cohort of >300 patients with premalignant lesions, we constructed the first high-resolution landscape of composition, lineage/functional states, developmental trajectories, and multicellular crosstalk networks, which revealed potential targets for therapeutic intervention. We uncovered that early lesions exhibit marked immune-suppressive phenotypes characterized by increased T lymphocyte exhaustion to cytotoxic scores, decrease in NKT cells, elevated Tregs, increased myeloid suppressor activity, accumulation of immunosuppressive myeloid cells activation of unfolded protein response (UPR) sensor IRE1α that activates the multitasking transcription factor XBP1 known to drive malignant progression. Targeting IRE1α endoribouclease with a small molecule drug limited disease progression with marked immunomodulation in our newly developed Kras and EGFR driven mouse models, which mirror progression of human precursor lesions to invasive disease. As an immunoprevention approach, we have generated LNP-mRNA vaccines targeting top two shared neoantigens in premalignant lesions, which have shown marked immunogenicity and efficacy in early disease. Our work provides the molecular foundation for precision oncology strategies to intercept transition of preinvasive to invasive adenocarcinoma. 1. Altorki, N.K., et al. Nat Rev Cancer, 2019. 2. Altorki, N.K., et al. Cell Rep, 2022.

Citation Format: Mitchell Martin, Yongfeng He, Bhavneet Bhinder, Liron Yoffe, Sijin Luo Zhong, Arshdeep Singh, Olivier Elemento, Shaoyi Jiang, Nasser Altorki, Vivek Mittal. Targeting premalignant lung cancer to intercept progression to invasive disease [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 6096.
Abstract 6114: Trends in hematological cancer subtype mortality by educational attainment and sex in the United States, 2000-2020
Authors: Marlow Emily C. , Islami Farhad , Jemal Ahmedin
Published: March 2024

Objective: To examine mortality trends for hematological cancer subtypes (leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and myeloma) by educational attainment and sex in the United States.

Methods: Using data on 1,082,234 U.S. deaths from 2000-2020, age-standardized death rates were calculated by sex and educational attainment (high school/GED or less, some college, and 4 years of college or more). Annual percentage change (APC) and 95% confidence intervals (CI) for mortality rates were generated using Joinpoint regression.

Results: For all hematological cancer subtypes, mortality rates were largest among males and those with the least education for all study years. In general, decreasing trends were observed in recent years for non-Hodgkin’s lymphoma, myeloma, and leukemia mortality rates. Non-Hodgkin’s lymphoma mortality rates, for example, decreased among males and females in 2009-2020 (APC: -2.0%; 95%CI: -2.4%, -1.5% and APC: -2.8%; 95%CI -3.2%, -2.3%). As another example, non-Hodgkin’s lymphoma mortality rates among most educated males decreased in 2000-2012 (APC: -1.8%; 95%CI: -2.2%, -1.3%) followed by a steeper decline in 2012-2020 (APC: -3.7%; 95%CI: -4.4%, -2.9%); a similar pattern was observed among most educated females (APC: -1.6%; 95%CI: -2.2%, -1.0% in 2000-2011 and APC: -4.1%; 95%CI: -4.9%, -3.4% in 2011-2020). Trends in Hodgkin’s lymphoma death rates however differed by educational attainment. For example, mortality rates among least educated males increased in 2000-2009 (APC: 1.7%; 95%CI: 0.8%, 2.5%) and remained unchanged in 2009-2020 (APC: -0.3%; 95%CI: -0.9%, 0.3%). Rates among least educated females also increased in 2000-2020 (APC: 0.4%; 95%CI: 0.1%, 0.7%). In contrast, mortality rates declined for most educated males from 2010-2020 (APC: -1.9%; 95%CI: -2.6%, -1.2%) and most educated females from 2011-2020 (APC: -3.5%; 95%CI: -4.8%, -2.2%).

Conclusion: Hematological cancer mortality rates were highest among males and those with least education. In general, mortality rates have declined in recent years for non-Hodgkin’s lymphoma, myeloma, and leukemia for males and females among all educational attainment groups, while Hodgkin’s lymphoma has shown a slight increasing trend among least educated males and females.

Citation Format: Emily C. Marlow, Farhad Islami, Ahmedin Jemal. Trends in hematological cancer subtype mortality by educational attainment and sex in the United States, 2000-2020 [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 6114.
Abstract 6118: Sex-related disparity in immune checkpoint inhibitor benefit for patients with esophageal squamous cell carcinoma: A systematic review and meta-analysis
Authors: Zhang Chaoqi , Wu Peng , Liu Jingjing , Li Dongyu , Sun Nan , He Jie
Published: March 2024

Sex-related dimorphism in cancer incidence and immune response is widely recognized, yet the impact of an individual's sex on the effectiveness of Immune Checkpoint Inhibitors (ICIs) for patients with advanced esophageal squamous cell carcinoma (ESCC) remains poorly understood. In this study, we conducted a comprehensive meta-analysis to evaluate the heterogeneity of ICIs in patients with advanced ESCC. We collected studies from PubMed, MEDLINE, Embase, and Scopus, spanning from the inception of the databases to September 30, 2023. These studies focused on phase III randomized trials comparing first-line ICIs (PD-1/PD-L1) plus chemotherapy with chemotherapy alone for advanced or metastatic ESCC. Additionally, we reviewed abstracts and presentations from AACR, ASCO, ESMO, and WCLC. Inclusion criteria mandated the reporting of overall survival (OS) data stratified by sex and nonselective baseline PD-L1 expression. The study adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The analysis included 6 randomized clinical trials comprising 3603 ESCC patients, of whom 3090 (85.8%) were male and 513 (14.2%) were female. A significant OS benefit was observed for ICIs plus chemotherapy in all patients (HR, 0.68; 95% CI, 0.62-0.74; P < 0.001). Similarly, ICIs plus chemotherapy correlated with a significantly prolonged OS in males (HR, 0.67; 95% CI, 0.61-0.74, P < 0.001). However, there was no significant OS benefit observed in females with ICIs plus chemotherapy (HR, 0.79; 95% CI, 0.58-1.09; P = 0.148). Females had a tendency toward less benefit than males (pooled HR, 1.18; 95% CI, 0.89-1.57; P = 0.245). Our findings suggest that there is no statistically significant association between patient sex and the efficacy of ICIs for ESCC patients. Importantly, we report, for the first time, a lack of survival benefit with the ICI plus chemotherapy regimen in the first-line setting compared to chemotherapy alone in female ESCC patients.

Citation Format: Chaoqi Zhang, Peng Wu, Jingjing Liu, Dongyu Li, Nan Sun, Jie He. Sex-related disparity in immune checkpoint inhibitor benefit for patients with esophageal squamous cell carcinoma: A systematic review and meta-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 6118.
Abstract 6132: Exploring genomic complexity in lung cancer at the Tijuana/California border: A real-world perspective through liquid biopsy comprehensive genomic profiling
Authors: Guadarrama-Orozco Jorge Alberto , Ramirez-Puente Jennifer , Dominguez-Gonzalez Elizabeth
Published: March 2024

Objective: This study explores the application of liquid biopsy with next-generation sequencing (NGS) in profiling the genomic landscape of lung cancer patients from the Tijuana/California Border region. Specifically, we employ blood-based comprehensive genomic profiling (CGP) to assess the complexity of the genomic profile in these patients.

Materials and Methods: From April 2019 to November 2023, 37 lung cancer patients from Tijuana underwent profiling using the FoundationOne®Liquid CDx (F1LCDx®) assay, focusing on circulating tumor DNA (ctDNA). The assay, which spans 324 cancer-related genes and genomic signatures, provides insights into tumor fraction (TF) and blood-based tumor mutational burden (bTMB). Variants were classified based on the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT).

Results: A notable 88.6% of patients exhibited at least one detectable alteration in plasma. The most frequently mutated genes were TP53 (51.3%), EGFR (16.2%), DNMT3A (13.5%), and KRAS (10.8%). Tumor mutational burden (TMB) was assessable in 9 out of 37 patients, with values ranging from 0 to 10 mut/Mb. According to ESCAT classification, 63.1% of samples revealed potentially actionable alterations (Tier I-II), while an additional 24.1% harbored alterations for which approved drugs are available in other cancer types (Tier III).

Conclusion: Liquid biopsy NGS emerges as a viable and valuable strategy for guiding personalized therapy. Given restricted accessibility to new drugs or clinical trials in Mexico, the use of blood-based CGP may enhance the identification of druggable alterations, thereby increasing the likelihood of accessing targeted drugs or enrolling in clinical trials.

Citation Format: Jorge Alberto Guadarrama-Orozco, Jennifer Ramirez-Puente, Elizabeth Dominguez-Gonzalez. Exploring genomic complexity in lung cancer at the Tijuana/California border: A real-world perspective through liquid biopsy comprehensive genomic profiling [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 6132.
Abstract 6153: Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal adenocarcinoma
Authors: Zhu Jingjing , Wu Ke , Liu Shuai , Masca Alexandra , Zhong Hua , Yang Tai , Ghoneim Dalia H. , Surendran Praveen , Liu Tanxin , Yao Qizhi , Liu Tao , Fahle Sarah , Butterworth Adam , Alam Md A. , Vadgama Jaydutt V. , Deng Youping , Deng Hong-Wen , Wu Chong , Wu Yong , Wu Lang
Published: March 2024

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified 40 associated proteins, of which 16 are novel. Functionally validating these candidates by focusing on two selected novel protein-encoding genes, GOLM1 and B4GALT1, we demonstrated their pivotal roles in driving PDAC cell proliferation, migration, and invasion. Furthermore, we also identified potential drug repurposing opportunities for treating PDAC. Our dual approach enhances our understanding of PDAC etiology and potentially opens new avenues for therapeutic interventions.

Citation Format: Jingjing Zhu, Ke Wu, Shuai Liu, Alexandra Masca, Hua Zhong, Tai Yang, Dalia H. Ghoneim, Praveen Surendran, Tanxin Liu, Qizhi Yao, Tao Liu, Sarah Fahle, Adam Butterworth, Md A. Alam, Jaydutt V. Vadgama, Youping Deng, Hong-Wen Deng, Chong Wu, Yong Wu, Lang Wu. Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal adenocarcinoma [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 6153.
Abstract 6161: Investigating the relationships between race and socioeconomic status on the biology of ER+ breast cancer
Authors: DeWitt Jerry Tyler , Oropeza Elena , Haricharan Svasti
Published: March 2024

Black women in the US have worse health care options, poorer educational opportunities, and decreased income quality which collectively contribute to an overall lower socioeconomic status (SES) compared to white women. Furthermore, although the incidence of estrogen receptor positive (ER+) breast cancer is similar for Black and white women in the US, Black patients have significantly worse outcomes. The field has traditionally focused on systemic factors such as SES to explain outcome disparities. Consequently, differences in the molecular biology between tumors from Black and White women remains a gap in knowledge in the field. Recent studies have found that Black cancer patients have a unique gene expression profile that may modulate treatment response. However, how SES contributes to these differences in molecular biology and whether these differences in SES alter treatment response remain unknown. One challenge to addressing these questions is that existing datasets significantly underrepresent Black women and are not sufficiently annotated to understand the complex interplay between molecular biology and SES. Here, we present analysis of RNA expression datasets from 60 ER+ patient tumors (38 Black, 22 White), with corresponding SES and patient outcome annotations which suggest that the ECM and TIME of ER+ breast cancer are influenced by race and factors of SES including BMI and community poverty burden. We further provide evidence that these alterations in the TME may also associate with worse patient outcomes.

Citation Format: Jerry Tyler DeWitt, Elena Oropeza, Svasti Haricharan. Investigating the relationships between race and socioeconomic status on the biology of 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 6161.
Abstract 6282: Novel androgen related gene network in prostate cancer cell model
Authors: McDonald Alex L. , Snow Spencer , Ho Shuk-mei , Leung Yuet-kin
Published: March 2024

Prostate cancer stands as the foremost cause of cancer-related deaths among men in the United States, with the primary treatment being androgen receptor (AR) antagonists relying on current androgen signaling knowledge. Most of this knowledge is derived from next-generation sequencing experiments, but the oversight of splice variants and highly similar sequences in multiple loci can hinder a comprehensive understanding. In an effort to unveil the complete androgen receptor transcriptional program, we employed a novel sequencing analysis protocol. Using a R1881-LNCaP model, we identified 212 upregulated and 92 downregulated genes, of which a notable one-third (68 upregulated and 39 downregulated) had not been previously associated with androgen. Among these novel transcripts, 5.6% lacked splice variants, while 16.3% exhibited one or more splice variants, including 3.8% from seven unique gene families. Recognized androgen-regulated genes, such as ORM1, STEAP4, NPPC, ORM2, and KLK3, were validated as upregulated, while GRB10, FN1, PPFIA2, and PLA2G2A were confirmed as downregulated in this in-vitro model. Utilizing chromatin immunoprecipitation-sequencing (ChIP-seq) data, we found that 13% of the genes contained at least one androgen response element within 5 kb upstream or downstream. Further validation through real-time PCR confirmed the expression levels of 90% of the selected genes (18). Ingenuity Pathway Analysis revealed two major regulators (ESRRA and ARFGEF2) in causal networks likely interacting with the novel genes. Intriguingly, 57.1% of ESRRA-involved genes contained at least one ESRRA binding site in a ChIP-seq dataset. Although ESRRA is known to activate androgen biosynthesis in castration-resistant prostate cancer, its interaction with AR and co-regulation of androgen signaling remain unknown. Ongoing studies involve the characterization of these networks in prostate cancer cell lines, examining anchorage-independent capacity, invasion, migration, proliferation, and progression. Data collection and comparison will ascertain whether the signaling is driven by mutated AR, and the role of ARv7 will be elucidated through gene lockdown experiments.

Citation Format: Alex L. McDonald, Spencer Snow, Shuk-mei Ho, Yuet-kin Leung. Novel androgen related gene network in prostate cancer cell model [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 6282.
Abstract 6290: Effects of a circuit, interval-based exercise program on vascular function among cancer survivors
Authors: Christopher Cami N. , Kang Dong-Woo , Gonzalo-Encabo Paola , Wilson Rebekah L. , Normann Amber J. , Norris Mary K. , Dieli-Conwright Christina M.
Published: March 2024

Background: Cancer survivors are at an increased risk of cardiovascular comorbidity, including atherosclerosis, hypertension, and heart failure, due to negative impacts of cancer treatments on vascular function. Exercise is recommended in recent cardio-oncology rehabilitation guidelines and has been shown to improve vascular function in clinical populations; however, its effects on vascular function are understudied in clinical oncology settings.

Purpose: This pilot study examined whether a circuit, interval-based exercise intervention can improve vascular function, assessed by brachial artery flow-mediated dilation (baFMD) and carotid intima media thickness (cIMT) in breast, prostate, and colorectal cancer survivors.

Methods: Overweight or obese (BMI>25.0 kg/m2), sedentary breast, prostate or colorectal cancer survivors were randomized to exercise (n=60) or usual care (n=30). Survivors in the 4-month exercise intervention trained three times/week, in a circuit, interval-based supervised moderate-vigorous aerobic (65-85% of VO2max) and resistance (65-85% of 1-repetition maximum) program. cIMT and baFMD were measured at baseline and post-intervention via an ultrasound. Paired t-tests and repeated-measures analysis of variance were run to assess within- and between-group differences.

Results: The study sample included breast (n=38), prostate (n=24), colorectal (n=28) cancer survivors who were 63.2 ± 10.8 years old, completed chemotherapy and/or radiation (75%) and were obese (87%). Post-intervention, baFMD significantly increased in the exercise group compared to the control group (between-group mean difference: 6.3%; 95% CI: [1.9 to 9.3], p=0.001). There was also a significant reduction in cIMT in the exercise group compared to the control group (between-group mean difference: -0.039mm, 95% CI: [-0.080 to -0.009], p=0.002).

Conclusions: Our findings in this pilot study support that a circuit, interval-based aerobic and resistance exercise intervention may improve vascular function in breast, prostate, and colorectal cancer survivors. Future studies are recommended to understand how exercise interventions can be utilized clinically to improve cardiovascular disease risk and co-morbidity among cancer survivors.

Citation Format: Cami N. Christopher, Dong-Woo Kang, Paola Gonzalo-Encabo, Rebekah L. Wilson, Amber J. Normann, Mary K. Norris, Christina M. Dieli-Conwright. Effects of a circuit, interval-based exercise program on vascular function among cancer survivors [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 6290.
Abstract 6335: Armoring CAR-T therapy with PD-1 blockade: a powerful strategy for enhancing anti-tumor effects in pancreatic cancer
Authors: Zhang Zhixiang , Huang Jingwei , Zhao Zhifeng , Wang Xiangyi , he Cnhui , Yang Sen , Gu Qingyang
Published: March 2024

Chimeric antigen receptor-modified T cells (CAR-T) have been widely applied in the treatment of hematological malignancies and are currently under investigation for their potential effectiveness against solid tumors. Nevertheless, the effectiveness of CAR-T in treating solid tumors remains unsatisfactory due to a range of factors, including CAR-T cell infiltration and heterogeneity. The efficacy of CAR-T therapy is substantially influenced by the tumor microenvironment. This is particularly evident when PD-L1 is activated through CAR-T, leading to the inhibition of CAR-T cell activity via the PD-1 pathway. In this study, we engineered a CAR-T therapy that targets mesothelin and concurrently expresses a membrane-bound PD-1 receptor. This design blocks the PD-1 on CAR-T cells, effectively counteracting the suppression of CAR-T function mediated by PD-L1. We observed a substantial upregulation of PD-L1 on AsPC-1 tumor cells after 4 hours of IFN-γ stimulation in vitro. CAR-T cells engineered to co-express PD-1 antibody (aMSLN-28BBZ-mPD-1) exhibited similar short-term cytotoxicity and cytokine secretion profiles to those of the traditional third-generation CAR-T (aMSLN-28BBZ). Notably, aMSLN-28BBZ-mPD-1 displayed significantly improved long-term target cell killing. Furthermore, in an in vivo model of pancreatic cancer, aMSLN-28BBZ-mPD-1 demonstrated enhanced anti-tumor activity when compared to the traditional aMSLN-28BBZ, as supported by RNAscope analysis and immunofluorescence assays of tumor tissues. These analyses revealed a marked upregulation of PD-L1 expression and enhanced CAR-T cell infiltration in the aMSLN-28BBZ-mPD-1 treatment group. In summary, our study demonstrates that co-expression of a membrane-bound PD-1 antibody overcomes PD-L1 mediated CAR-T suppression, as observed in both in vitro and in vivo. This innovative strategy underscores its therapeutic potential and value in treating solid tumors. Keywords: CAR-T, PD-1, Tumor Microenvironment, Pancreatic Cancer

Citation Format: Zhixiang Zhang, Jingwei Huang, Zhifeng Zhao, Xiangyi Wang, Cnhui he, Sen Yang, Qingyang Gu. Armoring CAR-T therapy with PD-1 blockade: a powerful strategy for enhancing anti-tumor effects in pancreatic 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 6335.
Abstract 6353: AM105: A novel bispecific antibody with Anti 4-1BB affibodies and EGFR antibody
Authors: Kim Dong-Wook , Lee Hyun-Jong , Kim Seong Yeol , Yoon Min , Lee Youngha , Hwang In-Sik , Lee Yoon , Kim Jong-Hoon , Lee Jong-Seo
Published: March 2024

T cell engaging bispecific antibodies have emerged as promising treatments for hematologic malignancies. While most antibodies are CD3-based, offering therapeutic benefits, they are often associated with severe side effects and limited efficacy in solid tumors. To address these challenges, we present AM105, a groundbreaking anti 4-1BB affibodies based bispecific antibody designed to target EGFR. We carefully engineered AM105 with distinct binding affinities for EGFR (KD = 1.8 nM) and 4-1BB (KD = 60 nM), favoring EGFR binding. Affibody specificity was confirmed through a cross-reactivity test with proteins of TNF-receptor superfamily and 21 cell lines expressing 4-1BB or not. In cytotoxicity assays, AM105 exhibited superior tumor cell killing compared to cetuximab, particularly in EGFR-expressing cell lines. Notably, AM105 displayed remarkable efficacy in cell lines harboring RAS and/or BRAF mutations, traditionally unresponsive to EGFR-targeting treatments. In vivo experiments utilizing humanized 4-1BB mice demonstrated AM105's exceptional tumor cell elimination compared to cetuximab. The anti-tumor effects persisted even in the face of new tumor cell introductions, suggesting the induction of T cell memory function. Our findings collectively establish AM105 as a potent therapeutic agent with strong anti-tumor T cell activity. The unique 4-1BB based Affibodies (AffiMab format) of AM105 holds promise for addressing the limitations of current bispecific antibodies, positioning it as a potential breakthrough in cancer immunotherapy.

Citation Format: Dong-Wook Kim, Hyun-Jong Lee, Seong Yeol Kim, Min Yoon, Youngha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee. AM105: A novel bispecific antibody with Anti 4-1BB affibodies and EGFR antibody [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 6353.
Abstract 6357: Establishing a reverse translational platform to dissect mode of action and mechanisms of resistance to GUCY2C-CD3 T cell engager
Authors: Borlido Joana , Lolarga Jade , Whaley Rachael , Damore Michael A. , Guo Cen , Abayasiriwardana Keith , Xu Xiaojun , Liu Maggie , Nocula-Lugowska Gosia , Stoner Sam , Kraser Christopher , Cheronis Ioanna , Delioukina Maria , Clark Lee , Bhadra Raj , Gururajan Murali
Published: March 2024

PF-07062119 (GUCY2C x CD3), a bispecific T cell engager (TCE) targeting Guanylyl Cyclase C (GUCY2C), a GI tumor associated antigen, is currently being evaluated in a Phase 1 clinical trial in colorectal cancer (CRC) and other GI malignancies. Improved pre-clinical understanding of the correlates of PF-07062119 resistance mechanisms and PD in a human disease relevant context is critical to better inform drug combination and patient selection strategy. Due to limited translatability of mouse syngeneic tumor models, establishing a more human disease-relevant platform leveraging tumor patient material to better inform PF-07062119 clinical strategy is needed. Here, we will discuss our efforts to perform immune profiling of T cell and myeloid tumor infiltrates, and to evaluate tumor cell depletion and cytokine production of colorectal carcinoma (CRC) samples treated ex vivo with PF-07062119. This platform may be leveraged to 1) provide clinically relevant disease insights to the effect of TCEs across a range of tumor indications; 2) determine impact of different combinatorial partners on tumor cell killing to inform clinical decisions; 3) address questions related to the minimal efficacy of TCEs in the solid tumor space; and 4) provide potential solutions for future combination partners to overcome immunosuppression in the tumor microenvironment.

Citation Format: Joana Borlido, Jade Lolarga, Rachael Whaley, Michael A. Damore, Cen Guo, Keith Abayasiriwardana, Xiaojun Xu, Maggie Liu, Gosia Nocula-Lugowska, Sam Stoner, Christopher Kraser, Ioanna Cheronis, Maria Delioukina, Lee Clark, Raj Bhadra, Murali Gururajan. Establishing a reverse translational platform to dissect mode of action and mechanisms of resistance to GUCY2C-CD3 T cell engager [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 6357.
Abstract 6361: KY-HC-mouse: A low-cost and rapid nanobody discovery platform
Authors: Wu Guojin , Hao Feng , He Feng , Peng Hao , Gu Yi , Ning Jinying
Published: March 2024

Nanobodies, primarily derived from camelid animals, have gained prominence in antibody-drug development due to their small molecular weight and ease of modification. However, the high cost associated with camelid animals for nanobody discovery led us to develop a strain of heavy-chain mice known as KY-HC-mouse. This genetically modified mouse expresses IgG without the CH1 domain, resulting in the production of nanobodies in IgG format. Utilizing hybridoma techniques, we developed a variety of nanobodies against multiple targets, such as PSMA, CD38, PD-L1, CD28, and 4-1BB, from KY-HC-mouse. These nanobodies all demonstrate high affinity, with KD ranging from 0.01 nM to 10 nM. We also selected antagonist nanobodies that block the interaction of PD1 and PDL1, as well as agonist nanobodies that stimulate 4-1BB signaling in T cells. After humanization, most nanobodies have a half-life of more than five days in the blood of both mice and monkeys. Subjected to various treatments, such as high concentration, low pH, repeated freezing and thawing, and high temperature, most humanized nanobodies show neither aggregation nor degradation, suggesting good developability of these nanobodies. Finally, we have developed multiple bispecific antibodies (BsAbs) targeting both PDL1 and 4-1BB, PSMA and 4-1BB, or B7H3 and 4-1BB. These BsAbs exhibit good developability and efficacy. In conclusion, our KY-HC-mouse is a powerful nanobody discovery platform.

Citation Format: Guojin Wu, Feng Hao, Feng He, Hao Peng, Yi Gu, Jinying Ning. KY-HC-mouse: A low-cost and rapid nanobody discovery platform [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 6361.
Abstract 6364: The bispecific antibody KA-3006 against both EGFR and MET surpasses amivantamab in efficacy
Authors: Wu Guojin , Liang Jiabei , Peng Hao , Hao Feng , Liu Tongtong , Ning Jinying
Published: March 2024

A bispecific antibody (BsAb) like amivantamab, which targets both the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) by blocking downstream pathways, has been proven to overcome resistance to targeted therapies, including EGFR inhibitors, in patients with various cancers. In this study, we developed a bispecific antibody, KA-3006, targeting both EGFR and MET using our common light chain antibody discovery platform. KA-3006 has a regular antibody structure with an identical light chain, developed through knob-into-hole technology. It exhibits high affinity for MET and relatively low affinity for EGFR. KA-3006 specifically blocks both the binding of EGF to EGFR and HGF to MET with higher efficiency than amivantamab, resulting in the blockade of downstream signaling from EGFR and MET. In comparison to amivantamab, KA-3006 demonstrates a faster internalization rate when binding to the surface of tumor cells expressing both EGFR and MET. KA-3006 showed superior antitumor activity over amivantamab in the HCC827-HGF in vivo model. Additionally, KA-3006 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this BsAb with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, and KA-3006 showed neither aggregation nor degradation. In conclusion, the BsAb KA-3006, developed with our common light chain antibody discovery platform, is a promising pre-clinical candidate drug for the treatment of various solid cancers with overactivated EGFR and MET signaling, and it holds potential for developing ADCs targeting both EGFR and MET.

Citation Format: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning. The bispecific antibody KA-3006 against both EGFR and MET surpasses amivantamab in efficacy [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 6364.
Abstract 6480: In-hospital mortality risk factors for uveal melanoma patients in the emergency department
Authors: Beneke Alice A. , Taneja Kamil , Ladehoff Lauren , Root Kevin , Toloza Eric
Published: March 2024

Purpose: A considerable amount of uveal melanoma patients present to the emergency department (ED) for a complication related to their primary tumor. However, there is not much research into the primary reasons for these patients to present to the ED and their outcomes.

Methods: The Nationwide Emergency Department Sample was queried from the last quarter of 2015 to 2019 to identify patients with a diagnosis of uveal melanoma. Multivariable logistic regression, with patient- and hospital-level characteristics as covariates, was used to identify factors associated with increased risk of in-hospital death.

Results: From the last quarter of 2015 to 2019, there were 7,561 ED encounters with a secondary diagnosis of uveal melanoma. Most patients were at least 65 years of age (43.5%), male (52.5%), and a Medicare beneficiary (44.2%), or belong to a family in the 3rd income quartile (25.6%). The median age of these patients was 61 years (IQR: 32-74). Most patients presented to hospitals in the South (40.8%), with a Trauma Level I designation (47.2%), and to a metropolitan teaching hospital (72.6%). The most common diagnosis for presentation to the ED were the following general clinical categories: blood disorders (7.1%), genitourinary tract disorders (5.1%), infections (6.0%), respiratory diseases (9.0%), nervous system disorders (4.8%), endocrine/nutrition disorders (4.3%), and vascular disorders (8.3%). The rate of metastatic uveal melanoma was 5.8%. The rate of in-hospital mortality was 3.6%. In a multivariable logistic regression identified the following clinical categories as factors associated with a higher risk of in-hospital death: infections (odds ratio [OR]=10.22; p<0.001), metastases (OR=10.22; p<0.001), genitourinary tract disorders (OR=7.05; p<0.001), respiratory diseases (OR=3.31; p=0.031), and vascular disorders (OR=3.14; p=0.044). Nervous system, blood, and endocrine/nutrition disorders were not associated with a higher rate of in-hospital mortality. The only demographic variable associated with a higher risk of in-hospital death was being part of the top income quartile (OR=3.10; p=0.14).

Conclusion: Physicians have to be mindful of different complications associated with uveal melanoma that can lead to presentation to the ED and possible in-hospital death. Specifically, physicians need to be mindful of infections, metastases, genitourinary tract disorders, respiratory diseases, and vascular disorders in these patients.

Citation Format: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza. In-hospital mortality risk factors for uveal melanoma patients in the emergency department [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 6480.
Abstract 6496: Assessment of tyrosine kinase inhibitor bypass mechanisms in lung cancer using single cell multiomics, patient derived organoids and rationally designed drug screens
Authors: Liu Liqiong , Strange Ann , Lee Schuyler , Gao Bifeng , Merrick Daniel , Patil Tejas , DeGregori James , Camidge D Ross , Pine Sharon R. , Sabaawy Hatim E.
Published: March 2024

Lung cancer (LC) is the leading cause of cancer-induced mortality, with 350 patients in the US dying from LC daily, the majority from non-small cell lung cancer (NSCLC). Molecular-targeted therapy such as tyrosine kinase inhibitors (TKI) are effective in first and subsequent lines of therapy against oncogenic drivers (KRAS, EGFR, or ALK fusions, others); however, nearly all treated patients progress eventually and run out of therapeutic options. Key reasons are the lack of predictive biomarkers and LC models that reflect the underlying heterogeneity and different phenotypic cell states among subclones within and between patients. Here, we developed a novel platform for refining the resolution of molecular interrogation to the single cell level, using single cell spatial multiomic (scSpMO), coupled with rational designed drug screens in patient-derived organoids (PDOs) from LC biopsies obtained upon progression. By deriving LC PDOs in epithelial and tumor microenvironment (TME) conditions to faithfully maintain the histological and genetic features of their respective LC tissues, we identified enrichment conditions for LC PDOs guided by tumor mutation variants and activated pathways. PDOs are maintained under the same treatment condition in the clinic (e.g., Lorlatinib) and drug testing is tailored to identify next lines of combined therapy. With six patients enrolled and others in ongoing studies, single cell PDOs (at >80% establishment rate) were used to determine key molecular bypass mechanism for resistance to TKI, including on-target variants, driver bypass, lineage plasticity and acquired resistance. Functional assays for acquired resistance such as PI3K/AKT signaling, Src kinase, BRAF fusion and MET hyperactivity allow the identification of potential novel combined lines of therapy for each patient through the compassionate care program and/or trial participation. Our platform when empowered with datasets of bulk, scRNA-seq and scSpMO signatures of primary human NSCLC, together with PDOs offer the ability to perform analysis of LC phenotypes such as lineage transformation in high-content assays, predict and/or act on resistance to therapy and provides a path for precision medicine-guided immediate impact on patient care.

Citation Format: Liqiong Liu, Ann Strange, Schuyler Lee, Bifeng Gao, Daniel Merrick, Tejas Patil, James DeGregori, D Ross Camidge, Sharon R. Pine, Hatim E. Sabaawy. Assessment of tyrosine kinase inhibitor bypass mechanisms in lung cancer using single cell multiomics, patient derived organoids and rationally designed drug screens [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 6496.
Abstract 6505: Targeting PINK1 reduces medulloblastoma progression in animal models
Authors: Alsubaiee Reema N. , Alghamdi Amani , Alrfaei Bahauddeen M.
Published: March 2024

Medulloblastoma is a brain cancer that mainly arises during infancy and childhood. Medulloblastoma is the most common pediatric malignant brain tumor worldwide. It comprises of approximately 20% of all childhood brain tumors and 63% of intracranial embryonic tumors. One of the major effects of proliferating cancer cells is altered mitochondrial metabolism, as well as aberrant metabolism. Medulloblastoma patients suffer severe complications due to intensive and long-term treatments. Thus, we aim to improve applications against medulloblastoma by targeting the PINK1 gene. We hypothesize that PINK1 inactivation slows down medulloblastoma progression. PINK1 is a mitochondrial serine/threonine protein kinase that protects cells by controlling mitochondria quality in response to cellular stress. PINK1 recruits parkin to target damaged mitochondria for degradation through autophagy. In this study, PINK1 has been knocked-out using gene editing technology (CRISPR/Cas9) in two commercial medulloblastoma cell lines (DAOY, and D283 cell lines). We validated PINK1 editing using RT-PCR and Western blot. Then, cell viability was studied in comparison to the control sample. The control sample contained scramble fragments with empty CRISPR/Cas9. We studied apoptosis and performed cell cycle analysis using flow cytometry. Next, orthotopic medulloblastoma mouse model was generated which showed differential survivals comparing the PINK1 knockout group and control. The results showed a low expression of PINK1 within the PINK1 knockout group. In addition, the Western blot showed reductions in PINK1 expression in the knockout group. The knockout group showed more apoptosis (cell death) 40% more than the control. The mouse model showed increased survival of the PINK1 knockout group compared to the control with a p-value of 0.0288 (log-rank). Our analysis shows that survival differences approximately extend human life by one year. We conclude that inhibiting the PINK1 gene in medulloblastoma decreases cell metabolic activities. PINK1 Knockout in medulloblastoma enhances the apoptosis pathways. Engrafted medulloblastoma mouse model treated with PINK1 inhibitor showed superior survival than the control. These results qualify PINK1 to be used as potential therapeutic target for medulloblastoma. The Future work needs additional preclinical studies to investigate the proper dose of PINK1 inhibitor and measurement of toxicity index.

Citation Format: Reema N. Alsubaiee, Amani Alghamdi, Bahauddeen M. Alrfaei. Targeting PINK1 reduces medulloblastoma progression in animal models [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 6505.
Abstract 6513: Discovery and characterization of a KRASG12C/D/V degrader with potent anti-tumor activity in KRASmut-driven preclinical models
Authors: Li Zhengqing , Xu Renqi , Yang Xiaofeng , Zou Zhengyao , Kong Xiaoqiang , Chen Haibo , Sun Yongqing , Zhao Ying , Guo Jing , Yang Cheng , Han Han , Liu Xiaoyun , Lan Hong , Ding Lieming , Zhou Quan , Wu Hao , Wang Jiabing
Published: March 2024

KRAS mutations are one of the most common oncogenic drivers for multiple cancers. KRASG12X mutations are identified in approximately 25% of lung cancer, 24% of colorectal (CRC), and 79% of pancreatic ductal adenocarcinoma (PDAC). Although the approval of Sotorasib in 2021 by the FDA partially addressed the needs of patients with KRASG12C mutant, other mutations, such as G12D and G12V, still lack effective target therapies. Here, we report RD0255359, a proteolysis targeting chimera (PROTAC) KRASG12C/D/V degrader with highly potent cell viability and KRASG12C/D/V degradation ability. In vitro, RD0255359 exhibited a remarkable KRAS degradation property in NCI-H358 (G12C), AGS (G12D), and SW620 (G12V) cell lines at concentrations below 10 nM. RD0255359 suppressed the proliferation of these cells with nanomolar IC50 without affecting the viability of KRASWT or KRAS-independent cell lines. Meanwhile, using protease inhibitor MG132 or corresponding ligand pretreatment and VHLKD-AGS cell experiment confirmed that RD0255359-induced KRAS degradation was VHL and UPS dependent. In vivo, weekly IV injection of 1-10 mg/kg RD0255359 led to tumor growth suppression or tumor regression in PK-59 PDAC xenograft model. The in vivo PK/PD demonstrated that durable KRAS degradation could be achieved with once- weekly IV injection. Notably, after injection, the drug can distribute into tumor tissue rapidly and abundantly, and maintaining a high concentration till the next administration. Taken together, RD0255359 is a highly potent and selective KRASG12C/D/V degrader with favorable PK properties. It exhibits a promising therapeutic index in preclinical studies.

Citation Format: Zhengqing Li, Renqi Xu, Xiaofeng Yang, Zhengyao Zou, Xiaoqiang Kong, Haibo Chen, Yongqing Sun, Ying Zhao, Jing Guo, Cheng Yang, Han Han, Xiaoyun Liu, Hong Lan, Lieming Ding, Quan Zhou, Hao Wu, Jiabing Wang. Discovery and characterization of a KRASG12C/D/V degrader with potent anti-tumor activity in KRASmut-driven preclinical models [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 6513.