bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2036: Characterizing PARP inhibitor and next-generation anti-androgen therapy responses in advanced prostate cancer
Authors: Moore Love A. , Gonzalez Bryan Correa , Gao Allen C. , Lombard Alan P.
Published: March 2024

PARP inhibitors (PARPi) have been shown to be effective in prostate cancer patients with certain DNA repair defects, thus ushering in the era of precision medicine for this disease. Despite this advance, barriers remain which impede further progress including an incomplete understanding of therapeutic response. Our previous and on-going work shows that PARP inhibition leads to both cell death and a more cytostatic, senescence-like arrest. We hypothesize that persistent cells may later promote progression and treatment resistance. Recent clinical trials such as PROpel and TALAPRO-2 have demonstrated success in combining PARPi’s with next-generation anti-androgen therapies (NGAT) including abiraterone and enzalutamide. Whether NGAT’s are synthetic lethal and cell death promoting with PARP inhibition is poorly understood. Additionally, given the evolving clinical landscape for prostate cancer, it is important to test whether prior NGAT exposure may preclude response to combination therapy. In this study, we sought to characterize these combinations to better understand tumor cell response to treatment and the placement of treatment within the overall therapeutic paradigm. We’ve previously used the C4-2B metastatic castration-resistant prostate cancer cell line as a model which responds well to PARP inhibition. Here, we additionally utilize the C4-2B-derived enzalutamide and abiraterone resistant lines MDVR and AbiR, respectively. The combination of olaparib with abiraterone (recently approved from results of PROpel) was significantly more efficacious than either monotherapy in all three models. Additionally, combination of talazoparib and enzalutamide (approved from results of TALAPRO-2) was also more effective than monotherapy. These data suggest that prior development of NGAT resistance does not prevent benefit from NGAT and PARPi combinations. Although both combinations were found to cause significantly less cell growth, cells appeared more cytostatic rather than apoptotic, suggesting NGAT’s do not induce significant synthetic lethality with PARPi’s. Our work suggests that combining a PARPi with an NGAT promotes a persistent cytostasis which may give rise to eventual tumor progression and the development of resistance. Future studies are directed at further characterizing combinations with PARPi’s and the development of novel strategies to enhance their efficacy.

Citation Format: Love A. Moore, Bryan Correa Gonzalez, Allen C. Gao, Alan P. Lombard. Characterizing PARP inhibitor and next-generation anti-androgen therapy responses in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2036.
Abstract 2039: Cellular characterization of small molecule PD-L1 inhibitors reveal their novel mechanisms of action
Authors: Pan Weiling , Zhang Yongxian , Qi Fangfei , Xin Wenqun , Feng Zhigang , Chen Zhui , Ying Haiyan
Published: March 2024

Introductions: Immune checkpoint inhibitors, including PD-1/L1, are key regulators of immune response and promising targets in cancer immunotherapy. Like anti-PD-1/L1 antibodies, small molecule PD-L1 inhibitors that have been discovered by us and others could also efficiently block PD-1 and PD-L1 interaction and exhibit anti-tumor efficacy in preclinical and clinically settings. In this study, we explore the cellular mechanism of small molecule PD-L1 inhibitors, unveiling their novel mechanisms of action in the regulation of PD-L1 and its functions.

Materials and Methods: The cellular effects of the small molecule PD-L1 inhibitor on PD-L1 protein and RNA levels were assessed through Western blot and real-time qPCR experiments. HTRF assay and cellular luciferase reporter assay were used to evaluate the blockade of PD-1 and PD-L1 interaction in vitro and in cells. Flow cytometry and confocal microscopy were used to investigate the internalization of PD-L1 upon treatment with inhibitors. MSD assay was used to evaluate the alteration of soluble PD-L1 proteins.

Results: Small molecule PD-L1 inhibitors discovered by Abbisko Therapeutics potently blocked PD-1/PD-L1 interaction in vitro and in cellular system. It could also rapidly and strongly induce PD-L1 internalization in cells. Further profiling suggested that small molecule PD-L1 inhibitors specifically disrupt PD-L1 N-glycosylation, resulting in aberrant PD-L1 glycosylation. This, in turn, may hinder the proper translocation of newly synthesized PD-L1 to the cell surface, thereby abolishing its interaction with PD-1 and functions in immune regulation.

Conclusion: Taken together, these results for the first time revealed the distinctive mechanisms of our small molecule PD-L1 inhibitors. With their multi-layer inhibitory effects stemming from various mechanisms, small molecule PD-L1 inhibitors may offer potentially improved activities and an alternative therapeutic treatment for the cancer patients.

Citation Format: Weiling Pan, Yongxian Zhang, Fangfei Qi, Wenqun Xin, Zhigang Feng, Zhui Chen, Haiyan Ying. Cellular characterization of small molecule PD-L1 inhibitors reveal their novel mechanisms of action [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 2039.
Abstract 2167: Microbial bile acid, 3-oxo-LCA, inhibits colorectal cancer progression
Authors: Sun Fei , Dong Xingchen , Qi Ming , Fu Ting
Published: March 2024

Colorectal cancer (CRC) affects a significant number of individuals each year, ranking as a leading cause of cancer-related deaths in the U.S. Bile acids (BAs), natural compounds crucial for digesting dietary fats, not only influence the gut microbiota but are also involved in gut health through their interaction with the Farnesoid X Receptor (FXR). Recent findings have highlighted certain microbiota-generated BAs like 3-oxo-lithocholic acid (LCA) and IsoLCA, modulate host immunity, hinder the expansion of intestinal pathogens, and potentially anti-aging. Despite the advancements in identifying the gut microbes behind these BAs, their precise impact on intestinal cells (IECs) and their role in disease progression are largely unexplored. Our pilot investigation unveiled 3oxoLCA as an FXR agonist, restoring FXR signaling in both cancer cells and APCmin/+ mice (a classic CRC mice model). As a result, 3-oxo-LCA inhibits the growth of both human and mouse CRC cells, such as MC38, CT26 and HCT116. Additionally, 3-oxo-LCA also restrained the intestinal stem cells (ISCs)’ proliferation in organoids from both wild-type and APCmin/+ mice, and patient-derived CRC organoids (PDCOs). Remarkably, treatment with 3-oxo-LCA decreased BAs levels, improved gut barrier function, reduced tumor load, and inhibited tumor progression in APCmin/+ mice. Furthermore, 3-oxo-LCA significantly suppressed tumor growth in cancer cell-derived xenograft model mice. Crucially, the 3-oxo-LCA-FXR interaction transcriptionally regulated key apoptotic genes, encouraging cancer cell death. These discoveries highlight the therapeutic promise of incorporating 3-oxo-LCA into strategies for treating CRC.

Citation Format: Fei Sun, Xingchen Dong, Ming Qi, Ting Fu. Microbial bile acid, 3-oxo-LCA, inhibits colorectal cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2167.
Abstract 2176: Differences in gut microbial composition alter pancreatic tumorigenesis
Authors: Howell Rian M. , Ortiz Jose Enriquez , Roux Olivia Le , Chandra Vidhi , Li Le , Bhattacharya Pratip K. , McAllister Florencia
Published: March 2024

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related deaths by 2030, and currently has a 5-year survival rate of roughly 10%. With long-term survival rates in patients being exceedingly low, understanding what factors delineate survival is imperative. When comparing spontaneous transgenic mouse models of pancreatic cancer housed in geographically distinct vivaria, regardless of a common lineage, we observed drastically different phenotype states in the respective locations. We hypothesize that the gut microbiome results in different gene expression profiles, leading to alterations in pancreatic tumorigenesis. Using various sequencing techniques, including 16s rRNA and RNA sequencing of the gut, we identified unique signatures at these respective institutions. Subsequent fecal microbiota transplantation and single bacterial species colonization experiments were performed to evaluate the ability of microbiomes/specific microbiota to alter the rate of tumorigenesis. In addition to probing the gut microbiome, circulating metabolites from individual mice were quantified, and correlated to phenotype state. Following identification of potentially tumorigenic bacterially derived metabolites, single bacteria colonization experiments were utilized to determine the downstream effects of identified metabolites as well as the ability of directly altering the metabolic landscape to drive tumorigenesis. Additionally, murine derived pancreatic cancer cells were exposed to both identified bacteria alone or bacterially produced metabolite and analyzed by metrics such as proliferation and relative expression of transcription factors associated with cancer development in vitro. Taken together, these data demonstrate the ability of distinct gut microbiomes to directly alter the metabolic landscape in mice, thus differentially altering the progression of pancreatic lesions. By better understanding the factors that stratify survivorship, we can begin to employ clinically actionable methodologies in the treatment or prevention of pancreatic cancer.

Citation Format: Rian M. Howell, Jose Enriquez Ortiz, Olivia Le Roux, Vidhi Chandra, Le Li, Pratip K. Bhattacharya, Florencia McAllister. Differences in gut microbial composition alter pancreatic tumorigenesis [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 2176.
Abstract 2195: Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study
Authors: Phung Minh Tung , Wang Yuting , Lee Alice W. , Pike Malcolm C. , Wu Anna H. , Pearce Celeste Leigh
Published: March 2024

Introduction: Ovarian, fallopian tube, and primary peritoneal cancers (hereafter referred to as ovarian cancer) are the most fatal gynecologic cancers. Thus, it is imperative to identify strategies that can reduce the risk of the disease. Several contraceptive methods have been shown to be associated with a reduced risk of ovarian cancer, including combined oral contraceptives, injectable progestins, and tubal ligation. However, the use of these contraceptive methods has been decreasing in the U.S., with a growing preference for intrauterine devices (IUDs) for pregnancy prevention. Previous case-control studies on the association between IUD use and ovarian cancer risk have found inconsistent results. Notably, previous studies had small sample sizes and did not restrict to invasive epithelial tumors. The current analysis assessed the association between IUD use and risk of invasive epithelial ovarian cancer in a large population-based case-control study.

Methods: This analysis used data from 1,713 people diagnosed with primary invasive epithelial ovarian cancer (cases) and 2,348 cancer-free people (controls) participating in a case-control study conducted in Los Angeles, CA from 1992-2010. The study consisted of four waves of recruitment with similar enrollment and data collection methods. Logistic regression models were fit to assess the association between IUD use and risk of invasive epithelial ovarian cancer. All models were adjusted for age, race/ethnicity, education, first-degree family history of ovarian cancer, endometriosis, body mass index, duration of combined oral contraceptive use, parity, duration of breastfeeding, tubal ligation, and study wave. Heterogeneity across the study waves and the ovarian cancer histotypes was evaluated using standard meta-analysis techniques.

Results: There was no statistically significant association between IUD use and risk of invasive epithelial ovarian cancer (odds ratio=1.09, 95% confidence interval 0.93-1.28). This result was consistent across the study waves and the ovarian cancer histotypes (p-values for heterogeneity>0.05).

Conclusion: IUD use was not associated with the risk of invasive epithelial ovarian cancer. Analysis by IUD type (i.e., hormone-releasing vs copper IUDs) was not possible in this study as these data were not collected. Future research should examine whether the type of IUD (i.e. copper versus hormone-releasing) may have different effects on risk of ovarian cancer.

Citation Format: Minh Tung Phung, Yuting Wang, Alice W. Lee, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study [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 2195.
Abstract 2213: Vaping, smoking and lung cancer: A case-control study
Authors: Bittoni Marisa A. , Carbone David , Harris Randall
Published: March 2024

Introduction: Nicotine exposure through the use of electronic delivery systems (vaping) has been found to elevate the risk of certain conditions of the lungs, e.g., vaping associated lung injury. However, the potential impact of vaping on lung cancer risk remains largely unexplored. We, therefore, examined the association of vaping and cigarette smoking with lung cancer risk in a case-control study conducted at The Ohio State University in Columbus, Ohio.

Methods: Medical records examined from the James Cancer Hospital and Solove Research Institute revealed 4,975 cases with newly diagnosed, pathologically confirmed lung cancer during 2013-2021. These cases were compared to 27,294 controls without cancer that were group-matched on a 5:1 ratio to cases by age, gender, race and year of ascertainment. Descriptive statistics were calculated, and logistic regression analyses were performed to assess the associations between vaping, smoking and lung cancer.

Results: The lung cancer cases in this study were 55% male, 88% white, with mean age at diagnosis of 62 years. The adjusted odds ratio (OR) for individuals who reported vaping and smoking was OR=21.1 (95% CI=17.1, 26.1) versus OR=6.3 (95% CI=5.8, 6.8) for smoking only. Estimates for gender and histologic cell type of lung cancer, e.g., pulmonary adenocarcinoma, squamous cell carcinoma and small cell carcinoma, were consistently over threefold higher for vaping and smoking compared to smoking only (p<0.001), and the vaping effect persisted even after adjustment for comorbidities, COPD and cardiovascular disease.

Conclusion: Adjusted estimates of odds ratios (OR) revealed over threefold higher risk of lung cancer among individuals who had vaped and smoked compared to individuals who only smoked. Our results suggest that the addition of vaping to smoking greatly accelerates the risk of developing lung cancer. Future studies are needed to further confirm these results.

Citation Format: Marisa A. Bittoni, David Carbone, Randall Harris. Vaping, smoking and lung cancer: A case-control study [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 2213.
Abstract 2260: Transcriptomic immuno-oncology investigation of B-cell lymphomas using a novel comparative workflow
Authors: Rapier-Sharman Naomi , Told Michael T. , Kim Sehi , O'Neill Kim L. , Pickett Brett E.
Published: March 2024

Patients with B-cell lymphoma currently have limited treatment options, often with serious side effects; for example, B-cell lymphoma patients undergoing chemo- and radiation therapies experience poor health from off-target toxicity. Similarly, though CD19 CAR T-cell therapy is very effective, patients suffer lifelong B-cell aplasia as a side effect. Comparing a cancer to an autoimmune disease in the same tissue type may grant us additional insights on the immune dysregulation of the cancer, leading to development of more immune-aware cancer treatments. We introduce a new data-driven comparative workflow for the analysis of immuno-oncology attributes by comparing a cancer and an autoimmune disease in the same tissue type. As an example use case, we compare primary B-cell lymphomas to primary B-cells from systemic lupus erythematosus with the goal of delineating new mechanisms that can be leveraged to treat B-cell lymphomas. Our analysis will utilize bulk RNA-sequencing (RNA-seq) of B-cells for initial discovery, followed by single-cell RNA-sequencing (scRNA-seq) of Peripheral Blood Mononuclear Cells (PBMCs) for validation. Our analytical framework incorporates differential gene analysis, GO Terms, known protein-protein interactions, principal component analysis, and machine learning for biomarker detection. Here, we describe our novel tool in detail and share the results of our lymphoma use case to gain a better understanding of the targetable immune-related attributes of B-cell lymphoma. We expect that this novel tool, along with the results of our B-cell lymphoma use case, will contribute to the continued development of immune-focused treatment options for B-cell lymphoma and other cancers.

Citation Format: Naomi Rapier-Sharman, Michael T. Told, Sehi Kim, Kim L. O'Neill, Brett E. Pickett. Transcriptomic immuno-oncology investigation of B-cell lymphomas using a novel comparative workflow [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 2260.
Abstract 2280: HPV integration identifies emerging oncogenes and carcinogenic mechanisms, potentially indicating tumor recurrences
Authors: Li Shiting , Xia Shaomiao , Lawas Maria , Qin Tingting , Grab Bailey , D'Silva Nisha , Rozek Laura , Sartor Maureen
Published: March 2024

HPV integration events in Head and neck squamous cell carcinomas (HNSCC) are strongly associated with carcinogenesis and tumor progression. Previous studies have elucidated the mechanisms and structures of HPV-human fusion events, pinpointing potential integration “hotspots” (i.e. genes with nearby HPV integration in recurrent patients). However, none has comprehensively investigated the effects of HPV integration on both HPV and human gene expression, nor assessed the clinical implications of these bidirectional expression changes.

In this study, we conducted bulk RNA sequencing on 67 Formalin-Fixed Paraffin-Embedded Oropharyngeal Squamous Cell Carcinoma (OPSCC) tumor samples from the University of Michigan hospital, and analyzed them in conjunction with bulk and single cell RNA-seq from another >200 HPV(+) HNSCC patients from four previous studies. Among the 117 samples confidently identified as HPV integration positive, we recaptured all previously known integration “hotspot” genes as well as several novel ones that have altered expression in the integrated samples.

Exploring the impact of HPV integration on the expression of human and HPV genes, we found that HPV integration in HNSCC is strongly associated with keratinization, immune response, and the development of HPV(+) HNSCC subtypes. Upon HPV integration, expression of non-oncogenic HPV genes is often lost. We hypothesized that the expression ratio of these potentially HPV immunogenic genes (E1-E5, L1,L2) to the HPV oncogenic genes E6 and E7 (termed the ImmunOnco Score) would predict clinical outcomes. Survival analysis of 70 University of Michigan patients showed low ImmunOnco Score is associated with tumor recurrence.

Citation Format: Shiting Li, Shaomiao Xia, Maria Lawas, Tingting Qin, Bailey Grab, Nisha D'Silva, Laura Rozek, Maureen Sartor. HPV integration identifies emerging oncogenes and carcinogenic mechanisms, potentially indicating tumor recurrences [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 2280.
Abstract 2282: Predictive association of tumor cells hijacked NFATC2 activities with resistance to immune checkpoint inhibition in melanoma patients
Authors: Lawal Bashir , Wang Yue , Lotfinejad Parisa , Wang Xiaosong
Published: March 2024

Background: Immune checkpoint blockade (ICB) has emerged as an effective cancer therapy. However, only a small fraction of patients receives benefits whereas a significant subset of patients experienced severe or even lethal autoimmune diseases. Stratifying patients that would benefit from immunotherapy remain a highly unmet clinical need. Dysregulations of transcriptional programs have been implicated in cancer initiation and progression. To date, there is a paucity of studies on the predictive values of transcriptional factors on ICB response based on the most recently emerged ICB clinical trial datasets. We reasoned that cancer cells may hijack key transcriptional programs in hematological cells to evade the attack from immune cells and acquired tolerance to immunotherapy.

Method: Herein, we used an R package singscore/1.14.0 to compute the TFs activity scores based on their validated gene targets (TGs). Leveraging melanoma clinical trial datasets, we analyzed the predictive association of the TF scores with resistance to anti-PD1 ICB. The R package, iGenSig was used to evaluate the potential confounding variables.

Results: Our landscape correlation analysis revealed NFATC2 (Nuclear Factor Of Activated T Cells 2)-TGs as the most significant predictor of anti-PD-1 ICB resistance in melanoma. NFATCT-TGS as a predictor of anti-PD1 resistance is confounded by liver metastasis and achieved AUC range between 0.71 to 0.74 in three datasets (PRJEB23709, GSE160638, and Phs000452). In addition, prior anti-CTLA4 exposure (AUC=0.87 and 0.89) is associated with higher predictive efficacy of NFATC2-TGS than anti-CTLA4 naïve tumor (AUC=0.61 and 0.69) in phs000452 and GSE91061 datasets. Survival analysis revealed that NFATC2 is a better predictor of progressive-free survival (PFS; HR=5.95), and overall survival (OS; HR= 3.28-3.38) in anti-CTLA4 exposed tumor than anti-CTLA4 naïve tumor (PFS: HR=1.92, and OS; HR=1.64-2.17). Finally, NFATC2-TGS show strong inhibitory correlation with B cells and T cells infiltration, but strongly correlated with tumor purity.

Conclusion: We demonstrate that NFATC2 TGS predicts ICB benefits in melanoma patients, and thus may guide the recruitment of melanoma patients for anti-PD1 ICB. Our data provide support to the hypothesis that melanoma acquired NFATC2 transcriptional program to avoid immune cells evasion and acquired tolerance to ICB immunotherapy

Citation Format: Bashir Lawal, Yue Wang, Parisa Lotfinejad, Xiaosong Wang. Predictive association of tumor cells hijacked NFATC2 activities with resistance to immune checkpoint inhibition in melanoma patients [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 2282.
Abstract 2326: Integrating single nucleotide variants (SNVs), copy number alterations (CNAs), and structural variants (SVs) into single-cell clonal lineage inference
Authors: Bristy Nishat , Fu Xuecong , Schwartz Russell
Published: March 2024

Background: We extend algorithms for clonal lineage inference (``tumor phylogenetics'') from single-cell DNA sequence (scDNA-seq) data to accommodate broader classes of genetic variants, including single nucleotide variants (SNVs), copy number alterations (CNAs), and structural variants (SVs).

Methods: We develop a computational method based on constrained optimization, posing a problem of inferring cellular lineage trees consistent with a given scDNA-seq data set constrained to follow a Dollo parsimony model for SNVs and SVs. We then seek an optimal tree consistent with these constraints so as to optimize for a CNA minimum evolution model balanced against measure of consistency of the different data types with one another relative to the reconstructed set of clones. We pose this problem as an integer linear program (ILP) that we solve heuristically via a coordinate descent algorithm. We tested the resulting method on a combination of synthetic scDNA-seq data and publicly available real data.

Results: Results on synthetic data show the method to be effective at constructing lineage trees under a variety of parameter domains, including variations in noise levels, clone numbers, single cells, and mutation rates. We further show it to yield improved accuracy over widely used prior models that operate on only subsets of these variant types. Application to previously published scDNA-seq data demonstrate the method to be effective at inferring clonal lineage trees incorporating all three variant types. The results further show how the different kinds of variants can contribute in tandem to progression along single cell lineages or to the emergence of clones exhibiting hallmarks of distinct mechanisms of progression.

Conclusion: The results support the effectiveness of our method in resolving accurate trees from scDNA-seq data including diverse variant types, as well as the value of considering these mutation types collectively in developing a comprehensive understanding of how various forms of somatic mutability together shape clonal evolution in cancers.

Citation Format: Nishat Bristy, Xuecong Fu, Russell Schwartz. Integrating single nucleotide variants (SNVs), copy number alterations (CNAs), and structural variants (SVs) into single-cell clonal lineage inference [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 2326.
Abstract 2329: Cancer region definition using spatial gene expression patterns by super resolution reconstruction algorithm for spatial transcriptomics data
Authors: Park Jeongbin , Cook Seungho , Lee Dongjoo , Choi Jinyeong , Yoo Seongjin , Im Hyung-Jun , Lee Daeseung , Choi Hongyoon
Published: March 2024

Background: Spatially resolved transcriptomics (ST) has enabled a variety of cancer research on the heterogeneity of tumor microenvironment. However, when identifying cancer boundaries based on ST, the limited resolution of ST such as Visium hinders the accurate identification of cancerous regions. To address these issues, we have developed a novel approach for accurately classifying regions of the tumor by using deep image prior (DIP) algorithm to convert Visium data into high-resolution images.

Methods: We proposed SuperST, which utilizes deep image prior to transform low-resolution ST data into high-resolution images, providing more accurate spatial marker expression patterns. This method was used to define cancer regions by combining with a pre-trained deep learning algorithm that recognizes spatial patterns. ST data of hepatocellular carcinoma (HCC) patients were used to apply SuperST. Firstly, 400 spatially variable genes were identified. SuperST leverages the deep image prior (DIP) algorithm and a U-Net neural network to transform ST data into high-resolution ones without needing ground-truth high-resolution data. The final high-resolution images of gene expression data were used to extract 512-dimensional feature vectors for each gene via a pre-trained convolutional neural network model (VGG16). Subsequently, we apply K-means clustering to these features to identify transcriptionally distinct tissue regions considering spatial information and compared with the human-labeled cancer regions.

Results: The cancer region detection using spatial gene expression data and our algorithm yielded results that substantially align with the human annotations on the H&E images. Furthermore, compared to the cancer definition obtained using the CopyKat and SPACET algorithms, our results were more spatially consistent for cancerous regions as well as providing high-resolution image-level definition of cancer region margin. This indicates that our algorithm better utilizes spatial information and more effectively overcomes the low resolution of ST data.

Conclusion: This research demonstrates the effective application of our SuperST algorithm to the challenging problem of cancer region detection only using spatial gene expression data. It suggests that our algorithm could be utilized for a variety of problems in spatial biology in cancer research.

Citation Format: Jeongbin Park, Seungho Cook, Dongjoo Lee, Jinyeong Choi, Seongjin Yoo, Hyung-Jun Im, Daeseung Lee, Hongyoon Choi. Cancer region definition using spatial gene expression patterns by super resolution reconstruction algorithm for spatial transcriptomics data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2329.
Abstract 24: Utilizing T cell receptor-based therapy to treat anaplastic thyroid cancer
Authors: Hung Shao-Hsi , Henderson Ying C. , Ke Pan , Chiu Yulun , Singh Shailbala , Chen Yunyun , Lai Stephen Y. , Yee Cassian
Published: March 2024

Anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumor in thyroid tissue, with a 6-month medium overall survival. The effectiveness of conventional treatments in extending the survival of patients is limited. Therefore, there is an urgent need to develop novel systemic therapeutic interventions. Adoptive cell therapy has revolutionized cancer immunotherapy by successfully treating B-cell malignancies through chimeric antigen receptor-based approaches. For solid tumors, there is a need to identify a broader spectrum of tumor target antigens, and the field has now shifted towards leveraging T cell receptors (TCRs) which can recognize both intracellular and extracellular antigen-derived epitopes. Our team has established an immunogenic epitope discovery pipeline, followed by a specialized protocol for empiric validation of candidate epitopes. We characterized immunogenic epitopes by coupling tandem mass spectrometry of MHC-eluted peptides with tumor proteome and MHC-peptide binding prediction databases. By integrating multi-omics data (genomics, transcriptomics, and immunopeptidomics) from both in-house and publicly available ATC databases, we find that ATC exhibits significant upregulation of pathways associated with microtubule-based movement, chromosome segregation, and kinetochore complex components. We have identified several HLA-A2- and A24-restricted immunogenic peptides representing these pathway-associated proteins that covered more than 60% of the patient population. These immunogenic peptides were subsequently utilized to isolate antigen-specific T cells from peripheral blood and identify cognate TCR. These peptide-specific T lymphocytes elicit cytotoxicity toward multiple HLA-matched ATC cell lines and tumor samples in vitro and in vivo. In conclusion, our studies contribute to the development of a new treatment paradigm for treating ATC.

Citation Format: Shao-Hsi Hung, Ying C. Henderson, Pan Ke, Yulun Chiu, Shailbala Singh, Yunyun Chen, Stephen Y. Lai, Cassian Yee. Utilizing T cell receptor-based therapy to treat anaplastic thyroid 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 24.
Abstract 2401: Changes in skeletal muscle mass after gastrointestinal cancer surgery by body composition
Authors: Maeda Yuto , Miyamoto Yuji , Ohuchi Mayuko , Hiyoshi Yukiharu , Yoshida Naoya , Baba Hideo
Published: March 2024

Background: Previous studies have extensively explored the correlation between preoperative skeletal muscle mass and long-term survival in gastrointestinal cancers. However, investigations into postoperative skeletal muscle mass alterations are limited. In gastrointestinal cancers, factors such as the tumor and surgical interventions can significantly impact dietary intake, nutritional status, and skeletal muscle mass, affecting postoperative body composition. This study aimed to examine these postoperative changes in skeletal muscle mass across different gastrointestinal cancers, including esophageal, gastric, and colorectum.

Methods: This study encompassed 969 patients with Stage I-III esophageal (307 cases), gastric (278 cases), and colorectal (384 cases) cancers who underwent radical resection between 2005 and 2019. Skeletal muscle mass was quantified as the total psoas volume (TPV), measured using Ziostation2® imaging software from preoperative and postoperative CT scans at 1, 2, and 3 years. The study compared postoperative TPV trends across the different cancer types.

Results: The study cohort comprised patients with esophageal (median age 66 years, 85% male), gastric (65 years, 60%), and colorectal cancers (67 years, 55%). Median BMIs were 21.5, 19.4, and 22.6 kg/m2, and median TPVs were 352.0, 305.8, and 309.5 cm3 for esophageal, gastric, and colorectal cancers, respectively. Esophageal cancer patients had significantly higher TPV and male predominance, while gastric cancer patients had notably lower BMI. Relative to preoperative TPV, the postoperative TPV at three years was 0.92, 0.91, and 0.96 for esophageal, gastric, and colorectal cancers, respectively. A year-by-year decrease in TPV was observed for each cancer type, with colorectal cancer demonstrating a less pronounced decrease compared to esophageal and gastric cancers (p<0.01). Stage-wise analysis revealed no significant differences among the cancer types. Regarding gender, no significant differences were noted between gastric and colorectal cancers, but esophageal cancer showed a more marked decrease in TPV in males compared to females. In recurrent cases, no significant TPV differences were observed in esophageal cancer, while recurrent gastric and colorectal cancers exhibited significant TPV decreases.

Conclusions: The study indicates a general decline in TPV following gastrointestinal cancer surgery, with the extent of reduction varying according to the type of tumor and treatment.

Citation Format: Yuto Maeda, Yuji Miyamoto, Mayuko Ohuchi, Yukiharu Hiyoshi, Naoya Yoshida, Hideo Baba. Changes in skeletal muscle mass after gastrointestinal cancer surgery by body composition [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 2401.
Abstract 2409: Circulating differential methylation allele fraction (DMAF) strongly correlates with circulating tumor DNA (ctDNA) variant allele fraction (VAF)
Authors: Srinivasan Preethi , Chen Tzu-Chun , Haghshenas Ehsan , Kordi Misagh , Tunc Ilker , Chan Wenching , Solari Omid Shams , Babiarz Joshua , Nakamura Yoshiaki , Yoshino Takayuki , Aleshin Alexey , Kawli Trupti , Reiter Johannes G.
Published: March 2024

Measurement of ctDNA has been established as a prognostic biomarker of cancer disease burden. Emerging evidence has demonstrated that differential methylation patterns can serve as an accurate biomarker both for cancer detection and for predicting the tissue of origin. While it is important to distinguish cancer-positive from cancer-negative patients, clinical decision making increasingly depends on the exact level of the measured biomarker. To that end, we report on the correlation between ctDNA VAF and DMAF across patients with colorectal cancer (CRC). Pre-surgical plasma samples from patients with CRC (N=70) were sourced from the prospective GALAXY, observational arm of ongoing CIRCULATE-Japan study trial (UMIN000039205). Samples classified as ctDNA-positive by a tumor-informed ctDNA assay (SignateraTM) were included in this analysis and ctDNA VAF (%) was calculated. We performed deep methylation sequencing (Illumina Novaseq) across multiple target regions using two independent target sets. DMAF was calculated computationally, which estimates the fraction of differential methylation alleles for circulating cell-free DNA across target regions. Among 70 CRC patients, 68 had positive ctDNA results. Median age at testing was 64.0 years and male individuals represented 55.9% (n=38) of the cohort. Among them, 9 (13.2%) were stage I, 24 (35.3%) were stage II, 22 (32.3%) were stage III, 8 (11.7%) were stage IV, and 5 (7.3%) had unknown staging. The correlation of DMAF with ctDNA VAF was 0.894 (Spearman’s Rank Correlation Coefficient) and was independent of disease stage, histology, age, and sex. Among MSS (micro-satellite stable; n=58) and MSI-H (micro-satellite unstable n=10) patients, the DMAF correlation was 0.9 and 0.915, respectively. The correlation between two target sets evaluating DMAF with differing numbers of targeted regions was high (0.89). These data demonstrate that abundance of differential methylation in CRC patients correlates with VAF regardless of clinicopathologic features of patients with CRC. Methylation-based assays are a promising tool for cancer detection and quantifying the disease burden.

Citation Format: Preethi Srinivasan, Tzu-Chun Chen, Ehsan Haghshenas, Misagh Kordi, Ilker Tunc, Wenching Chan, Omid Shams Solari, Joshua Babiarz, Yoshiaki Nakamura, Takayuki Yoshino, Alexey Aleshin, Trupti Kawli, Johannes G. Reiter. Circulating differential methylation allele fraction (DMAF) strongly correlates with circulating tumor DNA (ctDNA) variant allele fraction (VAF) [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 2409.
Abstract 2432: Improved liquid biopsy assay performance using sequencing by binding (SBB)
Authors: Nasko Dan , Pham Phillip , Joshi Stuti , Kim Kristi , Pezeshkian Nairi , Kim Young , Sockell Alexandra , Korlach Jonas
Published: March 2024

Liquid biopsy is revolutionizing the field of early cancer detection research through non-invasive detection of tumor DNA in the blood. However, existing liquid biopsy assays are limited in their sensitivity for ctDNA detection at low variant allele frequencies (VAFs), with most relying on extreme sequencing depth and computational error correction to separate the true ctDNA signal from background errors. This limitation is particularly problematic in the area of early cancer detection, in which expected ctDNA allele frequencies are extremely low. Novel strategies are therefore needed to help improve liquid biopsy assay sensitivity and reduce per-sample sequencing requirements. Here we describe PacBio’s application of the Onso short-read sequencing system to enable detection of ctDNA at low VAFs using the SeraCare Complete ctDNA Mutation Mix reference standard. The Onso system makes use of a novel sequencing by binding (SBB) method to achieve up to 15x greater quality scores, with ≥90% of reads at Q40 or above. We performed targeted capture and sequencing of libraries prepared from the SeraCare reference mix diluted into WT human DNA at the following VAFs: 0.00% (WT), 0.05%, 0.10%, 0.25%, and 0.50%, and compared the sensitivity at each VAF for SBB compared to a competitor method using sequencing by synthesis (SBS) at varying sequencing depths. We observed superior sensitivity for ctDNA detection at low VAFs (0.05%, 0.1%) using SBB at half the sequencing depth compared to SBS, in part due to reduced false positive calling in the WT sample for SBB. Furthermore, SBB was able to achieve comparable sensitivity results to SBS using four-fold less sequencing, and without the use of computational error correction. Finally, combining SBB with computational error-correction methods boosted sensitivity even further, suggesting an additive value for these technologies. Taken together, our results demonstrate the potential of SBB to improve upon existing methods of liquid biopsy and better enable research on early cancer detection.

Citation Format: Dan Nasko, Phillip Pham, Stuti Joshi, Kristi Kim, Nairi Pezeshkian, Young Kim, Alexandra Sockell, Jonas Korlach. Improved liquid biopsy assay performance using sequencing by binding (SBB) [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 2432.
Abstract 2446: Genomic landscape of longitudinally collected preinvasive airway lesions
Authors: Alhendi Ahmed , Kalinke Lukas , Pennycuick Adam , Davies Kate , Durrenberger Pascal , Gowers Kate , Grigoriadis Kristiana , McGranahan Nicholas , Janes Sam
Published: March 2024

Lung carcinoma in situ (CIS) lesions, as precursors to squamous cell carcinoma, exhibit microscopic uniformity while displaying diverse clinical trajectories. Half of these lesions progress to invasive cancer, while the remaining half either regress or remain indolent. Previous genomic profiling efforts have elucidated progression-specific genomic changes against a backdrop of inherent heterogeneity and notable chromosomal instability signatures. Here, we present a novel approach by analyzing longitudinally collected samples of preinvasive airway lesions, encompassing both progressive and indolent trajectories.

Our findings reveal that genomic integrity and cell cycle dynamics constitute key distinctions between progressive and indolent lesions. Notably, a decrease in clonal diversity and an inverse correlation between TCRA-Tcell fraction and genomic instability are observed as lesions approach invasion. Somatic mutations in cancer driver genes BRAC2, CSMD3, and MUC16 are found significantly associated with lesion progression. Furthermore, progressive lesions exhibit a higher frequency of copy number changes compared to indolent lesions. Copy number loss in 1p, 3p, 9p, and 17p are found to be significantly associated with lesion progression. Phylogenetic analysis further confirms positive selection for copy number loss in these specific genomic regions, providing insights into the evolutionary trajectory of alterations in progressive lesions. The comprehensive understanding derived from these genomic analyses is anticipated to advance early detection strategies, mitigate overtreatment, and facilitate the development of preventative therapies targeting early clonal events in lung cancer.

Citation Format: Ahmed Alhendi, Lukas Kalinke, Adam Pennycuick, Kate Davies, Pascal Durrenberger, Kate Gowers, Kristiana Grigoriadis, Nicholas McGranahan, Sam Janes. Genomic landscape of longitudinally collected preinvasive airway lesions [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 2446.
Abstract 2453: Soluble B7H3 has a potential of novel serum biomaker for colorectal cancer
Authors: Koizumi Akihiro , Ito Tomoaki , Kato Kazunori , Iwasawa Takumi , Kushida Tomoyuki , Sato Koichi , Okamoto Chikako
Published: March 2024

B7H3 (also known as CD276, an immune checkpoint molecule) is aberrantly over expressed in many types of cancer. Recently, several reports indicate a crucial role for B7H3 in promoting carcinogenesis and metastasis. We investigated whether concentration of the soluble B7H3 could be used as a new prognostic predictor of colorectal cancer by measuring serum level of B7H3. Recently we established a new mAb to B7H3 and developed sandwich ELISA-system detecting human serum B7H3 with high sensitivity and specificity. Measuring the levels of B7H3 in the serum specimens of colorectal cancer donors, we examined the usefulness of B7H3 as a novel biomarker for colorectal cancers. We tested the blood from the 82 donors of colorectal cancers and 9 healthy donors who agreed in writing to this research, just before the operation. The mean value + 2SD in 9 healthy donors was set as the cutoff value. We classified cancer patients into 2 groups with high value of B7H3 and low value of B7H3. We also analyzed the relationships between serum B7H3 levels and disease-free survival (DFS) and overall survival (OS). Serum B7H3 levels were also compared with diagnostic biomarkers such as CEA and CA19-9. B7H3 immunostaining was also performed on tissue samples. The serum levels of B7H3 in patients with colorectal cancer were significantly higher than those of healthy donors. However, there were no correlation between B7H3 and other diagnostic markers CEA and CA19-9. Regarding DFS, the higher value group of serum B7H3 showed a tendency for DFS to decrease in Stage II and III. Regarding OS, there was no significant difference of serum levels of B7H3 in Stage I and IV cases, however, in Stage II and III, OS decreased significantly in the high B7H3 group. In B7H3 immunostaining, the tissue was not sufficiently stained. These data indicate that serum B7-H3 should be useful for novel biomarker for a rationale of disease monitoring and prognosis of colorectal cancer.

Citation Format: Akihiro Koizumi, Tomoaki Ito, Kazunori Kato, Takumi Iwasawa, Tomoyuki Kushida, Koichi Sato, Chikako Okamoto. Soluble B7H3 has a potential of novel serum biomaker for colorectal 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 2453.