bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1881: Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-306 targeting IL-13Rα2 in immuno-oncology
Authors: Huang Wentao , Liu Zhifang , Li Yifan , Pan Heng , Li Yuan , Qin Xia , Fei Da , Li Runsheng 
Published: April 2023

Abstract
Interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed in various types of cancers including glioma and melanoma and is known to be associated with increased tumor invasiveness and metastases. Here, we present the preclinical efficacy and toxicity results for a novel, anti-IL-13Rα2 ADC-LM-306. In vitro binding activity and internalization of LM-306 and LM-106 (unconjugated antibody of LM-306) were assessed in human IL-13Rα2 overexpressing and endogenous cell lines using flow cytometry. The antibody-dependent cell-mediated cytotoxicity (ADCC) and direct cytotoxicity were assessed using viability assays. Cross-species reactivity of drug was assessed in cells expressing cynomolgus, rat and mouse IL-13Rα2. In vivo A375 CDX model was used to assess the effect of LM-306 anti-tumor activity. The toxicity of LM-306 was evaluated in repeated-dose intravenous dose range-finding (DRF) toxicity and single intravenous maximum tolerated dose (MTD) study in cynomolgus monkeys. Both LM-106 and LM-306 showed concentration dependent binding affinity to IL-13Rα2 in various cell lines (Table 1). In addition, LM-106 also showed a dose dependent internalization and ADCC and LM-306 showed significant cytotoxicity in all cell lines (Table 1). Furthermore, LM-306 showed comparable binding affinity to human IL-13Rα2 to its unconjugated counterpart LM-106 (KD:7.43E-10 vs 1.77E-9). LM-306 was also found to be cross-reactive toward cynomolgus IL-13Rα2. In vivo, LM-306 showed tumor growth inhibition at a dose of 1, 3, 10 mg/kg given intravenously once weekly, indicating its strong anti-tumor activity. The highest non-severely toxic dose of LM-306 was determined to be 9 mg/kg in the DRF study and MTD was determined to be 18mg/kg in MTD study for male monkey. In summary, LM-306 showed high binding affinity to human IL13Rα2 expressing cells with potent cytotoxicity in vitro and significant in vivo inhibition of tumor growth, suggesting its therapeutic benefit in immuno-oncology.
Summary of parameters of LM-106 and LM-306 binding affinity, internalization, ADCC and cytotoxicity Assay Antibody EC50 (nM) HEK293/H_IL-13Rα2 U251 A375 SKMEL5 Binding affinity LM-106 0.99 0.21 0.57 0.1 LM-306 1.47 0.33 0.8 0.12 Internalization LM-106 2.22 - 0.43 - ADCC LM-106 0.16 - 0.03 - LM-306 0.31 - 0.03 - Cytotoxicity (IC50) LM-306 0.03 0.05 0.01 0.005
Citation Format: Wentao Huang, Zhifang Liu, Yifan Li, Heng Pan, Yuan Li, Xia Qin, Da Fei, Runsheng Li. Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-306 targeting IL-13Rα2 in immuno-oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1881.
Abstract 1907: Unique and novel deleterious MSH6 mutation among African American patients with colorectal cancer
Authors: Rashid Mudasir , Rashid Rumaisa , Varma Sudhir , Sherif Zaki , Carethers John , Brim Hassan , Ashktorab Hassan 
Published: April 2023

Abstract
Background: Colorectal cancer (CRC) incidence and mortality in African Americans (AA) is higher compared to Caucasians (CAU). It has also been reported that the disparity is due to differences in the mutation spectrum particularly germline mutations in the DNA mismatch repair (MMR) genes (such as hMSH6). Aim: We aimed to determine MSH6 mutation profile in AAs with CRC.
Methods: We performed RNA sequencing in 8 paired CRC samples (AA, n=4 and CAU, n=4) to identify the unique transcript and novel pathogenic mutation in AA compared to CAU by comparing CRC matched to corresponding normal epithelia. In silico analysis of TCGA COAD RNA sequencing data was performed.
Results: We found non-synonymous germline mutations (p.G1139S) in exon 5 of MSH6 gene (one of the MMR genes) in AA CRC samples. Interestingly, this mutation is present in the active site of ATP binding (1135 to 11442 residue) motif of MSH6 protein. In silico analysis was used to determine the novelty and pathogenicity of this mutation by comparison to various publicly available databases. Also, the deleterious effect of p.G1139S missense mutation on the structure of MSH6 protein revealed that p.G1139S is destabilizing MSH6 protein. Based on Ramachandran plot analysis, we found lot of clash and outliers in the mutant type compared to wild type MSH6 protein. Structural analysis revealed that serine substitution results in a wide ATP binding site compared to glycine present in wild-type MSH6. In addition, we found a loss of hydrogen bonding or gain of ionic interaction between wild-type and mutant MSH6 protein.
Conclusion: Based on our in silico analysis, the deleterious effect of the detected missense mutation in the active site of ATP binding motif of MSH6 affects the structure and function of MSH6. This may result in the accumulation of mono-, or di-nucleotide repeats instability in the genome, leading to genomic alterations that associate with carcinogenesis in African American CRC patients.
Citation Format: Mudasir Rashid, Rumaisa Rashid, Sudhir Varma, Zaki Sherif, John Carethers, Hassan Brim, Hassan Ashktorab. Unique and novel deleterious MSH6 mutation among African American patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1907.
Abstract 191: CTC-derived organoids from liver and pancreatic cancer patients for personalized therapy
Authors: Galeano-Garces Catalina , Smith Kaylee J. , Heller Nicholas , Ahmadi Mahdi , Hong Jiarong , Parthasarathy Jayant , Drake Justin M. 
Published: April 2023

Abstract
Organoids are a widely used 3D culture system that has the potential to recapitulate the profile and phenotype of physiological cells. The culture of circulating tumor cells (CTCs) in this 3D system not only mimics the tumor physiological environment but allows researchers to test therapeutic responses to certain drugs based on a patient's own cancer phenotype. The purpose of our study is to perform an in vitro evaluation of patient-derived CTC organoids to more precisely identify personalized therapeutic options based on the response of these CTCs to each specified inhibitor. Using Astrin Bioscience’s proprietary CTC enrichment method, collected CTCs are plated as organoid cultures. The performance of our proprietary enrichment method has been assessed using both spiked cancer cell lines (in whole blood) and patient CTCs. We have successfully grown organoids from four prostate cancer cell lines and patient CTCs across multiple cancer types including pancreatic and liver adenocarcinoma. RNA sequencing of liver CTC organoids expressed EPCAM, a marker of CTC epithelial cells and coincided with data from a prostate epithelial cell line, LNCaP. This serves as robust evidence that our patient derived organoids truly originated as CTCs. Functional assays using different chemotherapies and targeted therapies will be applied to our organoid culture system. Drugs are uniquely selected for each patient based on cancer type, cancer stage and previous failed therapies. Efficacy of therapy is evaluated using imaging and cell viability assays to determine sensitivity or resistivity to each therapy. Transcriptomic and proteomic analyses will also be performed on these samples to aid in the identification of other predictive biomarkers and future novel therapy testing. Thus, this platform creates a pre-clinical drug screening tool to create a personalized guide to potential therapies for each patient.
Citation Format: Catalina Galeano-Garces, Kaylee J. Smith, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Jayant Parthasarathy, Justin M. Drake. CTC-derived organoids from liver and pancreatic cancer patients for personalized therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 191.
Abstract 1915: Cancer disparities in the University of Chicago Comprehensive Cancer Center Catchment Area
Authors: Zhang Stephanie , Ssepuuya Joel , Pierce Brandon 
Published: April 2023

Abstract
Disparities in cancer incidence and mortality have not been described for the University of Chicago Comprehensive Cancer Center’s patient catchment area (CA), the region from which the center draws its patients. The purpose of this research was to describe incidence and mortality rates (2013-2017) for leading cancers in the CA, which consists of Cook County, IL; DuPage County, IL; Lake County, IL; Will County, IL; and Lake County, IN. Age-adjusted rates (per 100,000) were calculated for leading cancers by sex for each county, the CA, U.S., and IL. Racial disparities were also examined by comparing Black rates to White rates. Incidence rates were higher in the CA compared to the U.S for all cancers data was available for: all sites combined, breast, and prostate. For males, mortality rates of prostate, colorectal, pancreatic, and stomach cancers were higher in the CA compared to the U.S. For females, mortality rates of breast, colorectal, myeloma, uterine, stomach, and bladder cancers, as well as all sites combined were higher in the CA compared to the U.S. By county, males experienced incidence rates 8% to nearly 2.5 times higher and mortality rates 3% to over 1.5 times higher compared to the U.S. for various cancers. By county, females experienced incidence rates 5% to over 4 times higher and mortality rates 4% to over 1.5 times higher compared to the U.S. for various cancers. Lake County, IN generally had the highest incidence and mortality rates. Racial disparities in incidence and mortality were present for most cancers in the CA overall and by county. For males, racial disparities in mortality for prostate, stomach, and larynx are of greatest concern. For females, racial disparities in mortality for myeloma, cervical, and uterine are of greatest concern. This research highlights important health inequities and priorities for the UChicago Cancer Center.
Citation Format: Stephanie Zhang, Joel Ssepuuya, Brandon Pierce. Cancer disparities in the University of Chicago Comprehensive Cancer Center Catchment Area [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1915.
Abstract 1937: Racial differences of epigenome in normal breast tissue reveal biological pathways implicated in racial disparities in breast cancer
Authors: Lin Nan , Castle James , Liu Jinpeng , He Chunyan 
Published: April 2023

Abstract
Racial disparity in breast cancer is well recognized. Compared to European American (EA) women, African American (AA) women are more often diagnosed with breast cancer at younger ages, have a more advanced or aggressive disease, and have poorer outcomes. Increasing evidence suggests that biological differences between EA and AA women, particularly differences in epigenetic changes of DNA methylation (DNAm), may contribute to the observed cancer disparity. We hypothesize that racial differences in DNAm in normal breast tissue may reflect distinct genomic susceptibility to breast cancer in different racial groups. Therefore, we investigated epigenome-wide differences of DNAm in normal breast tissue between 178 EA and 272 AA women using the Illumina TruSeq Methyl Capture EPIC library and NGS technology. We identified 17,340 differentially methylated CpG loci (DMLs) between EA and AA women, of which 7,744 were hypermethylated in AA women and 9,596 were hypermethylated in EA women. Pathway analyses of genes annotated to these racial DMLs suggested enrichment of biological processes including cell movement, cell motility, and cell migration, features that are likely linked to the aggressiveness and metastatic potentials of tumor cells. We further examined racial differences in DNAm of breast cancer-related candidate genes and GWAS-identified breast cancer risk loci. Approximately 30% of candidate genes were found to have racial differences in DNAm at more than three CpG sites and these candidate genes were enriched for pathways related to response to stimulus and anatomic structure development. Most interestingly, racial DMLs were found to be enriched for breast cancer risk loci that are associated with risk of estrogen-receptor negative (ER-) breast cancer, treatment response to aromatase inhibitor, and breast cancer-specific morality, phenotypes of which we observed differences between EA and AA breast cancer patients. Our results suggest that racial differences in DNAm in normal breast tissue may induce different biological processes that lead to distinct clinical features of breast tumors observed in EA and AA women and provide an epigenetic mechanism underlying the observed racial disparities. Further research is need to validate the findings of this study.
Citation Format: Nan Lin, James Castle, Jinpeng Liu, Chunyan He. Racial differences of epigenome in normal breast tissue reveal biological pathways implicated in racial disparities in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1937.
Abstract 195: Establishment and validation of pheochromocytoma organoids for high-throughput drug screening
Authors: Calucho Maite , Cheng ZiMing , Nguyen Huyen Thi-Lam , Shihabi Ahmad Al , Gonzalez-Cantu Hector , Guo Qianjin , Thaker Maneesha , Bechmann Nicole , Eisenhofer Graeme , Ding Yanli , Dahia Patricia , Soragni Alice 
Published: April 2023

Abstract
Pheochromocytomas and paragangliomas (PPGL) are rare catecholamine-secreting neuroendocrine tumors known for their genetic diversity. They can be categorized in discrete molecular subgroups, including tumors presenting with pseudohypoxia or kinase signaling activation. Metastatic and recurrent PPGLs have few therapeutic options, in part due to the lack of appropriate study models. Here, we report progress on the establishment of viable organoids from n=10 distinct sporadic or familial PPGLs spanning varios genotypes. We also perform detailed histological, molecular, biochemical, and functional characterization. The ten PPGLs were obtained from patients with distinct clinical history and diverse ethnic and genetic backgrounds. We show how we can generate PPGL organoids from fresh and frozen tissue in a format compatible with histologic characterization and high-throughput drug screening (mini-rings, Phan et al, 2019, Al Shihabi et al, 2022). Our mini ring approach uses fewer cells with no need for expansion in vitro, and is amenable to implement automation for facile high-throughput studies. We can quantify PPGL growth in culture using a machine learning-based pipeline (Al Shihabi et al, 2022). All PPGL organoids for which sufficient number of cells could be obtained grew, regardless of the genotype and molecular subtype. PPGL organoids could be cultured short term (6 days) as well as long term (4 weeks). We investigated cellular composition by staining for the neuroendocrine marker chromogranin A, the sustentacular cell marker S100, and the vascular marker CD34. We also analyzed the expression of catecholamines in the cell culture supernatant by LC/MS/MS. We confirmed that secreted catecholamines matched the primary tumor pattern. Lastly, we present the results of pilot drug screening on both short and long term cultures. Drug sensitivity profiles pinpoint tumor-specific responses. In conclusion, we can establish PPGL organoids that largely recapitulate features of the tumor of origin. These models will provide the ability to investigate tumor initiation and progression for various genetic backgrounds and may reveal novel patterns of drug sensitivity and resistance.
Citation Format: Maite Calucho, ZiMing Cheng, Huyen Thi-Lam Nguyen, Ahmad Al Shihabi, Hector Gonzalez-Cantu, Qianjin Guo, Maneesha Thaker, Nicole Bechmann, Graeme Eisenhofer, Yanli Ding, Patricia Dahia, Alice Soragni. Establishment and validation of pheochromocytoma organoids for high-throughput drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 195.
Abstract 1988: FAP-targeted non-internalising drug conjugates: A comparative evaluation between small molecules, antibodies and peptides
Authors: Zana Aureliano , Moreno Claudia Puig , Gilardoni Ettore , Neri Dario , Cazzamalli Samuele 
Published: April 2023

Abstract
Conventional cancer chemotherapy relies on the use of cytotoxic drugs which are not designed and capable of selective accumulation to neoplastic lesions. The conjugation to tumour-targeting delivery vehicles has been proposed as a strategy to enhance the therapeutic index of potent cytotoxic drugs. To date, fifteen Antibody-Drug Conjugate products have received marketing approval for the treatment of solid and liquid human malignancies. We present an in vivo comparative evaluation of ADCs against products based on small organic delivery vehicles (Small Molecule-Drug Conjugates, or SMDCs) or on tumour-targeting peptides (Peptide-Drug Conjugates, or PDCs). All products are designed to target and to be activated by Fibroblast Activation Protein in the tumour microenvironment. Our results reveal that both targeted ADC and SMDC products mediate potent anti-cancer activity and complete tumour remission in a FAP-positive preclinical murine model of cancer, when administered at the same molar dose. Non-targeted albumin and antibody conjugates included in our comparative studies delayed tumour growth but presented suboptimal anti-cancer efficacy in the same cancer model. Our results indicate that both FAP-targeted ADCs and SMDCs are promising product candidates for the treatment of multiple human malignancies.
Citation Format: Aureliano Zana, Claudia Puig Moreno, Ettore Gilardoni, Dario Neri, Samuele Cazzamalli. FAP-targeted non-internalising drug conjugates: A comparative evaluation between small molecules, antibodies and peptides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1988.
Abstract 1992: P-selectin-targeted delivery of intracranial therapeutics across an intact BBB in Sonic Hedgehog medulloblastoma
Authors: Heller Daniel A. , Tylawsky Daniel , Raju G. Praveen 
Published: April 2023

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor with ~30% mediated by Sonic hedgehog (SHH) signaling. While SHH effector Smoothened inhibition is promising, therapeutic index is reduced by high systemic doses required for sufficient intracranial drug concentrations. Treatment-related toxicities associated with radiation therapy result in lifelong morbidity, and SHH pathway inhibition in children notably results in permanent bone defects. Here, we found that nanoparticle-mediated P-selectin targeting on tumor vasculature induces caveolin-1-dependent transcellular passage across the blood-brain barrier. A vismodegib nanocarrier that targets P-selectin exhibited striking efficacy and markedly reduced both bone-related toxicities and drug exposure to healthy brain. These findings demonstrate a potent strategy and novel mechanism for targeted intracranial pharmacodelivery that overcomes the restrictive endothelial barrier to achieve enhanced tumor-selective penetration and has therapeutic implications for other diseases within the central nervous system.
Citation Format: Daniel A. Heller, Daniel Tylawsky, G. Praveen Raju. P-selectin-targeted delivery of intracranial therapeutics across an intact BBB in Sonic Hedgehog medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1992.
Abstract 2036: Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors
Authors: Mumphrey Michael , Hosseini Noshad , Parolia Abhijit , Geng Jie , Zou Weiping , Raghavan Malini , Chinnaiyan Arul , Cieslik Marcin 
Published: April 2023

Abstract
Disruption of antigen presentation via loss of MHC expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. We developed the personalized genomics algorithm Hapster and accurately called somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1663 nonsynonymous mutations that provide key insights into MHC mutagenesis. We found that MHC-I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC-II mutations are more restricted. Recurrent deleterious mutations are found within haplotype and cancer-type specific hotspots associated with distinct mutational processes. Functional classification of MHC residues revealed significant positive selection for mutations disruptive to the B2M, peptide, and T-cell binding interfaces, as well as MHC chaperones. At the cohort level, all cancers with positive selection for MHC mutations are responsive to immune checkpoint inhibitors, underscoring the translational relevance of our findings.
Citation Format: Michael Mumphrey, Noshad Hosseini, Abhijit Parolia, Jie Geng, Weiping Zou, Malini Raghavan, Arul Chinnaiyan, Marcin Cieslik. Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2036.