bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4209: Cancers of unknown primary: survival by histologic type, demographic features, and treatment in the US Military Health System
Authors: Bytnar Julie A. , Lin Jie , Moncur Joel T. , Shriver Craig D. , Zhu Kangmin
Published: April 2023

Background: Cancers of unknown primary (CUP), a group of heterogenous metastatic cancers lacking a known primary site, have poor prognosis. This study compared survival by histologic type, patient characteristics, and treatment in the U.S. Military Health System (MHS), which provides universal care to its members.

Methods: Patients diagnosed with CUP were identified from the U.S. Department of Defense’s Automated Central Tumor Registry. Median survival with 95% confidence intervals was calculated for demographic and treatment variables by histologic type. A multivariable accelerated failure time model estimated time ratios and 95% confidence intervals.

Results: The study included 3,358 CUP patients. The most prevalent CUP in this study was well and moderately differentiated adenocarcinomas. Median survival varied by histologic type with squamous cell carcinoma having the longest at 25.1 months and poorly differentiated carcinomas having the shortest at 3.0 months. For each histologic type, survival was generally similar by sex and active-duty status. Younger patients tended to have longer survival than those aged 65 years or older. Women with well and moderately differentiated adenocarcinoma had longer survival than their male counterparts. Generally, there were no racial differences in survival except poorer survival for Blacks than Whites with other histologic types. Patents with chemotherapy and radiation treatment generally had improved survival whereas patients with squamous cell carcinoma who received chemotherapy had shorter survival than those without.

Conclusion: Survival generally did not differ between racial groups, which may be related to equal healthcare access despite racial background. Further studies are warranted to better understand how survival in the MHS compares with that in the general U.S. population.

Disclaimer: The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions or policies of USUHS, HJF, the DoD or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products or organizations does not imply endorsement by the US Government.

Citation Format: Julie A. Bytnar, Jie Lin, Joel T. Moncur, Craig D. Shriver, Kangmin Zhu. Cancers of unknown primary: survival by histologic type, demographic features, and treatment in the US Military Health System. [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 4209.
Abstract 4266: Genomic landscape of prostate cancer: Bioinformatic analysis of TCGA PanCancer data by race and identification of key pathways and genes in PTEN mutation
Authors: Arigbede Olumide , Buxbaum Sarah G. , Falzarano Sara , Rhie Suhn K.
Published: April 2023

Issue: Prostate cancer (Pca) is still among the most frequently diagnosed cancers in adults. The most often mutated gene in PCa is PTEN (Phosphatase and Tensin Homolog), making it a possible biomarker for prospective customized therapy. The root causes of health inequalities in PCa have not received much attention. Numerous online databases, like The Cancer Genome Atlas (TCGA), provide gene expression data and other data, allowing researchers to further investigate new processes or therapy options. However, there hasn't been much study on tailored therapy up to this point since there may have been difficulties with access to genomic information and bioinformatic tools.

Methods: The PCa data in cBioPortal comprises 494 samples. We selected 154 samples comprising 7 Blacks and 147 Whites. We used the TCGA database to obtain the PCa gene expression and DNA methylation data for study. In order to examine the data by race/ethnicity, gene expression, DNA methylation, and genomic changes, we evaluated at the differentially expressed and methylated genes using online tools (cBioPortal). To evaluate gene methylation, expression, and alterations, log ratios of means in Blacks to means in Whites were computed across the data. Additionally, Kaplan-Meier survival analysis, protein interaction analysis, and multivariable data analysis were carried out.

Results: PCa data in the TCGA database showed PTEN mutation in 20% patients. The median age of participants was 63 years (range: 42-78). For every category of data assessed, there were significant differences by race/ethnicity (q < 0.05). In the survival analysis, SLC2A1, NUDT12, CUTALP, and other genes were associated with survival.

Conclusion: Genetic alteration, expression, and DNA methylation are each significantly different by the two race groups compared. According to our research, PTEN mutation in PCa may influence several genes and biological processes.

Citation Format: Olumide Arigbede, Sarah G. Buxbaum, Sara Falzarano, Suhn K. Rhie. Genomic landscape of prostate cancer: Bioinformatic analysis of TCGA PanCancer data by race and identification of key pathways and genes in PTEN mutation. [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 4266.
Abstract 4439: Negative impact of the GABA pathway on aPD(L)1 immunotherapy
Authors: Lyalina Svetlana , Ortiz-Munoz Guadalupe , Yuen Kobe , Mellman Ira , Mariathasan Sanjeev , Albert Matthew , Nagarkar Deepti , Moussion Christine
Published: April 2023

Although gamma-amino butyric acid (GABA) is well characterized as the primary inhibitory neurotransmitter of the central nervous system, its role in the periphery as an immunomodulatory agent is not well understood. Given the widespread use of GABA-A receptor agonists as palliative care in clinical practice, we examined here the impact of GABA on response to immunotherapy in preclinical tumor models and the association of GABA-A receptor agonist usage with outcomes in patients receiving immunotherapy.We show that important genes controlling the GABA pathway are enriched in human tumors versus normal tissue across indications, and tumor cells themselves are able to produce GABA. We found that several key genes of the GABA pathway are upregulated in non-responders to atezolizumab and we derived a 5-gene signature associated with poor outcomes in 2L urothelial cancer patients receiving atezolizumab. Preclinical models further indicated that GABA at the tumor site promotes tumor growth and dampens adaptive immunity preventing response to immunotherapy. Finally, we noted that 45% of urothelial cancer patients received concomitant GABA-A positive allosteric modulators, given as palliative therapy in atezolizumab trials IMvigor-210 and -211. This group exhibited significantly lower OS and PFS as compared to atezolizumab treated patients who did not receive GABA-A positive modulators. A similar negative impact was seen in patients receiving standard of care anti-PD(L)1 immunotherapy in 2L NSCLC using EHR derived deidentified Flatiron Health - Komodo Health claims linked data. These findings highlight the need for further evaluation of concomitant GABA modulators to understand potential risk associated with palliative care in the setting of cancer immunotherapy.

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Reprinted with permission.

Citation Format: Svetlana Lyalina, Guadalupe Ortiz-Munoz, Kobe Yuen, Ira Mellman, Sanjeev Mariathasan, Matthew Albert, Deepti Nagarkar, Christine Moussion. Negative impact of the GABA pathway on aPD(L)1 immunotherapy. [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 4439.
Abstract 4502: Aptamer conjugated prostate specific membrane antigen (PSMA) targeting nanobees for prostate cancer prevention and therapy
Authors: Rady Islam , Bakry Sayed , El-Azm Fatma Abou , Mukhtar Hasan
Published: April 2023

Melittin (MEL), a major peptide component of bee venom (BV), has shown chemopreventive as well as chemotherapeutic effects against many cancers in preclinical model systems. However, its applicability to humans has met with limited success due to several issues including its toxicity, nonspecificity, degradation, inefficient systemic delivery and limited bioavailability. Earlier, the concept of "nanochemoprevention" i.e. the use of nanotechnology to improve the outcome of cancer chemoprevention is introduced. Then, "non-targeted nanobees" i.e. nanoformulated mellitin is developed to exhibit excellent anti-prostate cancer efficacy in vitro and in animal models coining the concept as ‘Nanobee- Chemoprevention’. Here, we are extending this work and developed nanobees targeted with small molecular entities (A10 2′-fluoropyrimidine RNA aptamers (Apt)), able to bind to prostate specific membrane antigen (PSMA), a transmembrane protein that is overexpressed in prostate cancer (PCa) and evaluated their efficacy in preclinical studies. The Apt-Nanobees led to an enhanced anti-proliferative activity in PCa cell lines compared to the free melittin. The behavior of Apt-Nanobees in modulating apoptosis and cell-cycle, was also determined. Then, in vivo experiments, in mouse xenograft model of prostatic tumor using nanobees with a model of targeted nanosystems, were conducted. The obtained data supported our hypothesis of targeted nanobees enhanced the bioavailability and limited unwanted toxicity of melittin, thus leading to a significant potential for probable clinical outcome.

Citation Format: Islam Rady, Sayed Bakry, Fatma Abou El-Azm, Hasan Mukhtar. Aptamer conjugated prostate specific membrane antigen (PSMA) targeting nanobees for prostate cancer prevention and 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 4502.
Abstract 4634: Identifying and analyzing tumor subtypes using custom morphology markers for NanoString® GeoMx® Digital Spatial Profiler
Authors: Runyon Jessica , Baichwal Vijay , Stauffer Weston , Nievera Christian
Published: April 2023

Molecular subtyping studies have allowed the allocation of cancer into groups based on similar molecular, morphological, and clinical characteristics. Such studies are critical to help researchers identify actionable targets for drug design and biomarkers to predict therapeutic response. Based on multi-omics data, various approaches have been used to identify and analyze tumor subtypes and their correlation with tumor immunity and immunotherapy success. The NanoString GeoMx Digital Spatial Profiler is one approach that combines morphological context with spatial transcriptomics on a single tissue specimen. A critical step in this approach involves staining with morphology markers to identify relevant regions of interest (ROIs) for analysis. Yet, widespread adoption of GeoMx DSP has revealed a significant limitation, namely that researchers base transcriptional analysis of thousands of RNA targets on the spatial information provided by only a few morphology markers. Recent efforts have greatly expanded the availability of morphology markers to facilitate cell type-specific analyses. To evaluate the ability of this technology to selectively enrich specific cell types, we developed custom morphology markers to stain non-small-cell lung cancer (NSCLC) tissue specimens of various subtypes. Focusing on squamous cell carcinoma and adenocarcinoma, we stained with P40 and TTF-1 and transcriptionally profiled cell type-specific ROIs with the Cancer Transcriptome Atlas panel. Differential gene expression analysis of the whole transcriptome was performed using GeoMx DSP Analysis Suite software. The data reveal differences in gene expression in several key cancer pathways between tumor subtypes are correlated with the presence or absence of specific cell types. The data support the use of custom morphology markers for cell type stratification in tumor subtypes, providing more meaningful gene expression analysis. Ongoing work continues to explore the utility of this technology for cell type-specific gene expression analysis within different tumor subtypes.

Citation Format: Jessica Runyon, Vijay Baichwal, Weston Stauffer, Christian Nievera. Identifying and analyzing tumor subtypes using custom morphology markers for NanoString® GeoMx® Digital Spatial Profiler. [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 4634.
Abstract 4679: Molecular pathology and BTKi pharmacology of DLBCL-PDXs
Authors: Wang Jingjing , Wang Yueying , Qian Wubin , Xue Jia , Guo Sheng , Zhang Likun , Li Henry Qixiang
Published: April 2023

Diffuse large B-cell lymphoma (DLBCL), the largest subtype of non-Hodgkin’s lymphoma (NHL, ~40%), is a heterogeneous disease with diverse pathogenesis, represented by different subtypes/genotypes based on lymphoma related specific gene expression profiling according to cell-of-origin (COO) and/or mutation profiles, likely influencing their responses to drug treatment. Patient derived xenografts (PDXs) represent powerful experimental system to investigate heterogeneous molecular pathology, and their corresponding pharmacology of DLBCLs. We created a unique cohort of 19 PDXs representative of diverse subtypes of de novo DLBCL patients, along with 15 EBV transformed DLBCLs during xenografting, followed by comprehensive molecular pathological analysis, using “EBV scan”, COO and LymphGen algorithm. The 19 de novo DLBCL-PDXs were classified into activated B cell-like (7/19 ABC, including 2 EBV+), germinal center B-cell-like (4/19 GCB) and unclassified (8/19 including 4 EBV+); the 15 EBV transformed DLBCL include two ABC, one GCB and 12 unclassified. The de novo DLBCL-PDXs were also annotated as MCD, BN2, N1, A53, ST2, and unknown genotypes. Clustering and principal component analysis (PCA) clearly separated EBV+ DLBCL-PDXs (regardless of de novo DLBCL, EBV-associated, or EBV transformed DLBCLs) from the EBV− de novo DLBCL-PDXs, suggesting distinct molecular pathogenesis, while no apparent difference between the two EBV+ DLBCLs suggested the similar pathogenesis. The expanded mouse clinical trial of BTKi using drinking water administration of ibrutinib (0.16mg/ml) showed: 1) EBV− MCD and BN2 genotype are largely sensitive, suggesting these models’ dependency of chronic BCR signaling; 2) all EBV+ DLBCLs, regardless of the origin or genotypes, are all insensitive; 3) there are some cases of EBV− non-MCD/BN2 models being sensitive, likely due to the presence of certain related activating mutations. Molecular pathology analysis also demonstrated EBV+ PDXs, including significantly elevated BCL2 and down-regulated BCL6, in contrast to EBV− DLBCL-PDXs, implicating possible sensitivity to respective treatments. In summary, these observations in PDXs, some of which are consistent with the retrospective analysis of clinical trials, can be used to help develop BTKi and other treatment for DLBCLs.

Citation Format: Jingjing Wang, Yueying Wang, Wubin Qian, Jia Xue, Sheng Guo, Likun Zhang, Henry Qixiang Li. Molecular pathology and BTKi pharmacology of DLBCL-PDXs. [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 4679.
Abstract 4723: DNA G-quadruplex facilitates MYC enhancer-promotor interaction
Authors: De Lima Dieila Giomo , Guimarães Gustavo Narvaes , Bianco Bianca Caroline , De Souza Ana Paula , Planello Aline Cristiane
Published: April 2023

Background: G-quadruplexes (G4) are nucleic acid secondary structures formed in guanine-rich regions of DNA or RNA. The biological significance of G4 has been attributed to the regulation of gene expression, and more recently, to the stabilization and generation of enhancer-promotor interaction. Since G4 are enriched in the promoter region of the proto-oncogene MYC, we sought to investigate the role of G4 in stabilizing the enhancer-promoter loop using the locus 8q24 (hg38) 127,700,000-128,500,000 that contains the MYC gene as a model.

Methods: Two different cell lines were used, the spontaneously immortalized, non-oncogenic human epidermal keratinocyte (HaCaT), in which the enrichment of G4 in the MYC promoter was demonstrated, and the primary normal human epidermal keratinocyte (nHEK) that is depleted of G4 in MYC promoter. Both cell lines were exposed to the G4 selective stabilizer 360-A drug and the half-maximal inhibitory concentration (IC50) could be calculated. Gene expression was accessed by RT-qPCR and DNA methylation by Methylation-Sensitive High Resolution Melting (MS-HRM). Chromatin Conformation Capture (3C-qPCR) technique was performed interrogating the MYC gene (chr8:127,733,798-127,744,729) and the putative enhancer in the lncRNA PVT1 gene (chr8:127,914,509-127,922,393) to compare the frequency of promoter-enhancer interaction between the two cell lines.

Results: The HaCaT cells showed interaction between the MYC promoter and the distal region. The nHEK cells that are not enriched for G4 showed no promoter interaction with the distal region. The use of 360-A in IC50 did not change the results. The gene expression analysis of the MYC showed higher expression in HaCaT cells compared to nHEK. There was no difference in DNA methylation in the MYC promoter between the two cell lines.

Conclusions: The data suggest an important role of G4 for the interaction of the MYC promoter and downstream enhancer. Additional analyzes of other genomic regions enriched for G4 should be performed to confirm the mechanism.

Citation Format: Dieila Giomo De Lima, Gustavo Narvaes Guimarães, Bianca Caroline Bianco, Ana Paula De Souza, Aline Cristiane Planello. DNA G-quadruplex facilitates MYC enhancer-promotor interaction. [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 4723.
Abstract 4822: Signaling pathways associated with stress factors in gastrointestinal cancers
Authors: Sanchez Amayrani , Doxtater Kyle D. , Lopez Samantha , Leslie Sophia , George Elias , Dhevan Vijian , Jaggi Meena , Chauhan Subhash , Tripathi Manish K.
Published: April 2023

Gastrointestinal (GI) cancer affects various significant organs along the gastrointestinal tract, which contains several of the leading cancer-related deaths in the United States. According to the American Cancer Society, colorectal and liver cancers are among the top ten leading deaths due to cancer, ranking third and sixth, respectively. In the Rio Grande Valley region with a majority Hispanic population, colorectal cancer and liver have a higher occurrence than in the entire state of Texas. However, for many, a cancer diagnosis can worsen with stress, which is also a common occurrence within the Rio Grande Valley region due to 30% of its population living in poverty. Stress can cause changes to the immune system's functionality and the inflammatory response that could lead to insufficient surveillance for any potential oncogenicity. When the Hypothalamic-Pituitary-Adrenal (HPA) axis becomes activated by stress, it will release several stress hormones, such as leptin and cortisol, in response that can play a role in the progression and growth of cancer tumors. To further explore this relationship, hepatocellular carcinoma (HCC) cells and colorectal cancer (CRC) cells were treated with cortisol and leptin at various time points to create models mimicking acute and chronic stress exposure. Afterward, the mRNA mean fold change levels were obtained utilizing the RT-PCR method to determine the levels of each gene in various liver and colorectal cancer cell lines.Additionally, a kinase assay will provide further insight and evidence into the signaling pathway based on the results of the RT-PCR. The current results have shown an upregulation of lncRNA MALAT1, ZNF384, and YB-1 genes at varying degrees depending on the cell line, stress hormone, and duration of treatment. Consequently, these findings have shown an upregulation of oncogenic long non-coding RNA and transcription factors, presenting a signaling oncogenic pathway model by stress factors in HCC and CRC cell lines. Therefore, understanding the role of stress-factors in the oncogenicity and progression of cancer can aid in creating therapeutics for a population where stress can play a role in cancer disparity.

Citation Format: Amayrani Sanchez, Kyle D. Doxtater, Samantha Lopez, Sophia Leslie, Elias George, Vijian Dhevan, Meena Jaggi, Subhash Chauhan, Manish K. Tripathi. Signaling pathways associated with stress factors in gastrointestinal cancers. [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 4822.
Abstract 4842: Stress-induced mitochondrial adaptations in the polyaneuploid cancer cell state
Authors: Li Melvin , Kostecka Laurie G. , Amend Sarah R. , Pienta Kenneth J.
Published: April 2023

Metastatic cancer is responsible for 90% of cancer deaths and is incurable due to resistance to all systemic anticancer therapies. While the classic model of therapy resistance is described by the presence of pre-existing resistant clones from tumor cell heterogeneity, our lab proposes the polyaneuploid cancer cell (PACC) state as a survival mechanism that cancer cells access when exposed to environmental stress such as hypoxia and chemotherapy. Our preliminary data has shown that cells that enter the PACC state exhibit repeated whole genome doubling, an increase in cell size, and proliferative arrest. In addition, we observed that a subpopulation of PACCs can give rise to non-polyploid, proliferative progeny after release from chemotherapy, modeling cancer recurrence. We hypothesize that the PACC state drives therapeutic resistance and elimination of this adaptive state is key in tackling the incurability of cancer. Mitochondria are essential organelles that have multifaceted roles in the cellular stress response and drug resistance. They integrate metabolic pathways for ATP generation and macromolecule biosynthesis, regulate apoptotic cell death, and activate stress response mechanisms in presence of drug treatment. We found that cells in the PACC state increase mitochondrial biogenesis and live cell imaging with MitoTraker dyes indicate that they also have higher activity per mitochondria when compared to parental cells. Cells that accessed the PACC state also had higher levels of TCA cycle metabolites including citrate, isocitrate, alpha-ketoglutarate, succinate, fumarate, and malate, suggesting increased mitochondrial function. Future work includes analysis of mitochondrial morphology via live cell confocal microscopy and of mitochondrial function via metabolic flux analysis on glucose and glutamine metabolism of cells in the PACC state. Our eventual goal is to characterize how cells in the PACC state alter their mitochondrial structure and function to survive therapy. Identifying vulnerabilities of the PACC phenotype will enable new therapeutic approaches to overcome therapy resistance in cancer.

Citation Format: Melvin Li, Laurie G. Kostecka, Sarah R. Amend, Kenneth J. Pienta. Stress-induced mitochondrial adaptations in the polyaneuploid cancer cell state. [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 4842.
Abstract 4965: Targeting the mitotic kinesin, KIF18A, in chromosomally unstable cancers
Authors: Joseph James D. , Schutt Katherine , Fisher Kira , Queen Katelyn , Budington Olivia , Mao Weifeng , Liu Wei , Zhu Zhengqing , Zhang Xiangping , Xiao Yisong , Lai Kunmin , Gu Xiaohui , Stumpff Jason , Aswad Fred
Published: April 2023

Background: Chromosome instability (CIN), characterized by frequent and ongoing loss or gain of chromosome number, is commonly observed in tumor cells. Although long recognized as a vulnerability of cancer cells, potential CIN-selective therapeutic targets have only recently been discovered. Genetic studies from multiple groups have identified the mitotic kinesin, KIF18A, as selectively essential for the proliferation of CIN and aneuploid cells. By targeting KIF18A genetically and with novel small molecule inhibitors here we present data supporting KIF18A as therapeutic target in CIN tumors.

Methods and Materials: To explore the therapeutic potential of KIF18A, we evaluated the effects of KIF18A genetic depletion and small molecule inhibition in both CIN-positive and CIN-negative cell lines. Biochemical, cell proliferation and phenotypic assays were used to characterize the potency and cellular activity of reference and novel KIF18A small molecule inhibitors. Anti-tumor activity of KIF18A inhibitors was assessed in CIN-positive cell line xenograft models.

Results: In triple negative breast and colorectal CIN positive cancer cell lines siRNA mediated KIF18A knockdown and small molecule inhibition of the KIF18A ATPase activity both lead to a reduction in proliferation associated with an increase in mitotic index and multi-polar spindles. Consistent with KIF18A knockdown, KIF18A inhibition results in increased spindle length and chromosome alignment defects. Importantly, these effects are not observed with KIF18A knockdown or KIF18A inhibition in non-transformed, near diploid cells. In vivo, treatment of CIN-positive xenograft tumors with potent, novel KIF18A inhibitors results in robust anti-tumor activity with minimal impact on body weight.

Conclusions: Collectively our data support KIF18A as a therapeutic target and provide rationale for the continued development of potent selective small molecule KIF18A inhibitors for the treatment of CIN positive cancers.

Citation Format: James D. Joseph, Katherine Schutt, Kira Fisher, Katelyn Queen, Olivia Budington, Weifeng Mao, Wei Liu, Zhengqing Zhu, Xiangping Zhang, Yisong Xiao, Kunmin Lai, Xiaohui Gu, Jason Stumpff, Fred Aswad. Targeting the mitotic kinesin, KIF18A, in chromosomally unstable cancers. [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 4965.
Abstract 4981: The potent quadruplex-binding compound QN-302 down-regulates the S100P gene in in vitro and in vivo models of pancreatic cancer: a potential therapeutic target and biomarker for PDAC
Authors: Williams Nicole , Worthington Jenny , Ahmed Ahmed , Arshad Tariq , Neidle Stephen
Published: April 2023

The compound QN-302, a tetra-substituted naphthalene diimide (ND) derivative has been designed to have high affinity for G-quadruplex (G4) nucleic acids. It has single-digit nM anti-proliferative activity in a panel of human pancreatic cancer cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644) and anti-tumor activity in xenograft, orthotopic and genetic (KPC) models for pancreatic cancer (PDAC). Its mode of action involves the targeting of G4-forming sites in promoter regions of cancer-associated genes, where their prevalence is over-represented compared to other genes. Transcriptome analyses of QN-302 in MIA-PACA2 cells have confirmed genes involved in cancer-associated pathways and carry G4 motifs in their promoters as targets. We have found that expression of the S100P gene, a well-authenticated indicator of PDAC disease and progression, is highly down-regulated in QN-302 treated cells. The S100P gene contains at least five putative G4 motifs, including a classic G4 promoter site just upstream of the transcription start site. We have observed that transcriptome analyses on tumor material from human PDAC patients, and those from poorly differentiated as well as more highly differentiated tumors, have shown that the S100P gene is highly over-expressed (especially in poorly differentiated tumors). We now report on gene expression analysis of S100P using control and treated tumor tissues from a therapeutic study in PDAC MIA-PACA2 xenografts in mice, by means of RT-qPCR and Western blot analyses. The data shows statistically significant dose-dependent decreases in expression of S100P at both the mRNA (to ca 25% of control values) and protein levels (to ca 22% of control values), giving added confidence to the concept that the S100P gene is a therapeutic target in PDAC and may also be useful as a marker of QN-302 response in future clinical use. QN-302 is bio-available at therapeutic doses and is well tolerated at these levels in the animal models. It is being developed for clinical evaluation by Qualigen Therapeutics Inc and is currently at the pre-IND stage.

Citation Format: Nicole Williams, Jenny Worthington, Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The potent quadruplex-binding compound QN-302 down-regulates the S100P gene in in vitro and in vivo models of pancreatic cancer: a potential therapeutic target and biomarker for PDAC. [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 4981.
Abstract 5131: Pulmonary influenza infection promotes the awakening of dormant metastatic breast cancer cells
Authors: Chia Shi Biao , Johnson Bryan , Aguirre-Ghiso Julio A. , Rincon Mercedes , DeGregori James
Published: April 2023

Breast cancer is the most common form of cancer and the second cancer-causing death in females. Although remission rates are high if detected early, survival rates drop substantially when breast cancer becomes metastatic. The most common sites of metastatic breast cancer are bone, liver and lung. Respiratory viral infections inflict illnesses on countless people. The latest pandemic caused by the respiratory virus, SARS-CoV-2, has infected more than 600 million worldwide, with documented COVID-related death upward of 1 million in the United States alone. Respiratory viral infections result in increased inflammation with immune cell influx and expansion to facilitate viral clearance. Prior studies have shown that inflammation, including through neutrophils, can contribute to dormant cancer cells reawakening and outgrowth. Moreover, inhibition of IL6 has been shown to decrease breast cancer lung metastasis in mouse models. However, how respiratory viral infections contribute to breast cancer lung metastasis remains to be unraveled. Using MMTV/PyMT and MMTV/NEU mouse models of breast cancer lung metastasis and influenza A virus as a model respiratory virus, we demonstrated that acute influenza infection and the accompanying inflammation and immune cell influx awakens and dramatically increased proliferation and expansion of dormant disseminated cancer cells (DCC) in the lungs. Acute influenza infection leads to immune influx and expansion, including neutrophils and macrophages, with increased proportion of MHCII+ macrophages in early time points, and a sustained decrease in CD206+ macrophages starting 6 days post-infection until 28 days after the initial infection. Additionally, we observed a sustained accumulation of CD4+ T cells around expanding tumor cells for as long as 28 days after the infection. Notably, neutrophil depletion or IL6 knockout reversed the flu-induced dormant cell expansion in the lung. Finally, awakened DCC exhibited downregulation of vimentin immunoreactivity, suggesting a role for phenotypic plasticity in DCC outgrowth following viral infection. In conclusion, we show that respiratory viral infections awaken and increase proliferation of dormant breast cancer cells in the lung, and that depletion of neutrophils or blocking IL6 reverses influenza-induced dormant cell awakening and proliferation.

Citation Format: Shi Biao Chia, Bryan Johnson, Julio A. Aguirre-Ghiso, Mercedes Rincon, James DeGregori. Pulmonary influenza infection promotes the awakening of dormant metastatic breast cancer cells. [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 5131.
Abstract 5145: Targeting TREX1 induces innate immune response in chemoresistant small cell lung cancer
Authors: Murayama Takahiko , Mahadevan Navin R. , Tani Tetsuo , Ma Xueying , Watanabe Hideo , Barbie David A. , Cañadas Israel
Published: April 2023

Small cell lung cancer (SCLC) is the most lethal type of lung cancer. The uniqueness of this tumor consists of an initial exquisite response to chemotherapy. However, at relapse, which occurs nearly in all patients, the tumor is resistant to all available therapies, causing a premature death of the patient. Despite the addition of immune checkpoint blockade (ICB) therapy to standard chemotherapy, response rates are modest and only a very small fraction of SCLC patients responds to these therapies. The mechanistic basis for acquired chemoresistance and impaired immunogenicity in SCLC remains to be elucidated. Here, we report that the expression of three prime repair exonuclease 1 (TREX1) is strongly induced in chemoresistant SCLCs. ATAC-seq and ChIP-seq analyses revealed a significant increase in chromatin accessibility of TREX1 gene locus in drug resistant SCLC cells. Depletion of TREX1 in SCLC cells caused the activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway due to the cytoplasmic accumulation of DNA damage-associated double-stranded DNA (dsDNA) and micronuclei. Furthermore, targeting TREX1 induced an innate immune response and re-sensitized chemoresistant SCLC cells to chemotherapy. These findings suggest that TREX1 upregulation may be an important mediator of cGAS/STING pathway inactivation in cancer, contributing to the survival of resistant cells, and its inhibition may represent a promising therapeutic strategy to potentiate the efficacy of chemotherapy and immunotherapy in chemoresistant and immunologically ‘cold’ tumors, such as SCLC.

Citation Format: Takahiko Murayama, Navin R. Mahadevan, Tetsuo Tani, Xueying Ma, Hideo Watanabe, David A. Barbie, Israel Cañadas. Targeting TREX1 induces innate immune response in chemoresistant small cell lung 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 5145.
Abstract 5163: Local delivery of mRNA immunotherapy encoding HPV16 antigen, IL-12, and LIGHT/TNFSF14 results in superior immunogenicity and tumor clearance in a murine model of HPV16-driven cancer
Authors: Liu Weiqun , Da Silva Diane M. , Lemmens Edward E. , McKinlay Colin J. , Nath Sangeeta , Leong Meredith L. , Deutsch Samuel , Kast W. Martin , Haabeth Ole Audun W.
Published: April 2023

While intramuscular vaccination with HPV16 antigens has been shown to induce robust tumor-specific immune responses in the periphery, this has led to limited efficacy in the clinic. One potential explanation is the lack of sufficient infiltration of antigen-specific T cells into the tumor. The few T cells that make their way into the tumor are met with a plethora of negative signals that suppress their activity and abrogate local T cell expansion. To overcome this limitation of intramuscular cancer vaccines, we have developed an approach using in situ vaccination with a combination of immune modulators and tumor antigens, all encoded by mRNAs and delivered using nanoparticles. In this study, we show the superior efficacy and immunogenicity of a locally delivered mRNA cancer vaccine over that of an intramuscular HPV16 cancer vaccine. Both routes of administration result in robust induction of antigen-specific T cells, but local administration of mRNA-encoded antigens and immune modulators also resulted in enhanced infiltration of immune cells into the tumor, local Th1/M1 cytokine induction, and more-complete tumor clearance. Specifically, we found that the inclusion of the immunomodulators IL-12 and TNFSF14/LIGHT enabled tumor clearance in a murine tumor model. While tumors treated with mRNA-encoded HPV16 antigen alone induced robust systemic antigen-specific responses, minimal levels of local T cell expansion and infiltration, proinflammatory cytokine induction, and tumor control were observed. By contrast, tumors treated with mRNA-encoded HPV16 antigen, IL-12p70, and TNFSF14 completely cleared large established HPV16 expressing tumors with long-lasting recurrence free survival and immune memory. This observation was replicated in in a second murine tumor model, confirming the superior potency of locally delivered mRNA cancer vaccines in combination with immunomodulators. Consequently, we are developing a locally administrated mRNA therapy for the treatment of patients with cervical intraepithelial neoplasia (CIN).

Citation Format: Weiqun Liu, Diane M. Da Silva, Edward E. Lemmens, Colin J. McKinlay, Sangeeta Nath, Meredith L. Leong, Samuel Deutsch, W. Martin Kast, Ole Audun W. Haabeth. Local delivery of mRNA immunotherapy encoding HPV16 antigen, IL-12, and LIGHT/TNFSF14 results in superior immunogenicity and tumor clearance in a murine model of HPV16-driven 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 5163.
Abstract 5474: Combined use of MRI and TAM analysis in GB monitoring
Authors: Giordano Carolina , Pepa Giuseppe Maria Della , Romano Simona , Marrone Laura , Donzelli Carlo Maria , Romano Maria Fiammetta , Gaudino Simona
Published: April 2023

Glioblastoma (GB) is the most frequent and aggressive primary brain tumor. It is a highly infiltrating tumor. Complete eradication by surgery is difficult. The probability of survival beyond two years is very low. Magnetic resonance imaging (MRI) is a routine procedure for diagnosing gliomas. However, morphological MRI often fails to identify and quantify the presence of infiltration in peritumoral non-enhanced areas, resulting in inaccuracy in the assessment of invasive margins. Up to 50% of the patients show pseudo-progression. Morphological MRI fails to distinguish the marked enhancement in the tumor bed caused by radionecrosis from actual tumor progression. Diagnosis of GB recurrence through MR morphological sequences has a sensitivity and specificity of about 68% and 77%. Such percentages rise thanks to the use of non-morphological sequences (PWI, DWI, MRS), which are used in routine tumor protocols only in large centers and interpreted by expert neuroradiologists. Biomarkers in conjunction with MRI may help improve the classification, prognosis, and treatment choice. GB is highly infiltrated with monocytic cells, tumor-associated macrophages (TAMs), that invade the peripheral blood. Our group has recently identified a splice isoform of FK506-binding protein 51 (FKBP51) as a reliable TAM marker. We found an expansion in circulating CD163/FKBP51s monocytes in a cohort of GB patients. In patients with an MRI diagnosis of complete surgical tumor removal, these monocytes dramatically decreased. In patients with an MRI diagnosis of residual tumor, most of the peripheral CD163 monocytes that in the preoperative stage were FKBP51s- had turned into FKBP51s+. CD163/FKBP51s+ monocytes helped to distinguish between radionecrosis and actual tumor progression. These results suggest that circulating CD163/FKBP51s+ monocytes are associated with GB and can be helpful in monitoring GB patients.

Citation Format: Carolina Giordano, Giuseppe Maria Della Pepa, Simona Romano, Laura Marrone, Carlo Maria Donzelli, Maria Fiammetta Romano, Simona Gaudino. Combined use of MRI and TAM analysis in GB monitoring. [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 5474.
Abstract 5570: Development of prognostic index based on twenty-three genes for predicting superficial-to-invasive progression of non-muscle invasive bladder cancer patients
Authors: Kim Jae-Yoon , Park Seong-Hwan , Kim Seon-Young , Yoon Seok Joong , Kim Seon-Kyu
Published: April 2023

Background: Although recent advances in high-throughput technology and data-driven approach have provided many insights into non-muscle invasive bladder cancer (NMIBC), previous studies are still limited in their ability to predict the clinical behavior of NMIBC. Here, using deep learning method with long term follow-up data, we identified a prognostic gene set consisting of a small gene group for precisely predicting NMIBC heterogeneity.

Methods: We sought to identify progression-associated genes in patients with NMIBC using Cox regression analysis and verified their predictive values using a fully connected neural network (FNN) algorithm in five independent cohorts comprising more than 800 NMIBC patients. Based on these genes, a prognostic index (PI) in NMIBC progression was also developed. The association between the PI and prognosis of NMIBC patients was evaluated using Kaplan-Meier plots and log-rank tests.

Results: Gene expression profiling in NMIBC patients identified a prognostic gene set consisting of 1,789 genes for predicting NMIBC progression in a patient cohort (training set, n = 103). Their prognostic significances were validated based on FNN algorithm in other four independent cohorts (validation sets, n = 722). Pathway enrichment analysis revealed a twenty-three gene signature including known prognostic transcription factors such as FOXM1 and E2F1 along with novel genes. We incorporated these genes into the PI system, which was a significant prognostic indicator of NMIBC progression. The PI system was shown to be an independent risk factor by a multivariate analysis and subset stratification according to stage and grade (each P < 0.001). The subset analysis also revealed that the PI system could identify patients who would benefit from BCG immunotherapy.

Conclusions: The twenty-three gene-based PI represents a promising diagnostic tool for the identification of high-risk NMIBC patients who would display different clinical behaviours as well as response to BCG immunotherapy.

Citation Format: Jae-Yoon Kim, Seong-Hwan Park, Seon-Young Kim, Seok Joong Yoon, Seon-Kyu Kim. Development of prognostic index based on twenty-three genes for predicting superficial-to-invasive progression of non-muscle invasive bladder cancer patients. [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 5570.
Abstract 5659: Targeting solid cancers with a cancer-specific monoclonal antibody to surface expressed aberrant O-glycosylated proteins
Authors: Aasted Mikkel K.M. , Groen Aaron C. , Keane John T. , Dabelsteen Sally , Tan Edwin , Schnabel Julia , Liu Fang , Lewis Hyeon-Gyu S. , Theodoropulos Constantine , Posey Avery D. , Wandall Hans H.
Published: April 2023

The lack of antibodies with sufficient cancer selectivity is currently limiting the treatment of solid tumors by immunotherapies. Most current immunotherapeutic targets are tumor-associated antigens also found in healthy tissues. Such targets often do not display sufficient cancer selectivity to be used for potent antibody based immunotherapeutic treatments, such as chimeric antigen receptor (CAR) T cells. Many solid tumors, however, display aberrant glycosylation that results in the expression of tumor-associated carbohydrate antigens that are not present on healthy tissues. Targeting aberrantly glycosylated glycopeptide epitopes within existing or novel glycoprotein targets may provide the cancer selectivity needed for immunotherapy of solid tumours, but only a few such glycopeptide epitopes have been targeted. Here, we used O-glycoproteomics data from multiple cell lines to identify a glycopeptide epitope in CD44v6, a cancer-associated CD44 isoform, and through a glycopeptide immunization strategy developed a cancer-specific monoclonal antibody, 4C8. 4C8 selectively binds to Tn-glycosylated CD44v6 in a site-specific manner with low nanomolar affinity. 4C8 was shown to be highly cancer selective by immunohistochemistry of sections from multiple healthy and cancerous tissues. 4C8 CAR T cells demonstrated target-specific cytotoxicity in vitro and significant tumor regression, and increased survival in vivo. Importantly, 4C8 CAR T cells selectively killed target cells in a mixed organotypic skin cancer model without affecting healthy CD44v6+ keratinocytes, indicating tolerability and safety. Targeting aberrantly glycosylated glycopeptide epitopes may provide the cancer selectivity needed for solid tumour immunotherapy.

Citation Format: Mikkel K.M. Aasted, Aaron C. Groen, John T. Keane, Sally Dabelsteen, Edwin Tan, Julia Schnabel, Fang Liu, Hyeon-Gyu S. Lewis, Constantine Theodoropulos, Avery D. Posey, Hans H. Wandall. Targeting solid cancers with a cancer-specific monoclonal antibody to surface expressed aberrant O-glycosylated proteins. [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 5659.