tbuckley/cabot-search huggingface dataset:
Abstract 3851: Beta-lapachone promotes tumor associated neutrophils (TANs) polarized towards anti-tumor (N1) phenotype
Authors: Xiumei Huang, Soumya Tumbath, Liangxiang Jiang, Yang-Xin Fu
Journal: Cancer Research (2024)

Abstract NAD(P)H:quinone oxidoreductase1 (NQO1) is overexpressed in most solid cancers, emerging as a promising target for tumor selective killing. β-lapachone (β-lap), an NQO1bioactivatable drug, exhibits significant antitumor effects on NQO1+ human solid cancer cell lines. It also induces immunogenic cell death in the tumor microenvironment (TME)and synergizes with anti-PD-L1 immunotherapy. However, the interaction between β-lap-mediated anti-tumor immune response and neutrophils, a novel antigen presenting cells(APCs), remains unknown. This study found β-lap treatment increased intracellular ROS formation and DNA damage to kill NQO1+ murine tumor cell lines and dicoumarol spared the lethality. Furthermore, flow cytometric analysis of immune cells in TME of subcutaneous tumor models indicated that there is a significant infiltration of neutrophils(CD11b+ Gr1high cells) or Tumor Associated Neutrophils (TANs) following β-lap treatment. Depletion of neutrophils by co-addition of anti-Ly6G antibody abolished β-lap-induced anti-tumor efficacy in immune competent mice. Neutrophil mediated tumor cell killing determined ex vivo using bone marrow derived neutrophils and it was observed that in the presence of β-lap induced antigen, neutrophils were killing murine tumor cells. Moreover, exposure of these neutrophils to β-lap induced antigen medium induce antitumor N1-like properties, include increase in certain surface markers such as CD95(Fas) and CD54 (ICAM-1) as well as increase in intracellular cytokine IFN-β and decrease in TGF-β revealed by flow cytometric analysis. Corroborating to this, there is a significant increase of CD95 and IFN-β and a decrease in TGF-β were observed with TANs infiltrated into β-lap treated TME compared to vehicle treated tumors. Additionally, TLR/MyD88signaling deficiency decreased β-lap induced neutrophil tumor infiltration. BlockingHMGB1, depleting neutrophils, or TLR4/MyD88 deficiency lessened the antigen-specific T cell response. This study highlights that β-lap kills NQO1+ murine tumor cells through ROS production and DNA damage, and neutrophils play a pivotal role in its antitumor effects. Citation Format: Xiumei Huang, Soumya Tumbath, Liangxiang Jiang, Yang-Xin Fu. Beta-lapachone promotes tumor associated neutrophils (TANs) polarized towards anti-tumor (N1) phenotype [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 3851.
Abstract 6739: Efficacy and toxicity of microbial mimetic mesoporous silica nanoparticles in a mouse model of ovarian cancer
Authors: Lorel Y. Medina, Rita E. Serda, Benjamin Marwedel, Melanie S. Jun, Josh Adogola
Journal: Cancer Research (2024)

Abstract Ovarian cancer is predominately left undetected and untreated until the later stages of the disease where it becomes incredibly difficult to treat. Preclinical studies demonstrate that immunotherapy can be highly effective. Our lab has been working on an immunotherapy approach to treat women with ovarian cancer that utilizes mesoporous silica nanoparticles(MSN). MSN that present pathogen-associated molecular patterns (PAMPS) are able to significantly reduce tumor burden in mouse models of serous epithelial ovarian cancer when administered by intraperitoneal injection. These microbial mimetic particles are decorated with polyethyleneimine (PEI), CpG oligonucleotide, and monophosphoryl lipid A (MPLA). When in the presence of antigen presenting cells, they bind to Toll-like receptors (TLR) present on the cell surface and within the endosome. To better understand mechanisms underlying their efficacy, we injected fluorescent MSN-PEI-CpG-MPLA (100 or 500 nm) or unmodified MSN into mice with advanced ovarian cancer. The particles, regardless of the presence of TLR-agonists, were rapidly internalized by myeloid cells, with trafficking almost exclusively to immune clusters located in tumor-burdened adipose tissues when administered by intraperitoneal injection. Conversely, intravenous injection of MSN-PEI-CpG-MPLA led to predominate accumulation in liver, with no particles found in tertiary lymphoid clusters 24 hours post injection. Furthermore, unlike intraperitoneal injection, intravenous injection of MSN-PEI-CpG-MPLA was without therapeutic effect. Currently we are studying MSN safety and the impact of administration route and dose on efficacy and cytotoxicity. In summary, MSN, with and without TLR agonists, are trafficked by myeloid cells to tumor-burdened fat-associated lymphoid clusters when administered by intraperitoneal injection. Intraperitoneal injection of TLR-agonist modified MSN effectively reduces tumor burden in mice with ovarian cancer. Citation Format: Lorel Y. Medina, Rita E. Serda, Benjamin Marwedel, Melanie S. Jun, Josh Adogola. Efficacy and toxicity of microbial mimetic mesoporous silica nanoparticles in a mouse model of ovarian 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 6739.
Abstract 2801: Identifying gut microbial determinants of clonal hematopoiesis of indeterminate potential (CHIP) in immunotherapy treated melanoma patients
Authors: Eleanor A. Fallon, Samuel Urrutia, Reed Ayabe, Manoj Chelvanambi, Ashish Damania, Sarah Johnson, Tomoyuki Tanaka, Zongrui Li, Yongwoo David Seo, Samuel Cass, Matthew C. Wong, Nadim Ajami, Jennifer Wargo, Koichi Takahashi
Journal: Cancer Research (2024)

Abstract INTRO: Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is associated with poor outcomes in those with non-hematologic cancers. CH mutated macrophages and neutrophils have increased capacity to home to peripheral tissues, driving local inflammation; they are also implicated in immunotherapy related toxicity. The relationship between CH and the microbiome in those treated with immunotherapy is not well understood. RESULTS: 35 patients with stage IV melanoma treated with upfront immunotherapy; treatment and cohort characteristics are below (Table 1). We performed error corrected duplex sequencing on peripheral blood mononuclear cells using a panel previously validated for CH mutations. With a cutoff of 0.5% variant allele frequency (VAF), among 10 CHIP positive patients, we found mutations in TET2 (8/10), DNMT3A (7/10), PPM1D (2/10), and JAK2 (1/10). There was no difference in either survival or response based on CHIP status (Log-Rank Chi-Square p=0.44); however, CHIP positivity was associated with greater microbiome richness as measured by alpha diversity (p=0.0012 Shannon diversity) and distinct structural/compositional diversity vs CHIP negative patients as measured by beta diversity (p=0.032, R Squared= 0.045). We inferred KEGG pathway activity from whole genome sequencing and identified that CHIP positive patients were enriched for exopolysaccharide biosynthesis while CHIP negative patients had higher expression of nucleotide sugars biosynthesis and amino acid metabolism pathways. DISCUSSION: In patients treated with immunotherapy for melanoma, microbiome diversity signatures correlate with presence of CHIP. The analysis suggests that there are distinct taxonomic and functional features defining CHIP positivity. The effect of these cells in the tumor microenvironment and their role in immunotherapy response requires further exploration. Citation Format: Eleanor A. Fallon, Samuel Urrutia, Reed Ayabe, Manoj Chelvanambi, Ashish Damania, Sarah Johnson, Tomoyuki Tanaka, Zongrui Li, Yongwoo David Seo, Samuel Cass, Matthew C. Wong, Nadim Ajami, Jennifer Wargo, Koichi Takahashi. Identifying gut microbial determinants of clonal hematopoiesis of indeterminate potential (CHIP) in immunotherapy treated 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 2801.
Abstract 1780: Utilizing bisbiguanide compounds to disrupt metabolic heterogeneity in non-small cell lung cancer
Authors: Veronika Y. Matsuk, Christina M. Knippler, Jamie L. Arnst, Isaac E. Robinson, Tala O. Khatib, Mala Shanmugam, Thota Ganesh, Janna K. Mouw, Adam I. Marcus
Journal: Cancer Research (2024)

Abstract Metastasis accounts for 90% of cancer-related deaths; however, the molecularmechanisms by which cancer cells invade and metastasize remain poorly understood.Around 80% of lung cancer patients present with metastatic disease and have only a 5%5-year relative survival. Metastases are often seeded by heterogeneous cells that invadecollectively in cellular packs. However, most studies and treatments focus on bulk cellularpopulations leaving subpopulations that drive metastasis masked. We previouslypublished on metabolic heterogeneity within collectively invading lung cancer cells andidentified the bisbiguanide compound alexidine as a disrupter of lung cancermitochondrial metabolism and invasion. To expand on these findings, we developed newbiguanides and identified promising candidates, AX-4 and AX-7. These analogs inducemitochondrial structural defects and cause metabolic rewiring. Treated lung cancer cellsexhibited reduced oxygen consumption and increased lactate production. Importantly,AX-4 and AX-7 reduced collective cell invasion, highlighting the potential of these newbiguanides to limit cancer metastasis. Taken together, we have developed new chemicaltools to disrupt mitochondrial metabolism. These tools will be useful to further parse theroles of metabolically heterogenous cancer cells on tumor growth and metastasis. Citation Format: Veronika Y. Matsuk, Christina M. Knippler, Jamie L. Arnst, Isaac E. Robinson, Tala O. Khatib, Mala Shanmugam, Thota Ganesh, Janna K. Mouw, Adam I. Marcus. Utilizing bisbiguanide compounds to disrupt metabolic heterogeneity in non-small cell lung 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 1780.
Abstract 3133: A novel bispecific antibody-drug conjugate targeting HER2 and Trop-2 displays potent antitumor activity in a variety of tumor models with promising preclinical characteristics
Authors: Haihong (Helen) Zhong, Yan Xiong, Han Huang, Yuming Pan, Na Wang, Bin Sun, Shen Liu, Wei Yuan, Dingguo Liu, Jan Fang, Haifeng Bao
Journal: Cancer Research (2024)

Abstract Antibody-drug conjugates (ADCs) have exhibited considerable advancements in cancer therapy, though their efficacy is often confined to specific patient subsets or results in modest clinical responses due to low and heterogenous expression of drug targets in tumors. Targeting more than one tumor-associated antigens (TAAs) represents a new strategy to broaden treatment applicability and minimize on-target toxicity of ADC. Our analysis of co-expression of HER2 and Trop-2, two clinically validated ADC targets, in tumors of various histological malignancies manifests the great potential for an ADC simultaneously targeting these two antigens. We describe here a novel bispecific ADC (BIO-201) designed to co-target HER2 and Trop-2. This compound comprises a bispecific anti-HER2/Trop-2 antibody conjugated with a novel topoisomerase I inhibitor via a cleavable linker. BIO-201 demonstrates increased or comparable cell binding and internalization compared to parental antibodies. In in vitro cytotoxicity assays, BIO-201 effectively kills cancer cells with an IC50 in the sub nM range, irrespective of whether they co-express HER2 and Trop-2 or express only one antigen. Co-culture studies reveal that BIO-201 possesses a good bystander killing effect on drug target-negative tumor cells. In vivo studies further demonstrate the superior anti-tumor activity of BIO-201 in various tumor xenograft models, including those expressing different levels of HER2 and/or Trop-2, as well as models resistant to HER-2-targeting therapies. Moreover, BIO-201 exhibits favorable plasma stability, preclinical pharmacokinetics (PK), and toxicity profiles. In conclusion, these findings suggest that the anti-HER2/Trop-2 bispecific ADC, BIO-201, holds significant promise as an effective therapy for a diverse range of cancers, especially those expressing heterogenous levels of HER2 or Trop-2, and has the potential to benefit a broad patient population. Citation Format: Haihong (Helen) Zhong, Yan Xiong, Han Huang, Yuming Pan, Na Wang, Bin Sun, Shen Liu, Wei Yuan, Dingguo Liu, Jan Fang, Haifeng Bao. A novel bispecific antibody-drug conjugate targeting HER2 and Trop-2 displays potent antitumor activity in a variety of tumor models with promising preclinical characteristics [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 3133.
Abstract 1474: Interleukin-8 and NF-κB mediated signaling axis: A potential driver for cadmium-induced prostate carcinogenesis
Authors: Kunj Bihari Gupta, Rajendra K. Singh, Juliette R. Seremak, Vinata B. Lokeshwar, Bal L. Lokeshwar
Journal: Cancer Research (2024)

Abstract Cadmium (Cd) is a toxic heavy metal, ubiquitous in nature, and an industrial pollutant. Cadmium exposure can cause irreversible damage to lungs, liver and kidney including cancers. Alarmingly, abnormally high levels of cadmium are found in human prostate tissues. Studies on rodents have shown cadmium exposure causes liver, lung, and prostate cancers. The mechanism of carcinogenesis caused by Cd is multifactorial and specific organ carcinogenesis remains unclear. We and others have reported that the CXC-chemokine IL-8 drives cancer progression in prostate cancer (PCa). We tested a hypothesis that chronic cadmium-exposure induces upregulation of proinflammatory cytokines, such as IL-1β, IL-6, and IL-8, which individually or combined promote carcinogenesis and progression. The study used two non-transformed prostate epithelial cell lines (RWPE-1 and NHPrE1) to test whether continuous exposure to Cadmium chloride (CdCl2) perturbs cytokine expression pattern and selective silencing of elevated cytokines delays carcinogenesis and invasive potential. The CdCl2 exposed cells and culture conditioned media were analyzed regularly for changes in inflammatory milieu and for hallmarks of carcinogenesis. These studies measured changes in cell proliferation, production of cytokines (IL-8, IL-1β, IL-6, IFN-γ, TGF-β, and others), activation of Nuclear Factor-kB (NF-κB), and pro-tumorigenic factors, e.g., vascular endothelial growth factors (VEGF-A and B), cellular motility, and invasive potential, etc. Cells exposed to CdCl2 showed increased cell proliferation and clonogenic potential and specifically, increased expression of IL-8, it’s receptors (CXCR1 and CXCR2), IL-1β, and other cytokines &amp; related genes. While un-exposed RWPE-1 cells did not express IL-8, it was the first cytokine to increase when exposed to CdCl2, followed by activation of NF-κB (p65-rel), VEGF-A, &amp; B, CXCR1 and other markers. Gene silencing of IL-8 suppressed motility, invasion, and survival activity. These data supported that immediate-early IL-8 expression probably upregulates NF-κB mediated inflammatory signaling axis which is critical for Cd-induced carcinogenesis and may expose targets for countermeasures to prevent metal-induced toxicity &amp; carcinogenesis. Citation Format: Kunj Bihari Gupta, Rajendra K. Singh, Juliette R. Seremak, Vinata B. Lokeshwar, Bal L. Lokeshwar. Interleukin-8 and NF-κB mediated signaling axis: A potential driver for cadmium-induced prostate carcinogenesis [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 1474.
Abstract 4412: Defining chromatin alterations in liver cancer at single cell resolution
Authors: Miguel Ramirez, Tabea Stephan, Daivd Schaeffer, Pamela Hoodless
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is the most common liver cancer and arises from the malignant transformation of hepatocytes. HCC tumors often express genes critical for hepatocyte development but the regulatory mechanisms driving aberrant expression remain unclear. Recent evidence indicates that epigenetic alterations contribute to HCC progression with nearly 50% of cases associated with mutations in chromatin modifiers. Thus, it is imperative to understand how chromatin is altered in HCC and identify the DNA regulatory sequences associated with HCC tumorigenesis. Our study aims to map the chromatin landscape and transcriptome in HCC tumors using a multiomic approach at single cell resolution. Single-cell ATAC- and RNA-seq will be conducted in HCC tumors, matched controls and normal livers to identify regulatory sequences and their target genes critical for HCC tumor progression. We will characterize these regulatory sequences in the context of liver development using genetic manipulation and epigenomic datasets generated from human pluripotent stem cells differentiated to hepatic lineages. Our goal is to elucidate how epigenetic alterations in HCC drive cancer progression and how they relate to a dedifferentiated state. Citation Format: Miguel Ramirez, Tabea Stephan, Daivd Schaeffer, Pamela Hoodless. Defining chromatin alterations in liver cancer at single cell resolution [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 4412.
Abstract 2437: Distinct DNA methylation patterns in male urogenital cancers
Authors: Guopeng Yu, Jiangyi Wang, Long Li, Wenchuan Xie, Yushan Liu, Qing Yang, Bin Xu
Journal: Cancer Research (2024)

Abstract Background: Male urogenital cancers including prostate cancer (PCa), bladder cancer (BLCA) and kidney renal cancer (KIRC), account for 38% of the total number of new male cancers. Previous studies have shown that changes in DNA methylation patterns are associated with the occurrence and progression of these cancers. Here, we performed whole-genome bisulfite methylation sequencing (WGBS) on tissue samples from these cancers to comprehensively characterize the methylation patterns to provide insights into the potential biological functions of methylation and to identify possible early detection biomarkers. Methods: Tissue samples were collected from patients with PCa, BLCA and KIRC who had not received any treatment prior to surgery from Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine. Samples with the cancer cells content ≥30% in cancer tissues and no cancer cells in the adjacent tissues was deemed qualified. A total of 43 samples were sequenced by whole-genome bisulfite methylation sequencing (WGBS) with a depth of 30X, including PCa, BLCA, KIRC cancer tissues, and their adjacent cancer tissues. Results: Distinct methylation patterns were observed in the 3 cancers. By comparing cancer and adjacent tissues, the numbers of differentially methylated sites (DMSs) were 21,195 (31% hyperDMSs and 69% hypoDMSs), 587,010 (23% hyperDMSs and 77% hypoDMSs) and 7,855,162 (5% hyperDMSs and 95% hypoDMSs) in PCa, BLCA and KIRC, respectively. The distribution of hyperDMSs and hypoDMSs across various chromosomes was relatively consistent in KIRC and BLCA. However, in PCa, the hypoDMSs were mainly located on chromosome 8 (5265/14666, 36%). Among the three cancers, only 2-3% of hypoDMSs were located in gene promoter regions, while the proportions of hyperDMSs in gene promoter regions were higher with 4%, 8% and 17% for PCa, BLCA and KIRC, respectively. Among the above DMSs, 1901 DMSs-related genes were shared by PCa, BLCA and KIRC and 251, 4252, 2475 DMSs-related genes were unique in PCa, BLCA and KIRC, respectively. Gene Ontology analysis revealed that the shared DMSs-related genes were enriched in Wnt signaling pathway and positive regulation of MAPK cascade. Conclusions: Our present study demonstrated the differential methylation patterns in male urogenital cancers, which may provide insights into the potential biological functions of methylation and to identify possible early detection biomarkers. Citation Format: Guopeng Yu, Jiangyi Wang, Long Li, Wenchuan Xie, Yushan Liu, Qing Yang, Bin Xu. Distinct DNA methylation patterns in male urogenital cancers [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 2437.
Abstract 1473: Exposure of arsenic promotes malignant stemness and induces bladder malignancy in preclinical models
Authors: Bhawna Tyagi, Mohit Vashishta, Neha Tyagi, Balaji Chandrasekaran, Vaibhav Shukla, Ashish Tyagi, Chendil Damodaran
Journal: Cancer Research (2024)

Abstract Numerous epidemiological and scientific studies have consistently demonstrated that populations exposed to arsenic (As) concentrations ranging from &amp;gt;10 ppb to 2500 ppb in their drinking water face an elevated risk of urogenital cancers, with a particular emphasis on bladder cancer (BCa). Hence, the goal of the study is to investigate the underlying mechanisms that trigger malignant transformation in the bladder using physiologically relevant arsenic concentrations observed in BCa patients. In our results, we observed significantly elevated levels of arsenic in the urine of BCa patients, ranging from 20 to 50 mg/L, in stark contrast to the levels observed in healthy controls (&amp;gt;10 mg/L) and the recommended guidelines set by the Environmental Protection Agency (EPA) and Centers for Disease Control and Prevention (CDC). We used a median physiological concentration of arsenic (30 PPM) in drinking water-induced bladder hyperplasia in male and female mice over six months. Likewise, chronic exposure of healthy bladder epithelial cells (TRT-HU1) to similar arsenic concentrations (250nM:30 PPM) for 12 months resulted in malignant transformation, and arsenic-transformed cells (AsT) were capable of inducing tumors in xenografted and orthotopic models. Nonetheless, the molecular mechanism responsible for this malignancy remains to be elucidated. Our molecular analysis has pointed towards the activation of stem cells, notably ALDH1A1 (with a 50,000-fold increase), as a pivotal factor driving this transformation. Furthermore, our research has demonstrated that the activation of ALDH1A1 is contingent on the induction of Metal Response Element-Binding Transcription Factor-1 (MTF1). Consequently, silencing MTF1 inhibited the expression of ALDH1A1 and its associated malignant properties in As-transformed cells, strongly suggesting that MTF1 functions as the master regulator in As-induced bladder carcinogenesis. We have also observed similar molecular signatures (MTF1 and ALDH1A1 expression) in arsenic-exposed versus non-exposed mice and bladder cancer patients. In conclusion, our studies suggest that activation of stem cells is a critical step in arsenic-induced bladder carcinogenesis. Citation Format: Bhawna Tyagi, Mohit Vashishta, Neha Tyagi, Balaji Chandrasekaran, Vaibhav Shukla, Ashish Tyagi, Chendil Damodaran. Exposure of arsenic promotes malignant stemness and induces bladder malignancy in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1473.