tbuckley/cabot-search huggingface dataset:
Abstract 2903: CTHRC1 induces PSCs (pancreatic stellate cells) into myCAFs (myofibroblast-like cancer-associated fibroblasts)
Authors: Jin Gyeong Lee, Min Kyung Kang, Fen Jiang, Kyoungjin Ryu, Juwon Kim, Yun-Yong Park, Sang Seok Koh
Journal: Cancer Research (2024)

Abstract Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein that contributes to the progression of various cancers, including pancreatic cancer. The higher expression of CTHRC1 in tumor tissues is associated with poorer survival outcomes. However, its specific roles in tumor extracellular matrix (ECM) remodeling remain unclear. Our study aims to investigate the influences of CTHRC1 on pancreatic stellate cells (PSCs), a main source of ECM production in pancreatic cancer. The analyses of the publicly available pancreatic cancer patient data revealed that CTHRC1 is mainly expressed in cancer stroma and highly correlated with ECM-related genes. An in vitro study showed that more than 40% of these genes can be upregulated by CTHRC1. CTHRC1 specifically activated PSC into myofibroblast-like cancer-associated fibroblasts (myCAFs), which are characterized by a significantly upregulated POSTN gene expression. Periostin (coded by the POSTN gene) has a central role in the CTHRC1-PSCs-cancer metastasis axis. Furthermore, CTHRC1 promoted pancreatic cancer cell proliferation through PSC activation to a greater extent than via direct stimulation. Proof-of-concept experiments showed that the long-term (4-week) inhibition of CTHRC1 led to significant tumor suppression and ECM reduction, and also resulted in an unexpected shift in the CAF subtype from myCAFs to inflammatory CAFs (iCAFs). PSC activation was demonstrated to be the key molecular mechanism responsible for the tumor-promoting effects of CTHRC1, and CTHRC1 has a critical role in CAF subtype differentiation and tumor microenvironment (TME) remodeling. The inhibition of CTHRC1 as a therapeutic strategy for the treatment of pancreatic cancer warrants further investigation. Citation Format: Jin Gyeong Lee, Min Kyung Kang, Fen Jiang, Kyoungjin Ryu, Juwon Kim, Yun-Yong Park, Sang Seok Koh. CTHRC1 induces PSCs (pancreatic stellate cells) into myCAFs (myofibroblast-like cancer-associated fibroblasts) [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 2903.
Abstract 853: Assessment of racial and ethnic disparities in environmental exposure-related cancer burden
Authors: Jessica R. Bobbitt, Fangzhou Liu, Jennifer Cullen, Ruth A. Keri
Journal: Cancer Research (2024)

Abstract The United States Environmental Protection Agency designates superfund sites as regions contaminated with hazardous waste. These sites have previously been associated with adverse health outcomes, including an increased incidence of cancer. Historically, communities with racial and ethnic minorities and people of low socioeconomic status have served as prime locations for these sites, as these communities have lacked the ability to advocate against this land use. Here, we ask whether racial and ethnic minorities are disproportionately exposed to these sites or other regions of hazardous waste in our catchment area at the Case Comprehensive Cancer Center, and in the state of Ohio. Further, we are examining whether areas of high exposure are associated with adverse health outcomes including higher cancer incidence and mortality. We utilized the Environmental Justice Index (EJI) database from the Centers for Disease Control and Prevention to assess, on a census tract level, the percent of racial and ethnic minorities in a region, defined as all persons except white, non-Hispanic individuals. We also queried hazardous and toxic waste sites including regions with a national priority list site, a toxic release inventory site, treatment, storage, and disposal sites, risk management plan sites, coal mines, and lead mines. We intersected these data and found that census tracts with a higher percentage of minority persons were more likely to be exposed to hazardous and toxic sites. Our current studies are assessing whether this high environmental burden is contributing to disproportionately worse cancer burden for these individuals. We will test this by comparing EJI data with data from the Ohio Cancer Incidence Surveillance System database to assess cancer incidence and mortality in Ohio. This will also provide an avenue for identifying specific exposures that may contribute to different cancer types. Further, we plan to assess if persons with low socioeconomic status or those living with disabilities are disproportionately affected by environmental burden. Overall, understanding environmental burden and health outcomes will facilitate the prioritization of communities at greatest need, contributing to greater health equity. Citation Format: Jessica R. Bobbitt, Fangzhou Liu, Jennifer Cullen, Ruth A. Keri. Assessment of racial and ethnic disparities in environmental exposure-related cancer burden [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 853.
Abstract 1405: Development of a humanized anti-IL-22 antibody for cancer and inflammation therapy
Authors: Jian Chen, Cathy Chang, Gerhard Frey, Haizhen Liu, Jing Wang, William J. Boyle, Jay M. Short
Journal: Cancer Research (2024)

Abstract Interleukin-22 (IL-22) is an inflammatory cytokine involved in the pathology of autoimmune diseases such as psoriasis, atopic dermatitis, and ulcerative colitis. IL-22 has also been shown to promote epithelial cell proliferation, stemness and tumorigenesis in cancer, and is associated with a more aggressive phenotype in a variety of cancers including inflammatory colon cancer models. IL-22 plays a central role in this pathogenic process by driving activation of STAT3 and other signaling cascades. Recent studies demonstrated that neutralization of IL-22 reduced dysplasia and tumor development in preclinical models. However, there has not been a clear application for anti-IL-22 therapy for cancer and autoimmune diseases, likely due to identifying the right disease indication and their low potency and efficacy. Thus, there remains an opportunity to explore the potential of more potent anti-IL-22 therapeutics. We have developed humanized anti-IL-22 antibodies with high affinities to human, cynomolgus and mouse IL-22 using BioAtla’s proprietary antibody discovery and engineering platforms. In vitro data demonstrated that our anti-IL-22 antibodies inhibited IL-22-induced p-STAT3 activities. In addition, our antibodies showed a 10-fold increased binding activity to human IL-22 compared to Fezakinumab, which was previously developed by Pfizer for the treatment of autoimmune diseases. To test the functions of our antibodies in vivo, we established an inflammation-driven sporadic colitis-associated colorectal (CAC) cancer mouse model. Our humanized anti-IL-22 antibody, a potent, species cross-reactive anti-IL-22 blocking antibody, significantly reduced tumor progression in CAC model. These data suggest that targeting IL-22 reduces tumor occurrence by reducing inflammation-induced tumorigenesis. In addition, we evaluated our anti-IL22 antibodies in an imiquimod-induced psoriasiform skin inflammation mouse model. The mice treated with anti-IL22 antibodies had significantly reduced skin lesions compared to isotype antibody-treated mice. Q-PCR analysis of the mouse skin demonstrated that treatment with our anti-IL-22 antibody led to significantly decreased RNA levels of the imiquimod-induced inflammatory marker CXCL3. In conclusion, the development of a potent, species cross-reactive anti-IL-22 antibody using BioAtla’s antibody discovery and engineering platforms addresses the past challenges of anti-IL-22 therapeutics and allows for translational studies in relevant animal efficacy and safety models. Citation Format: Jian Chen, Cathy Chang, Gerhard Frey, Haizhen Liu, Jing Wang, William J. Boyle, Jay M. Short. Development of a humanized anti-IL-22 antibody for cancer and inflammation therapy [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 1405.
Abstract 7268: The SOS1 inhibitor MRTX0902 demonstrates activity across cancer models with mutations in proximal components of the RAS-MAPK pathway
Authors: Niranjan Sudhakar, Larry Yan, Fadia Qiryaqos, Jade Laguer, David Briere, Allan Hebbert, Andrew Calinisan, Silvia Coma, Jonathan Pachter, James G. Christensen, Peter Olson, Shilpi Khare
Journal: Cancer Research (2024)

Abstract Genetic alterations in the RAS-MAPK pathway are one of the most frequent causes of human cancers. While targeted therapies are approved for patients harboring mutations in KRAS G12C in advanced or metastatic non-small cell lung cancer, there remains a need for an effective therapy for cancers characterized by additional RAS-MAPK pathway mutations across cancer types. Previous studies have shown that genetic or pharmacological inhibition of Son of Sevenless homolog 1 (SOS1) demonstrates antiproliferative activity in cancer cells addicted to KRAS signaling, including cell lines with oncogenic mutations in KRAS, SOS1, PTPN11, or EGFR or a loss-of-function mutation in NF1. These genetic alterations each function to increase SOS1-mediated GTP-loading of KRAS and increase signaling flux through the MAPK pathway. Inhibition of SOS1 by MRTX0902 is anticipated to shift the tumor cell equilibrium of KRAS towards the inactive GDP-bound KRAS, leading to MAPK pathway inhibition. MRTX0902 is a selective inhibitor of SOS1 under evaluation in clinical trials for the treatment of advanced, unresectable, or metastatic cancers with mutations in the KRAS-MAPK pathway. In the present studies, we have shown that MRTX0902 demonstrates single-agent anti-proliferative activity and modulates ERK1/2 phosphorylation (pERK) across a panel of human tumor cell lines harboring oncogenic mutations in SOS1, PTPN11, BRAF (class III) and NF1. Furthermore, oral administration of MRTX0902 as a monotherapy in preclinical human tumor cell-derived xenograft models harboring these oncogenic mutations results in significant tumor growth inhibition. Additionally, combination with the RAF/MEK clamp avutometinib demonstrated greater antitumor activity versus either monotherapy treatment. These data support the clinical utility of MRTX0902 as a single agent or combination partner of avutometinib for the treatment of human cancers harboring oncogenic mutations implicated in dysregulation of RAS-dependent signaling including SOS1, PTPN11, NF1, and BRAF (class III). Citation Format: Niranjan Sudhakar, Larry Yan, Fadia Qiryaqos, Jade Laguer, David Briere, Allan Hebbert, Andrew Calinisan, Silvia Coma, Jonathan Pachter, James G. Christensen, Peter Olson, Shilpi Khare. The SOS1 inhibitor MRTX0902 demonstrates activity across cancer models with mutations in proximal components of the RAS-MAPK pathway [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 7268.
Abstract 850: Androgenic alopecia and risks of overall and aggressive prostate cancer: An updated meta-analysis
Authors: Sapir Amar, David Hanelin, Ilir Agalliu
Journal: Cancer Research (2024)

Abstract Background: Androgenic alopecia, known as male pattern baldness (MPB), is a common hair loss disorder among men. MPB has similar risk factors with prostate cancer (PrCa) including advancing age, family history, and sex hormones. Several studies have examined the associations between MPB and PrCa but the evidence remains unclear. We carried out a meta-analysis of epidemiological studies that examined the relationship between patterns of baldness: frontal, vertex, or both and PrCa risk. Methods: A literature search was performed in October 2022 using PubMed and Web of Science databases for epidemiological studies published between 1/1/2000 and 10/31/2022, which examined the above hypothesis. From each eligible study, relevant data were extracted on study design, population, sample size, prevalence of MPB at various ages, and corresponding associations with risks of total and aggressive PrCa. Pooled relative risks (RR) and corresponding 95% confidence intervals (CI) were calculated using the DerSimonian and Laird random-effects models. Heterogeneity across studies was assessed by I2 statistic. Results: A total of 14 studies: 14,573 cases and 132,434 controls/non-cases were included. The prevalence of MPB increased from 5% to 70% with aging and varied across studies. Vertex MPB at ages 40 years or older was associated with a pooled RR of 1.08 (95%CI 1.00-1.17) of total PrCa, but there was no association with frontal MPB. The onset of MBP at younger ages was also associated with RR=1.10 (95% CI 0.93 - 1.29) of PrCa, although results were not statistically significant. Results were similar when data were stratified by clinical features of PrCa, although there was large heterogeneity in the definition of aggressive PrCa across studies. Conclusions: Men with vertex MPB may have modest increased risk of PrCa. However, the majority of studies were conducted in Caucasian men and they did not evaluate effect modifications by genetic variations in androgen metabolism pathway genes or changes in serum levels of androgens. Further, large well-designed prospective cohort studies are needed to better understand the complex relationship between genetic susceptibility, endogenous hormones, MBP and risk of PrCa. Citation Format: Sapir Amar, David Hanelin, Ilir Agalliu. Androgenic alopecia and risks of overall and aggressive prostate cancer: An updated meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 850.
Abstract 7106: Distinct functions of EHMT1 and EHMT2 in cancer chemotherapy and immunotherapy
Authors: Zhihua Kang, Pan Fu, Hui Ma, Tao Li, Kevin Lu, Juan Liu, Vasudeva Ginjala, Peter Romanienko, Zhaohui Feng, Ming Guan, Shridar Ganesan, Bing Xia
Journal: Cancer Research (2024)

Abstract EHTM1 (GLP) and EHMT2 (G9a) are closely related protein lysine methyltransferases often thought to function together as a heterodimer to methylate histone H3 and non-histone substrates in diverse cellular processes including transcriptional regulation, genome methylation, and DNA repair. Here we show that EHMT1/2 inhibitors cause DNA replication stress, accumulation of single-stranded replication gaps, increased expression of STING, emergence of cytosolic DNA, and activation of the cGAS-STING pathway. Remarkably, EHMT1/2 inhibition strongly potentiates the efficacy of alkylating chemotherapy and anti-PD-1 immunotherapy in mouse models of tripe negative breast cancer. Mechanistically, the effects of EHMT inhibition on DNA replication and alkylating agent sensitivity are largely caused by the loss of EHMT1-mediated methylation of DNA ligase I (LIG1), whereas the elevated STING expression is, at least part, caused by its promoter demethylation. Moreover, depletion of EHMT2, and not EHMT1, leads to STING induction, which is correlated with more complete demethylation of the STING1 promoter. On the other hand, depletion of EHMT1, and not EHMT2, results in cytosolic DNA accumulation, which presumably activates the cGAS-STING pathway. These results reveal distinct functions of the two EHMT paralogs and provide enlightening paradigms and corresponding molecular basis for combination therapies involving alkylating agents and immune checkpoint inhibitors. Citation Format: Zhihua Kang, Pan Fu, Hui Ma, Tao Li, Kevin Lu, Juan Liu, Vasudeva Ginjala, Peter Romanienko, Zhaohui Feng, Ming Guan, Shridar Ganesan, Bing Xia. Distinct functions of EHMT1 and EHMT2 in cancer chemotherapy and immunotherapy [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 7106.
Abstract 6258: Inference of gene expression using fragmentation patterns from targeted high-depth sequencing of cell-free DNA
Authors: Emily Leff, Alexander Tseng, Victoria Cheung, Ehsan Tabari, Kimberly Walter, Alex Lovejoy, Cheng-Ho J. Lin
Journal: Cancer Research (2024)

Abstract Cell-free DNA (cfDNA) circulating in blood plasma arises primarily from cellular chromatin fragmentation and release due to cell death. Studies have demonstrated that the assessment of fragmentomic features of cfDNA enables gene expression inference and tissue-of-origin classification with potential applications for noninvasive cancer detection. However, due to low depth of coverage of sites of interest, current whole genome sequencing (WGS) methods have not been able to infer expression of individual genes or limited gene sets. Therefore, we developed a targeted sequencing approach that enables individual gene expression inference from cfDNA fragmentation patterns based on transcriptional start-site gene activation probability (TSS-GAP). To assess the sensitivity of this method for cfDNA-inferred gene expression profiling, we applied TSS-GAP to blends of micrococcal nuclease (MNase)-digested DNA from a cancer cell line (LS180) and sorted peripheral blood mononuclear cells (PBMC), with LS180 DNA at varying concentrations (0.1-10%). This enabled the determination of the limit of detection (LoD), relative to healthy donor background levels, on the basis of the genes’ activation probabilities (TSS-GAP scores). We found 936 genes with high inferred expression in the LS180 cancer cell line and low inferred expression in non-cancer samples (i.e. CD4, CD14, and plasma cfDNA from 4 healthy donors) and used those for healthy donor background and LoD assessment. Using these gene-level background values as cutoffs, blends were assessed to determine the lowest blend level at which expression of the gene was able to be differentiated from background. Out of the 936 genes, 326 (34.8%) were detectable at a blend level of 0.1%, 59 (6.3%) at 0.3%, 31 (3.3%) at 1%, 19 (2.0%) at 3%, and 39 (4.2%) at 10%. In total, 416 genes could be detected by TSS-GAP at levels 1% of or lower above background, highlighting the potential of our method for detecting expression of certain genes even from a small fraction of cells contributing cfDNA to liquid biopsy samples. Further expansion of this work could consider the utility of such a method for circulating tumor DNA (ctDNA) detection, cfDNA tissue-of-origin classification, and deconvolution of cell types contributing to cfDNA found in blood. Citation Format: Emily Leff, Alexander Tseng, Victoria Cheung, Ehsan Tabari, Kimberly Walter, Alex Lovejoy, Cheng-Ho J. Lin. Inference of gene expression using fragmentation patterns from targeted high-depth sequencing of cell-free DNA [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 6258.
Abstract 5971: F3 targeted near-infrared photoimmunotherapy: The ideal therapeutic approach for numerous malignancies
Authors: Seiichiro Takao, Aki Furusawa, Hiroshi Fukushima, Shuhei Okuyama, Makoto Kano, Hiroshi Yamamoto, Peter L. Choyke, Hisataka Kobayashi
Journal: Cancer Research (2024)

Abstract Introduction: F3 is a cell surface protein that plays a role in blood clotting, but recent research has revealed its implication in cancer proliferation, metastasis, angiogenesis, and immune escape. TCGA cohort analysis has shown that elevated F3 is a common feature of many cancers, and generally correlates with poor patient survival. Therefore, the potential of F3 as a therapeutic target in cancer is worth exploring. Tisotsumab-vedotin, an antibody-drug conjugate (ADC) that targets F3, was approved by the FDA for cervical cancer and is undergoing clinical trials in some solid cancers. However, ADCs may give rise to concerns about drag resistance following cellular internalization. Herein, we developed and tested an F3 targeted near-infrared photoimmunotherapy (NIR-PIT) to overcome some of these resistance mechanisms. Methods: We created a conjugate of tisotumab as an F3 antibody and IR700. The efficacy of F3-targeted NIR-PIT was investigated using multiple cancer cell lines (A431; epidermoid carcinoma, HPAF-II; pancreatic adenocarcinoma, HSC-2; oral carcinoma, HT-1376luc; bladder carcinoma, MDAMB231; breast adenocarcinoma, and SKOV-3; ovarian serous cystadenocarcinoma) in vitro. In vivo, the efficacy of F3-targeted NIR-PIT was evaluated in HPAF-II tumor using xenograft mouse models. In addition, the pathological change after NIR-PIT was also evaluated in A431, HPAF-II, HSC-2, HT-1376luc, MDAMB231, and SKOV-3 tumors. Results: These cell lines showed F3 expression in vitro and in vivo. Additionally, F3 expression was specific to cancer cells in HPAF-II tumor model. In vitro, F3-targeted NIR-PIT damaged the multiple cell lines in an NIR light dose-dependent manner. In vivo, F3-targeted NIR-PIT suppressed tumor growth and improved survival rates compared to the untreated group. Pathologically, A431, HPAF-II, HSC-2, HT1376-luc, MDAMB231 and SKOV-3 tumors after NIR-PIT contain large numbers of necrotic cells that are shown typically less dark nuclei and eosinophilic cytoplasm with some vacuolar degeneration than untreated tumors. Conclusions: F3-targeted NIR-PIT holds the efficacy against multiple cancers expressing F3, regardless of the specific cancer type. Therefore, this modality exhibits significant promise as a potential NIR-PIT option. Citation Format: Seiichiro Takao, Aki Furusawa, Hiroshi Fukushima, Shuhei Okuyama, Makoto Kano, Hiroshi Yamamoto, Peter L. Choyke, Hisataka Kobayashi. F3 targeted near-infrared photoimmunotherapy: The ideal therapeutic approach for numerous malignancies [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 5971.