tbuckley/cabot-search huggingface dataset:
Abstract 7062: CIP2A enhances mitochondrial respiratory electron transport chain complexes and induces lung cancer <i>in vivo</i>
Authors: Fu-Ying Yang, Di Wang, Li-Jun liang, Gui-Zhen Wang, Guang-Biao Zhou
Journal: Cancer Research (2024)

Abstract Identification of oncogenes that can induce cancer in vivo is critical to elucidation of tumorigenesis and development of targeted therapies. Here, we reported for the first time that forced ectopic expression of CIP2A, the cancerous inhibitor of protein phosphatase 2A (PP2A), in lung tissues induced lung adenocarcinoma in mice. CIP2A upregulated the transcription and translation of mitochondrial DNA (mtDNA), and increases the enzymatic activity of mitochondrial electron transport chain (ETC) complex IV and V, thus enhancing the function of mitochondria and promoting the level of oxidative phosphorylation in tumors. CIP2A inhibited the binding of PP2A-B56α to FOXO3a, leading to the enhancement of the phosphorylation level of FOXO3a. The phosphorylated FOXO3a then translocated into the mitochondrion, and acted as a transcription factor to regulate CIP2A-mediated metabolic reprogramming in cancer cells. We found that oxidative phosphorylation inhibitors effectively inhibited CIP2A-induced cell proliferation. In non-small cell lung cancer, CIP2A level in tumor tissues was positively associated with the level of mtDNA. Our results indicated that CIP2A is able to induce lung adenocarcinoma in mice and has a critical role in mitochondrial oxidative phosphorylation, and represents a promising therapeutic target for non-small cell lung cancer. Competing interests: The authors declare no competing interests. Citation Format: Fu-Ying Yang, Di Wang, Li-Jun liang, Gui-Zhen Wang, Guang-Biao Zhou. CIP2A enhances mitochondrial respiratory electron transport chain complexes and induces lung cancer in vivo [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 7062.
Abstract 5986: Significance of LIF/LIFR axis in the progression of inflammatory breast cancer
Authors: Bianca Romo, Zenaida Fuentes, Lois Randolph, Bindu Santhamma, Hareesh Nair, Christoforos Thomas, Ratna Vadlamudi, Suryavathi Viswanadhapalli
Journal: Cancer Research (2024)

Abstract Background: Inflammatory breast cancer (IBC) is a rare form of locally progressed breast cancer. Even though it is uncommon, IBC accounts for 7% of breast cancer deaths. There is a critical need for novel therapeutic targets to develop new therapeutics. IBC is more common in young women. Altered levels of growth factors, and cytokine signaling are suspected to play a role in the progression of IBC. Leukemia inhibitory factor (LIF) is the most pleiotropic member of the interleukin-6 family of cytokines. LIF and its receptor LIFR have been linked to the progression of many cancers including triple negative breast cancer. We recently developed a first-in-class inhibitor targeting LIFR named EC359. However, the role of the LIF/LIFR axis in IBC progression remains unknown. In this study, we examined the significance of LIFR and the effectiveness of LIFR inhibitor EC359 in treating IBC. Methods: The effect of LIFR inhibitor EC359 on cell survival, colony formation, and apoptosis was evaluated using three well-established IBC model cells (SUM149, SUM190PT, and KPL4). Mechanistic studies were conducted using Western blotting, CRISPR KO, reporter assays, and RT-qPCR. KPL4 cell-based xenografts were used to test the efficacy of EC359 in vivo. Results: Our results using Western blotting confirmed increased expression of LIF and LIFR in IBC cells compared to normal and ER+ breast cancer cells. Treatment with EC359 significantly decreased IBC cell viability, long term colony formation ability with an IC50 of ~10-20 nM. Similarly, knock out of LIFR significantly reduced the progression of IBC model cells in cell viability and colony formation assays. Further EC359 treatment promoted apoptosis of IBC cells. Mechanistic studies confirmed that EC359 treatment substantially reduced LIF/LIFR downstream signaling including STAT3, AKT, and mTOR signaling. We also tested the utility of EC359 in treating IBC in vivo using KPL4 xenografts. EC359 (5mg/kg/day) is highly efficacious in reducing IBC xenograft tumor growth in vivo. IHC analyses of tumors confirmed decreased cell proliferation as measured by Ki67 staining. Conclusion: Collectively, these studies demonstrated the therapeutic benefit of using EC359 to target the LIF/LIFR axis and opened the door for the development of new treatment approaches. Citation Format: Bianca Romo, Zenaida Fuentes, Lois Randolph, Bindu Santhamma, Hareesh Nair, Christoforos Thomas, Ratna Vadlamudi, Suryavathi Viswanadhapalli. Significance of LIF/LIFR axis in the progression of inflammatory breast 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 5986.
Abstract 2882: Investigating mechanisms of radioresistance in TYK2 knockout head and neck cancer cells
Authors: Nicole Mayerli Constante, Vanessa Kelley, Joseph Contessa
Journal: Cancer Research (2024)

Abstract Radiation therapy is the primary form of treatment of head and neck squamous cell carcinoma (HNSCC). However, more than half of patients experience disease progression with standard of care treatment. To investigate novel therapeutic targets, a CRISPR screen was done to identify genes that are associated with radioresistance. The screening results indicated that JAK1 and TYK2 knockout (KO) resulted in radioresistance in HNSCC. Preliminary data suggests that loss of JAK1 causes an enhanced G2/M arrest phenotype and enhanced genome stability that contribute to radioresistance. To investigate whether TYK2 KO caused changes to the cell cycle and genome stability as observed in JAK1 KO, Western blots, cell cycle assays, and micronuclei staining experiments were performed. Cal27, a HNSCC cell line, was used. Cal27 cells were transduced with a non-targeting control (NT2) guide RNA (gRNA) or two different gRNAs targeting TYK2 to generate TYK2 KO cells. Western Blot analysis was performed to determine changes in signaling upon TYK2 KO. Additional conditions included radiation and treatments with Interferon gamma, Interferon alpha and Interleukin-6 to activate the canonical JAK-STAT pathways. Overall, there were minimal changes in downstream signaling between the treatments and the knockouts. Cell cycle analysis via flow cytometry revealed no changes between the NT2 and TYK2 KO cells, potentially corroborating signaling results. Forty percent of TYK2 KO cells were arrested at the G2/M checkpoint at 8 hrs and 24 hrs after radiation treatment, but twenty percent returned to the G1 phase at 24 hrs. This indicates that loss of TYK2 is not responsible for cell cycle arrest. Lastly, micronuclei formation was observed to measure genomic instability. Twenty thousand Cal27 NT2 and TYK2 KO cells were seeded. They were allowed to incubate for 48 hrs before treatment with 4 Gy. Micronuclei staining revealed minimal differences between NT2 and TYK2 KO cell lines, although there were significant differences between the control and the radiation groups. Overall, radioresistance by TYK2 KO is not caused by changes in cell cycle or genomic instability as demonstrated with JAK1 KO. To understand how TYK2 is causing radioresistance in HNSCC, next steps would be to see if there are changes in proliferation. If MTT assays demonstrate significant changes, downstream signaling in growth pathways will be measured. If there is no increased proliferation, we will examine changes in DNA damage repair. Citation Format: Nicole Mayerli Constante, Vanessa Kelley, Joseph Contessa. Investigating mechanisms of radioresistance in TYK2 knockout head and neck cancer cells [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 2882.
Abstract 3073: ACTL6a drives metabolic reprogramming and chemoresistance in head and neck squamous cell carcinoma
Authors: Mehri Monavarian, Andrey Finegersh
Journal: Cancer Research (2024)

Abstract Actin like protein 6A (ACTL6a), a subunit of the SWI/SNF chromatin remodeling complex, is amplified in a third of all squamous cell carcinomas including head and neck (HNSCC) cancers. Recent studies implicate ACTL6a as an oncogenic driver that potentiates SWI/SNF-related chromatin remodeling; however, the underlying mechanisms in HNSCC progression yet to be elucidated. Using the HNSCC cell lines FaDu, SCC90, and SCC2, ACTL6a knockdown (siACTL6a) led to a significant reduction in cell proliferation compared to control when measured by sulforhodamine B but not resazurin, suggesting up-regulation of oxidative phosphorylation with siACTL6a. We used RNA-seq datasets of siACTL6a in FaDu cells and found that there was a significant up-regulation of components of complex I and IV of the electron transport chain compared to control. Gene set enrichment analysis also demonstrated a significant up-regulation in glycolysis in ACTL6a amplified tumors within the HNSCC TCGA dataset. Since metabolism is a key driver of chemotherapy resistance, we studied effects of ACTL6a expression on cisplatin-mediated cytotoxicity. Compared to control, siACTL6A of the HNSCC cell lines FaDu and SCC2 had significantly decreased IC50 to cisplatin, indicating ACTL6a mediates toxicity. We also observed significantly decreased migration in a transwell migration assay in siACTL6A FaDu and SCC2 cells compared to control. We are studying the effects of shRNA directed against ACTL6a using a syngenic in vivo tumor model with a mouse oral cavity (MOC2) cell line that grows in C57BL/6J mice. Subcutaneous injection of MOC2 cells demonstrated significantly decreased tumor growth in shACTL6a cells compared to control. We are performing additional studies to identify specific mechanisms of ACTL6a mediated metabolic reprogramming in tumor cells. In conclusion, ACTL6A amplification is common in HNSCC and facilitates metabolic reprogramming, which drives tumor proliferation, cell migration, and drug resistance. Citation Format: Mehri Monavarian, Andrey Finegersh. ACTL6a drives metabolic reprogramming and chemoresistance in head and neck squamous cell carcinoma [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 3073.
Abstract 5330: Intestine-specific homeobox edits macrophage polarization in the disease microenvironment by activating inflammasome activity
Authors: Li-Ting Wang, Shih-Hsien Hsu
Journal: Cancer Research (2024)

Abstract Inflammasome activity has a pivotal role in the innate immune system, highlighting its importance in the development of various inflammatory diseases, including cancers. However, the specific impact of inflammasome-produced cytokines from tumor cells on disease progression remains uncertain. In this study, we show that the expression levels of inflammasome-related genes (NLRP1 and NLRP3), combined with levels of the intestine-specific homeobox (ISX), significantly correlate with factors like lesion count, disease stage, and lymph vascular invasion. Tumor cells enhance the secretion of key cytokines such as IL-1β and IL-18, exacerbating disease progression via the ISX-TWIST1 complex. In terms of mechanism, transcriptomic analysis and molecular evidence reveal that ISX interacts with the basic helix-loop-helix (bHLH) domain of TWIST1 through its homeobox domain. This interaction forms a transcriptional complex that activates inflammasomes by directly binding to the conserved sequence "-GGDWYR-" in promoter regions of several NF-κB and inflammasome-related genes (NFKBs, RELs, NLRP1, NLRP3, NEK7, AIM2, and ASC). Elevated levels of IL-18, induced by active inflammasomes, lead to the shift of M0 macrophages into the M2-like phenotype within the hepatic microenvironment. In mice with liver-specific ISX mutations, inflammasome-related genes and activities were eliminated, stopping disease progression in an acute hepatic disease model. These findings underscore the critical role of the ISX-TWIST1 complex in liver disease and tumor progression on both mechanistic and clinical levels. They also offer new insights for potential preventive and therapeutic targets in liver disease. Citation Format: Li-Ting Wang, Shih-Hsien Hsu. Intestine-specific homeobox edits macrophage polarization in the disease microenvironment by activating inflammasome activity [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 5330.
Abstract 1576: The heterogeneity between pancreatic ductal adenocarcinoma with &amp; without lymphovascular invasion
Authors: Yiping Zou, Yongjie Xie, Song Gao, Tianxing Zhou, Jun Yu, Jihui Hao
Journal: Cancer Research (2024)

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignant solid tumors, with a five-year survival rate less than 10%. Lymphovascular invasion (LVI) is a poor prognostic indicator for PDAC, yet the difference between tumors with or without LVI is unclear. Methods We used scRNA-seq analysis on the PDAC tissue of 24 patients obtained from the National Genomics Data Center (Project number: PRJCA001063) to compare T-cell, macrophage, &amp; cancer-associated fibroblast (CAF) heterogeneity between LVI-positive &amp; LVI-negative PDAC. To validate the scRNA-seq results, complementary techniques, including multiple immunofluorescence assays &amp; flow cytometry, were used. Additionally, we analyzed the characteristics of LVI-positive PDAC tumor cells. Results LVI-positive PDAC thrives in an immunosuppressive microenvironment. We discovered that CD8+ T cells were more deficient in LVI-positive PDAC than in LVI-negative PDAC. Furthermore, the effective &amp; cytotoxic markers (such as GZMB &amp; IFN-γ) of CD8+ T cells also decreased in LVI-positive PDAC. M2 macrophage polarization was found to be higher in LVI-positive PDAC compared to LVI-negative PDAC. In addition, we discovered a more fibrotic TME signature in LVI-positive PDAC. LVI-positive tumor cells, in particular, had a mesenchymal transition phenotype &amp; a hypoxic microenvironment. Conclusions This study adds to our understanding of the intricate heterogeneity seen in LVI-positive PDAC. It sheds light on the distinct characteristics of LVI-positive PDAC &amp; advances our understanding of its underlying biology. Citation Format: Yiping Zou, Yongjie Xie, Song Gao, Tianxing Zhou, Jun Yu, Jihui Hao. The heterogeneity between pancreatic ductal adenocarcinoma with &amp; without lymphovascular invasion [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 1576.
Abstract 7151: Targeting metabolic pathway in triple negative breast cancer with a small molecule inhibitor
Authors: Arpit Dheeraj, Fernando Jose Marques, Dhanir Tailor, Abel Bermudez, Benedikt Grau, Sharon Pitteri, Sanjay V. Malhotra
Journal: Cancer Research (2024)

Abstract Background: Triple Negative Breast Cancer (TNBC) is the most aggressive type of breast cancer, making up 15-20% of diagnosed cases, and has high rates of metastasis and recurrence. Most women with this disease experience a recurrence after curative-intent therapy for early breast cancer, while a smaller proportions are diagnosed with distant metastases initially. Cancer cells are characterized by their reprogramming of glucose metabolism. Cancer cells show increased proliferation along with higher energy and substrate demands. Through our efforts to find effective therapies for TNBC, we have identified CET019, a new small molecule that effectively suppresses the growth of breast cancer cells. Methods: Cell viability and clonogenic assays were performed on a range of TNBC cells, including MDA-MB-231, MDA-MB-468, SUM159, HCC1395, HCC1806, EMT6, and 4T1. Cell cycle distribution was assessed through flow cytometry. LC-MS/MS analysis was performed on TMT-labeled samples for global proteome profiling. The efficacy of CET019 (30 mg/kg) was tested using tumor and patient derived xenograft studies. Results: Our studies show that CET019 suppresses the clonogenic potential and growth of various triple-negative breast cancer cells. The CET019 treatment causes cell cycle arrest in TNBC cells at the G2/M phase. Proteomics analysis suggests that CET019 specifically affects metabolic and proteosomal pathways. In vivo studies with CET019 found an inhibition of tumor growth kinetics in the mouse xenograft study with different TNBC models, as compared to the control group. We also observed that CET019 inhibited metastatic lung nodules. The results were further substantiated in three Patient Derived Xenograft (PDX) models. Conclusion: In summary, our study has identified a novel small molecule candidate CET019 as a promising lead candidate for TNBC treatment, paving the way for further development.“The complete chemical structures of the compounds used will be disclosed at the time of presentation at the meeting.” Citation Format: Arpit Dheeraj, Fernando Jose Marques, Dhanir Tailor, Abel Bermudez, Benedikt Grau, Sharon Pitteri, Sanjay V. Malhotra. Targeting metabolic pathway in triple negative breast cancer with a small molecule inhibitor [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 7151.
Abstract 7277: Discovery of INV-9956, an orally available and highly selective Cyp11A1 inhibitor for the treatment of castration-resistant prostate cancer with drug resistant AR mutations
Authors: Chang Bai, Danqi Chen, Zilei Xia, Shujuan Huang, LIshan Lin, Zhaopie Zeng, Jing Su, Yongkui Sun
Journal: Cancer Research (2024)

Abstract Androgen Receptor (AR) signaling plays a profound role in prostate cancer and development. Efforts in harnessing androgen and AR axis for castration-resistant prostate cancer treatment have led to discovery of several therapeutics, including AR antagonists and Cyp17 inhibitors. However, resistance to these approved therapeutics has emerged, and remained a significant unmet medical need. Among the prominent resistance mechanisms of action are restored androgen signaling via AR amplification and overexpression, and gain-of-function mutations occurring at AR ligand binding domain that can be agonized by existing AR antagonists and/or non-androgenic steroids such as glucocorticoids. Targeting Cyp11A1 that catalyzes the formation of pregnenolone is effective to ablate biosynthesis of androgens and all steroids and thus holds promise to deliver coverage of a significant percentage of drug resistant AR mutations and benefit CRPC patients post treatment with AR antagonists or Cyp17 inhibitors. Here we present discovery and characterization of INV-9956, an orally available, selective, and potent Cyp11A1 inhibitor with well-acceptable pharmacokinetic properties. INV-9956 potently inhibits biosynthesis of pregnenolone and other androgens in H295R cells with IC50 at single-digit nanomolar, suppresses proliferation of prostate cancer cell lines harboring major clinically acquired drug resistant AR LBD mutations, such as AR L702H using coculture assays. Orally administered INV-9956 showed consistent dose dependent PK/PD correlations across animal species. Particularly, INV-9956 displayed pronounced tumor inhibition superior to known competitors in a CRPC VCaP xenograft model and in a “humanized” animal model. Furthermore, INV-9956 displayed a good tox profile in 14-day repeated dosing rat and dog studies, supported by a high selectivity to Cyp11A1 over other Cyp family members, clean hERG and mini-Ames, and no significant off-target activity in a safety panel screen. The promising preclinical profiles of INV-9956 lend strong support to its potentials in addressing unmet needs in CRPC treatments and warrant clinical development. Citation Format: Chang Bai, Danqi Chen, Zilei Xia, Shujuan Huang, LIshan Lin, Zhaopie Zeng, Jing Su, Yongkui Sun. Discovery of INV-9956, an orally available and highly selective Cyp11A1 inhibitor for the treatment of castration-resistant prostate cancer with drug resistant AR mutations [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 7277.
Abstract 3457: Distinct signatures of tumor-associated macrophage subpopulations predict survival in renal cell carcinoma
Authors: Youngsoo Han, Aidan Shen, Zhaohui Wang, Aliesha Garrett, Chongming Jiang
Journal: Cancer Research (2024)

Abstract Background: Comprising 90% of renal cancer cases in adults, renal cell carcinoma (RCC) is marked by significant heterogeneity in its tumor microenvironment. This study aims to test the hypothesis that tumor-associated macrophages (TAMs) play a role in modulating RCC progression and patient response to treatment. We explored the prognostic implications of TAM signatures on RCC survival, leveraging immunomics to decipher TAM-related alterations in the tumor microenvironment. Methods: Utilizing independent single-cell RNA-seq data from human RCC samples, we crafted 8 distinct RCC TAM signatures reflective of TAM presence. A LASSO Cox regression model was developed to prognosticate survival, tested against the TCGA dataset and independently validated across multiple RCC cohorts. Model performance was corroborated through Kaplan-Meier survival plots, receiver operating characteristic (ROC) curves, principal component analysis, and t-SNE analyses. Results: We identified two TAM signatures that correlate positively with patient survival, indicative of the abundance of specific subsets of TAMs in RCC. These signatures showed a strong association of specific TAM markers and macrophage infiltration. Survival analysis demonstrated that specific TAM signature gene expressions are significant prognostic markers. Forest plots underscored their prognostic relevance. A 32-gene risk score model was established, successfully stratifying patients into distinct risk categories, with low-risk patients exhibiting markedly improved overall survival. Conclusions: The study underscores the positive association between abundance of specific TAM subsets of and RCC patient survival. The precision of our LASSO Cox regression model, informed by novel abundance markers of specific TAM subsets, advances our understanding of TAM roles in TIME and RCC progression. These TAM signatures could potentially provide additional insights and targets to enhance the efficacy of RCC treatments. Keywords: Tumor associated macrophage, renal cell carcinoma, prognosis, tumor microenvironment, immunomics. Citation Format: Youngsoo Han, Aidan Shen, Zhaohui Wang, Aliesha Garrett, Chongming Jiang. Distinct signatures of tumor-associated macrophage subpopulations predict survival in renal cell carcinoma [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 3457.