tbuckley/cabot-search huggingface dataset:
Abstract 408: NEK1 phosphorylation modulates ERCC6 in transcription coupled nucleotide excision repair with implications for prostate cancer
Authors: Oluwatobi M. Ogundepo, Arrigo De Benedetti
Journal: Cancer Research (2024)

Abstract NER operates through two distinct pathways: global genome repair (GGR) and transcription-coupled repair (TC-NER). TC-NER, as its name suggests, is specifically dedicated to rectifying lesions that obstruct the progression of RNA polymerase during active transcription. This process is imperative for the maintenance of cellular homeostasis, as lesions encountered by the transcription machinery can lead to stalling, erroneous transcription, and ultimately, deleterious cellular outcomes. At the heart of the TC-NER pathway lies ERCC6, a helicase orchestrating the repair of DNA lesions within transcribed regions of the genome. ERCC6 (AKA CS-B) plays a pivotal role in detecting and coordinating the repair of transcription-blocking lesions and has been implicated in a plethora of cellular processes underscoring its multifaceted nature and its broader impact on genome stability and cellular health, as exemplified by the severity of syndromes in individuals with loss-of-function mutations. In the US, compared to Caucasians (CC), AA are at higher risk for developing PCa and have more aggressive disease that is refractory to treatment, to some extent explained by genetic differences in some cases attributed to alterations of their “Repairome”. GWAS revealed that, unlike CC, 89% of AA-PCa have at least one mutation in NER pathway genes. A defect in ERCC6 activity, either through reduced expression or mutation (e.g., M1097V found frequently in AA) may result in impaired TC-NER. This may be compounded by aging or obesity-related oxidative stress, resulting in progressive accumulation of damaged bases (e.g., 8-OG) and consequent (cancer-propensity) mutations, the correction of which involves BER or NER. This was investigated in part with PCa cell lines engineered via CRISPR-SDM to carry that particular genomic mutation, by studying their sensitivity to UV and the efficiency of removal of CPDs in vivo. In addition, we have begun investigation of its function in the variants (engineered and naturally found in PCa. Lines) in vitro, after IP from cells, by studying its intrinsic ATPase activity. We have also identified the kinase NEK1 as an important novel interactor and regulator of ERCC6. We previously identified NEK1 as being an early regulator of the adaptive response of PCa cells to ADT. Citation Format: Oluwatobi M. Ogundepo, Arrigo De Benedetti. NEK1 phosphorylation modulates ERCC6 in transcription coupled nucleotide excision repair with implications for prostate 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 408.
Abstract 3350: The pan-quadruplex drug QN-302 targets up-regulated genes in pancreatic cancer and in other cancer types and correlate with poor patient prognosis
Authors: Stephen Neidle, Ahmed A. Ahmed, Tariq Arshad
Journal: Cancer Research (2024)

Abstract We have previously disclosed (Ahmed et al, ACS Med Chem Lett, 2020) a novel small molecule G-quadruplex binding compound, QN-302, that is highly potent in pancreatic ductal adenocarcinoma (PDAC) cells and in several in vivo models for this disease. QN-302 was invented at University College London UK and has been subsequently developed by Qualigen Therapeutics Inc. It was cleared by the FDA in August 2023 for clinical evaluation and is currently in a Phase 1 clinical trial at select oncology centers in the USA. Genes that are significantly down-regulated by QN-302 are mostly up-regulated genes in human PDAC. We report here that some of these genes are also up regulated in other cancer types, whose expression frequently correlates with poor patient prognosis. We have used human cancer data from https://www.proteinatlas.org which contains pathology information based on mRNA and protein expression data from 17 different forms of human cancer, together with millions of in-house generated immunohistochemically stained tissue sections, images and Kaplan-Meier plots showing the correlation between mRNA expression of each human protein gene and cancer patient survival. We have revisited the RNA-seq data for QN-302 in PDAC MIA-PACA2 cells exposed to QN-302 for 24 hrs. (GSE151741 at https://www.ncbi.nlm.nih.gov/geo/) in detail and now identify a small group of eleven down-regulated genes, all with &amp;gt;3-fold expression changes. Interestingly all these genes and their gene products have been previously identified as playing a role in human PDAC (they also have varying roles in other cancer types). Some have been validated as anticancer targets. 10/11 of these genes (https://www.proteinatlas.org/) have been previously reported as being over-expressed in significant fractions of large (&amp;gt;150) groups of human cancer patients from The Cancer Genome Atlas (TCGA) project. Members of the PDAC susceptible gene panel are mostly disfavored in prostate, lung and breast cancer. However, the patient data does not discriminate between cancer sub-types nor does it show resistant data. They are especially favored in colorectal, liver and renal cancers, suggesting that QN-302 may have anticancer effects in these cancers as well as in PDAC. We also do not exclude the strong possibility that each cancer type also has its own group of G-quadruplex containing genes that are sensitive to QN-302. Citation Format: Stephen Neidle, Ahmed A. Ahmed, Tariq Arshad. The pan-quadruplex drug QN-302 targets up-regulated genes in pancreatic cancer and in other cancer types and correlate with poor patient prognosis [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 3350.
Abstract 5366: ATR promotes extracellular matrix stiffness mediated cytoskeleton remodeling and immunosuppression
Authors: Xinyi Tu, Zhenkun Lou, Robert Mutter
Journal: Cancer Research (2024)

Abstract The stiffening of the extracellular matrix (ECM), a phenomenon that often promotes metastasis and immunosuppression in many cancers, is a process that is not yet fully understood. Our study reveals that ATR, a molecule primarily recognized for its role in maintaining the genome, plays a crucial role in ECM stiffness-induced immune evasion and metastasis in triple negative breast cancer (TNBC) through DNA repair independent manner. In response to ECM stiffness, ATR activates SUN2, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. This activation enhances the interaction of SUN2 with outer nuclear membrane proteins KASH1 and KASH2. The interaction between SUN2 and KASH1/2 facilitates the nuclear localization of β-catenin, which in turn promotes epithelial mesenchymal transition (EMT) and reduces the expression of E-cadherin. E-cadherin is essential for attracting CD103+ immune cells that perform anti-tumor immunity. Interestingly, inhibiting ATR reduces EMT in tumor cells, leading to an increase in CD103+ dendritic cell infiltration while decreasing neutrophil and polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration. Further, we found that ATR levels are inversely correlated with immunotherapy response rates in patients. The alteration in immune cell composition sensitizes tumors to immunotherapy, thereby suppressing tumor growth and metastasis. In conclusion, the role of ATR in remodeling the immune environment could be crucial for optimizing the clinical use of ATR inhibitors. This makes ATR a promising target for overcoming immunotherapy resistance. We suggest early or prolonged treatment with an ATR inhibitor to potentially reduce metastasis rates and improve the prognosis of TNBC patients. Furthermore, we suggest using ATR levels as a marker to predict response rates and prognosis in TNBC patients. For patients with higher ATR expression levels, combination treatment with ATR inhibitors and immunotherapy may yield better outcomes. Enhanced anti-tumor immunity could increase the chances for patients to eliminate cancer cells and help end breast cancer. Finally, our research suggests the combined treatment of ATR inhibition and immunotherapy for patients without necessarily applying DNA damage stimulation. This approach could potentially reduce toxicity while still benefiting patients. Citation Format: Xinyi Tu, Zhenkun Lou, Robert Mutter. ATR promotes extracellular matrix stiffness mediated cytoskeleton remodeling and immunosuppression [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 5366.
Abstract 4389: The role of Rab5 in epithelial growth factor stimulated E-cadherin internalization in spheroid growth of colon cancer cells
Authors: Yu-Chun Wang, Yu-Chien Ching, Hui-Chun Chen, Chun-Pu Cheng, Chia-En Ku, Shin-Ru Lee, Wei-Ting Chao
Journal: Cancer Research (2024)

Abstract In epithelial based cancer formation, such as colon cancer, the tumor growth is accompanied with malfunction of cell-cell contact inhibition which is regulated by E-cadherin. However, the dynamics of E-cadherin is complicated, the underlying mechanism in tumor nest growth and collective cell migration is still not clear. Rab5 is the endocytic vesicle protein for the membrane receptor internalization into early endosome. Therefore, this study is to investigate the role of Rab5 in E-cadherin turnover of spheroid formation in colon cancer cells. HT-29 colon cancer cells were used in this study. The cells with less anchorage ability were isolated for spheroid formation. The distribution of Rab5, E-cadherin and focal adhesion kinase were observed by immuno-confocal microscopy. The molecular expressions were analyzed by western blot. HT-29 cells showed well defined epithelial phenotype. In the result of immunostaining, Rab5 was distributed in the cytosol and the cell-cell contacts where it colocalized with E-cadherin. Rab5 was also observed in the cell leading edge, however, not much associated with focal adhesions. When HT-29 cell clusters were stimulated with epidermal growth factor, Rab5 was found abundant in the cell-cell contacts. In cell spheroid that derived from HT-29 cells, Rab5 and E-cadherin co-localization at cell-cell contacts was also increased. Furthermore, when cells were treated with Nocodazole, the tubulin inhibitor blocking tubulin-mediated endocytosis, Rab5 accumulated and colocalized with E-cadherin in the cell leading edge. The results of this study demonstrated Rab5 plays the novel role in E-cadherin turnover upon epidermal growth factor stimulation in the progress of spheroid formation and Rab5 may mediate E-cadherin endocytosis through the cell leading edge. Citation Format: Yu-Chun Wang, Yu-Chien Ching, Hui-Chun Chen, Chun-Pu Cheng, Chia-En Ku, Shin-Ru Lee, Wei-Ting Chao. The role of Rab5 in epithelial growth factor stimulated E-cadherin internalization in spheroid growth of colon 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 4389.
Abstract 5590: Engineered destabilized 3’UTR of TEAD1 therapeutically inhibits and degrades TEAD1 mRNA and YAP1 interactors across multiple cancers
Authors: Chidiebere U. Awah
Journal: Cancer Research (2024)

Abstract The hippo pathway mediated by TEAD1 is overexpressed and oncogenic in multiple cancers. We report here the development of engineered destabilized 3’UTR of TEAD1 which overwrote and degraded oncogenic TEAD1 in ethnically diverse breast cancers, prostate cancers, ovarian cancers, and pancreatic cancer. We validated the destabilization and degradation of TEAD1 on the transcript and protein levels. This led to the loss of cancer cell size causing severe shrinkage as hippo pathway controls cells size , impaired cancer cell migration abilities and loss of cancer cell viability. These properties are titratable and specific demonstrating the specific engagement of the engineered destabilized 3’UTR of TEAD1 with oncogenic TEAD1 mRNA in destabilizing and degrading it. In a dose dependent titration analysis, we determined the IC50 of the engineered destabilized 3’UTR of TEAD1 across many cancers. IC50 dose dependent titration comparison with the engineered destabilized 3’UTR of TEAD1 constructs and chemotherapies (DNA damaging agents, microtubules inhibiting drugs, alkylating agents) as well as immune checkpoint inhibitor. We found evidence that suggests that the engineered destabilized 3’UTR of TEAD1 is superior. Mechanistically, the loss of TEAD1 led to the loss of TEAD2,3 and YAP1 and FOSL1 , JUN and c-MYC. Citation Format: Chidiebere U. Awah. Engineered destabilized 3’UTR of TEAD1 therapeutically inhibits and degrades TEAD1 mRNA and YAP1 interactors across multiple 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 5590.
Abstract 3371: PRMT blockade induces defective DNA replication stress response via ATR suppression and synergizes with PARP inhibition
Authors: Deepa Bisht, Yang Li, Lacey E. Dobrolecki, Christina Sallas, Xudong Zhang, Travis D. Kerr, Yalong Wang, Sharad Awasthi, Babita Kaundal, Siqi Wu, Weiyi Peng, Marc L. Mendillo, Yiling Lu, Collene R. Jeter, Guang Peng, Jinsong Liu, Shannon N. Westin, Anil K. Sood, Michael T. Lewis, Jishnu Das, S. Stephen Yi, Mark T. Bedford, Daniel J. McGrail, Nidhi Sahni
Journal: Cancer Research (2024)

Abstract Aberrant protein arginine methylation has been observed in multiple cancer types, making it an attractive drug target. Proteins can undergo asymmetric arginine methylation by type I protein arginine methyltransferases (PRMTs), predominately by PRMT1 and to a lesser extent PRMT4, or symmetric arginine methylation by type II PRMTs, predominately PRMT5. Here, we performed targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across cancer cell lines. We found that inhibition of both type I and type II PRMTs suppressed levels of total and phosphorylated ATR protein in cancer cell lines, and down-regulated expression of the ATR gene. Loss of ATR from PRMT inhibition resulted in defective DNA replication stress response activation in following exogenous replication stress. Since PARP inhibitors are known to induce replication stress, we next combined PRMT inhibition with PARP inhibition and found inhibition of PRMT1 or PRMT5 greatly exacerbated PARP inhibitor induced DNA damage. Based on this observation, we assessed the combination of PARP and PRMT inhibition in a panel of cell lines. While inhibition of both type I and type II PRMTs were synergistic with PARP inhibition in both cells with intact and deficient homologous recombination, type I PRMT inhibition resulted in higher toxicity in non-malignant cells. Therefore, we validated the synergy of combined PARP/PRMT5 inhibition in primary patient-derived organoids. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves overall survival in both BRCA-mutant and wild-type patient-derived xenograft models without any detectable hematological toxicities typically associated with PARPi combination therapies. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to improve tumor sensitivity to PARP inhibition. Citation Format: Deepa Bisht, Yang Li, Lacey E. Dobrolecki, Christina Sallas, Xudong Zhang, Travis D. Kerr, Yalong Wang, Sharad Awasthi, Babita Kaundal, Siqi Wu, Weiyi Peng, Marc L. Mendillo, Yiling Lu, Collene R. Jeter, Guang Peng, Jinsong Liu, Shannon N. Westin, Anil K. Sood, Michael T. Lewis, Jishnu Das, S. Stephen Yi, Mark T. Bedford, Daniel J. McGrail, Nidhi Sahni. PRMT blockade induces defective DNA replication stress response via ATR suppression and synergizes with PARP inhibition [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 3371.
Abstract 4790: Hospitalization as an opportunity to improve lung cancer screening in high-risk patients
Authors: Ellen M. Nielsen, Jingwen Zhang, Justin Marsden, Chloe Bays, William P. Moran, Patrick D. Mauldin, Leslie A. Lenert, Benjamin A. Toll, Andrew D. Schreiner, Marc Heincelman
Journal: Cancer Research (2024)

Abstract Background: Lung cancer screening with annual low-dose computed tomography (LDCT) in high-risk patients with exposure to smoking reduces lung cancer-related mortality, yet the screening rate of eligible adults is low. As hospitalization is a critical moment to engage patients in their overall health, it may be an opportunity to improve rates of lung cancer screening. Prior to implementing a hospital-based lung cancer screening referral program, this study assesses the association between hospitalization and completion of lung cancer screening. Methods: A retrospective cohort study of evaluated completion of at least one LDCT from 2014-2021 using electronic health record data using hospitalization as the primary exposure. Patients aged 55-80 who received care from a university-based internal medicine clinic and reported cigarette use were included. Univariate analysis and logistic regression models evaluated the association of hospitalization and completion of LDCT. The secondary outcome was completion of any CT of the chest. Results: Of the 1,935 current smokers identified, 47% had at least one hospitalization, and 21% completed a LDCT during the study period. While a higher proportion of patients with a hospitalization had a LDCT (24%) compared to patients without a hospitalization (18%, p&amp;lt;0.001), there was no association between hospitalization and completion of a LDCT after adjusting for potentially confounding covariates (95%CI 0.680 - 1.149). Of cohort patients, 38% completed any CT of the chest and hospitalization was associated with increased odds of receiving chest CT imaging in the adjusted model (OR 1.72; 95%CI 1.37 - 2.17). Conclusions: In a cohort of patients at risk for lung cancer, only 1 in 5 completed lung cancer screening with LDCT and hospitalization events were not associated with LDCT completion. A hospitalist driven lung cancer screening program has the potential to increase the suboptimal rates of lung cancer screening in high-risk patients. Citation Format: Ellen M. Nielsen, Jingwen Zhang, Justin Marsden, Chloe Bays, William P. Moran, Patrick D. Mauldin, Leslie A. Lenert, Benjamin A. Toll, Andrew D. Schreiner, Marc Heincelman. Hospitalization as an opportunity to improve lung cancer screening in high-risk 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 4790.
Abstract 5367: Single cell resolution spatial transcriptomics reveals genetic driver and TME interaction in clear cell renal cell carcinoma
Authors: Ilya Strunilin, Wagma Caravan, Atieh Abedin-Do, Andrew Houston, Yize Li, Yizhe Song, Song Cao, Chia-Kuei Mo, Siqi Chen, Russel Pachynski, Feng Chen, Li Ding
Journal: Cancer Research (2024)

Abstract BAP1 mutations are associated with increased T cell and tumor-associated macrophage infiltration in clear cell renal cell carcinoma (ccRCC) and are predictive of poor prognosis. BAP1 mutations have also been found to be associated with T-cell infiltration in peritoneal mesothelioma and uveal melanoma. Because BAP1 mutations are known to be associated with aggressive disease and poor survival, we hypothesize that these mutations lead to a more immunosuppressive microenvironment. Using single nucleus RNA sequencing and high-resolution spatial transcriptomics, we confirmed that BAP1 mutant tumors are immune hot with a high fraction of Treg, exhausted CD8+ T cells, CD4+ T cells, and macrophages. At the same time, these tumors have a lower proportion of endothelial cells and pericytes. Evident of pro-tumor microenvironment we have found BAP1 mutations to be associated with the upregulation of SPP1, CD163, and MARCO immunosuppressive genes in tumor-associated macrophages. Here we propose a mechanism by which BAP1-mutant cancer cells induce an immunosuppressive microenvironment: through activation of the complement system and TGF-β signaling to attract macrophages. Taken together, our results suggest that BAP1 mutations contribute to poor ccRCC outcomes not only through cell-intrinsic effects, but also by promoting infiltration of Tregs and tumor-associated macrophages and polarizing infiltrated macrophages towards immunosuppressive phenotype. Citation Format: Ilya Strunilin, Wagma Caravan, Atieh Abedin-Do, Andrew Houston, Yize Li, Yizhe Song, Song Cao, Chia-Kuei Mo, Siqi Chen, Russel Pachynski, Feng Chen, Li Ding. Single cell resolution spatial transcriptomics reveals genetic driver and TME interaction in clear cell 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 5367.
Abstract 5495: Multiplexed analysis across cancers of diverse origins to unravel spatial interactions within the tumor microenvironment
Authors: Vasundhara Agrawal, Lisa Arvidson, Michael J. Smith, Katie O. White, Richard A. Heil-Chapdelaine, Samuel Jensen, ARINDAM BOSE
Journal: Cancer Research (2024)

Abstract The tumor microenvironment (TME) is heterogeneous and is primarily composed of fibroblasts, extracellular matrix, immune cells, and blood vessels. Importantly, the tumor immune microenvironment (TIME) is a major source of cancer heterogeneity and influences both disease progression and response to therapeutic interventions. Malignant cells typically recruit various cell types such as vascular endothelial cells, cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs) to promote tumor growth. Therefore, studying such a complex interplay among tumor, stromal cells, and immune cells within the TME necessitates a multiplexed analytical approach to investigate cancerous tissues from diverse origins, to ultimately predict clinical outcomes and design novel therapies. While numerous studies have been focused on investigating the expression patterns of immune-oncology markers within specific tissues, the extent to which such marker expression patterns are shared across tumors originating from various tissues is not adequately understood. In this study, we analyzed a large panel of Cell Signaling Technology (CST®) antibodies that are targeting immune, stromal, epithelial, and vascular markers in cancer tissues derived from various origins including lung, colon, and pancreas. Using multiplexed Cell DIVE imaging, key spatial interactions in the tumor microenvironment that are (1) tissue-specific, and (2) shared across tumors irrespective of origin were determined. Specifically, cluster analysis of a common panel of markers across tissues of different origins uncovered molecular signatures that are common to all cancer tissue types as well as those that are unique to specific tissue types to advance our understanding of the disease, and its progression, shedding light on the intricate interactions within the TME. Citation Format: Vasundhara Agrawal, Lisa Arvidson, Michael J. Smith, Katie O. White, Richard A. Heil-Chapdelaine, Samuel Jensen, ARINDAM BOSE. Multiplexed analysis across cancers of diverse origins to unravel spatial interactions within the tumor microenvironment [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 5495.