tbuckley/cabot-search huggingface dataset:
Abstract 4931: The Cancer Proteome Atlas: Expanded datasets and empowered with an AI-driven chatbot
Authors: Han Liang, Wei Liu, Jun Li, Yitao Tang
Journal: Cancer Research (2024)

Abstract Reverse-phase protein arrays (RPPAs) represent a powerful functional proteomic approach to elucidate cancer-related molecular mechanisms and develop novel cancer therapies. To facilitate community-based investigation of the large-scale protein expression data generated by this platform, we have developed a user-friendly, open-access bioinformatic resource, The Cancer Proteome Atlas (TCPA, http://tcpaportal.org), which contains several applications. The first one focuses on RPPA data of patient tumors, which contains &amp;gt;8,000 samples of 32 cancer types from The Cancer Genome Atlas (TCGA) and other independent patient cohorts. The second application focuses on the RPPA data of &amp;gt;1,500 cancer cell lines with publicly available, high-quality DNA, RNA and drug screening data. The third one focuses on perturbed RPPA profiles of &amp;gt;14,000 samples given drug treatments. We recently expanded our RPPA protein set from 200 to 500 proteins Importantly, this highly selected set is enriched in therapeutic targets and biomarkers and covers key oncogenic pathways such as PI3K/AKT, RAS/MAPK, Src/FAK, TGFβ/SMAD, JAK/STAT, epithelial-mesenchymal transition, DNA damage repair, Hippo, Notch, cell cycle, apoptosis, and immune-oncology. Using this upgraded RPPA platform, we generated an harmonized, expanded RPPA dataset of 8000 TCGA patient samples and 1000 CCLE cell line samples. To further address the informatic challenges of analyzing such large, diverse datasets, in addition to the GUI interfaces, we recently developed a chatbot through which users can analyze the RPPA data through human nature languages and obtain the results and related analytic reports without a learning curve. Such a chatbot empowers a broad research community to explore high-quality RPPA datasets and generate testable hypotheses in an effective and intuitive manner, representing the direction of next-generation data analytics. Citation Format: Han Liang, Wei Liu, Jun Li, Yitao Tang. The Cancer Proteome Atlas: Expanded datasets and empowered with an AI-driven chatbot [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 4931.
Abstract 6473: Evaluation of bladder cancer patients' utilization of urologic telehealth services
Authors: Steven Goldenthal, Tasha Posid, Victor Heh, Dairon Denis-Diaz, Hafsa Asif, Chase Arnold, Henry Gold, Tae-Hee Kim, Amara Ndumele, Sabrina Amin, Matthew Lierz, Vivian Xu, Tyler Cronin, Aliza Khuhro, Cheryl Lee
Journal: Cancer Research (2024)

Abstract Introduction: Infection control practices and public policy in response to the COVID-19 pandemic shifted healthcare practices towards a telemedicine format. Even two years after peak onset of the pandemic, many clinics, including our own institution, maintain a working telehealth option for patient visits. Our objective was to evaluate patient utilization of telehealth visits versus in-person visits at our institution and whether this was impacted by clinical stage, rural/urban status, distance from a large urban academic center, payor status, or comorbidities. Methods: Medical Record Numbers for all patients with bladder cancer were pulled via the Qlik platform from the period 7/1/2019-2/28/2022. Chart review was conducted to pull clinical data on patients including telehealth versus in person visits, demographic data, clinical stage, comorbidities (diabetes, smoking status, BMI), rural/urban status by zip code (&amp;gt;50,000, &amp;lt;50,000 individuals) and income levels by zip code (25K-49.9K, 50K-99.9K, &amp;lt;100K), payor status (Medicare, Managed care, Medicaid, other government, ODRC, or self-pay), patient distance, and gas savings/carbon footprint. Results: 430 patients completed in person visits while 268 completed telehealth visits. There was no statistically significant difference for in person visits vs. telehealth visits regarding patients’ race (p=0.541), ethnicity (p=0.394) age (p=0.862), urban/rural status (p=0.507), payor status (p=0.127), mean zip code income (p=0.175), and comorbidities (p=0.626 for diabetes, p = 0.706 for smoking, p = 0.459 for BMI), and clinical stage (p=0.07). There was a statistically significant difference in mean distance (14.85 miles versus 26.86 miles, p&amp;lt;0.01). Conclusion: Patients’ with bladder cancer receive care from their urologist via in person visits versus telehealth at similar rates irrespective of their urban/rural status, demographics, payor status, relevant comorbidities, or relative income. Patients are more likely to engage in care with their urologist via telehealth if they live farther from a large urban academic center, which produces an economical and environmental impact via gas/time savings and reduced carbon footprint. Citation Format: Steven Goldenthal, Tasha Posid, Victor Heh, Dairon Denis-Diaz, Hafsa Asif, Chase Arnold, Henry Gold, Tae-Hee Kim, Amara Ndumele, Sabrina Amin, Matthew Lierz, Vivian Xu, Tyler Cronin, Aliza Khuhro, Cheryl Lee. Evaluation of bladder cancer patients' utilization of urologic telehealth services [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 6473.
Abstract 1569: Keratin X promotes cell metastasis and sorafenib resistance via the AMPKα/Snail axis in hepatocellular carcinoma
Authors: Yang-Hsiang Lin, Chau-Ting Yeh
Journal: Cancer Research (2024)

Abstract A great majority of liver cancers are developed from cirrhotic livers. The key molecules involved in cirrhosis-mediated hepatocarcinogenesis have not been clearly defined. Understanding the oncogenic pathways and their associations with cancer growth, metastasis and drug resistance may help scientists devise new effective therapeutic agents. In the present study, we identified the intermediate filament-forming protein keratin X (KRTX) as a key factor in cirrhosis-mediated hepatocarcinogenesis. KRTX was highly expressed in HCC tissues and correlated with poor survival outcomes. Experimental verification revealed that overexpression of KRTX enhanced cell growth, tumor cell metastasis, glycolysis and sorafenib resistance. Conversely, knockdown of KRTX led to opposite effects. Mechanistically, KRTX inhibited AMPKα phosphorylation, thereby enhancing Snail protein stability. Additionally, TGFβ1 positively regulated KRTX expression, resulting in a KRTX/AMPKα (Thr172)/Snail axis-mediated increase in cell motility. Treating with 2-deoxyglucose reversed the KRTX-induced metastasis and sorafenib resistance. In clinic, KRTX expression is positively correlated with Snail overexpression and high KRTX/Snail expression had poor prognosis in HCC patients. Our data revealed a signaling pathway from TGFβ1, KRTX, through p-AMPKα (Thr172) to Snail. Targeting KRTX and its pathway may be effective for treating patients with metastatic HCC. Citation Format: Yang-Hsiang Lin, Chau-Ting Yeh. Keratin X promotes cell metastasis and sorafenib resistance via the AMPKα/Snail axis in hepatocellular 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 1569.
Abstract 4614: Inhibition of NEK2 promotes chemosensitivity and reduces primary effusion lymphoma burden
Authors: Maria C. White, Jason P. Wong, Blossom Damania
Journal: Cancer Research (2024)

Abstract Non-Hodgkin lymphoma (NHL) is a common cancer in both men and women, and represents a significant cancer burden worldwide. Primary effusion lymphoma (PEL) is a subtype of NHL infected with Kaposi sarcoma-associated herpesvirus (KSHV). PEL is an aggressive and lethal cancer with no current standard of care, owing largely to its propensity to develop resistance to current chemotherapeutic regimens. Here, we report a reliance of PEL on the mitotic kinase, NEK2, for survival. Genetic and pharmacologic targeting of NEK2 resulted in caspase 3-mediated apoptotic cell death of PEL. Furthermore, inhibition of NEK2 significantly prolonged survival and reduced tumor burden in a PEL mouse model. We also report that the ABC transporter proteins, MDR1 and MRP, are most active in PEL and that NEK2 inhibition of PEL reduced the expression and activity of these ABC transporter proteins, which are known to mediate drug resistance in cancer. Additionally, NEK2 inhibition sensitized both viral and non-viral NHL to other chemotherapeutic agents such as rapamycin, resulting in enhanced cancer cell death. Overall, these data offer insight into the mechanisms underlying PEL survival and drug resistance, and suggest that NEK2 is a viable therapeutic target for PEL. Citation Format: Maria C. White, Jason P. Wong, Blossom Damania. Inhibition of NEK2 promotes chemosensitivity and reduces primary effusion lymphoma 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 4614.
Abstract 211: Applying cellular thermal shift assays to uncover novel regulators of epithelial to mesenchymal transition in triple negative breast cancer
Authors: Jessica A. Lidster, Ser Yue Loo, Zhengwei Wu, Lingyun Dai, Seow Qi Ng, Nayana Prabhu, Dennis Kappei, Wai Leong Tam
Journal: Cancer Research (2024)

Abstract Metastatic Breast Cancer is accountable for over half a million deaths worldwide each year, the majority of which are from the triple negative breast cancer (TNBC) subtype, known to be highly aggressive, metastatic and resistant to targeted therapy. Metastasis is driven by the ability of cancer cells to undergo epithelial to mesenchymal transition (EMT), a cell state transition involving a gain of stemness, cell motility and chemoresistance. EMT has been well characterized using a range of techniques based upon quantitative proteomics and transcription profiling, yet targeting EMT to prevent tumor metastasis and chemoresistance is an obstacle that remains to be fully overcome. Using a cellular thermal shift assay coupled with mass spectrometry (CETSA-MS), we have measured changes in protein stability upon induction of EMT and have uncovered key enzymes in the citric acid (TCA) cycle that are stabilized during EMT of human mammary epithelial cells. Such enzymes are responsible for the conversion of TCA cycle intermediates required for a recently discovered post-translational modification. In TNBC cells, we find that loss of these enzymes causes not only global changes to crucial post-translational modification of mitochondrial proteins, but very specific alterations in several cytoskeletal proteins, leading to altered EMT status as well as reduced tumor growth and initiation both in vitro and in vivo. This demonstrates the importance of TCA cycle-controlled post-translational modification of cytoskeletal proteins in tumorigenesis and establishes basis for further investigation into their role in EMT and metastasis of breast cancer. Through pharmacological inhibition and immunofluorescence imaging, we discovered regulators of post-translational modifications that may be viable drug targets to overcome chemoresistance and relapse in TNBC patients with limited and inefficacious options. Citation Format: Jessica A. Lidster, Ser Yue Loo, Zhengwei Wu, Lingyun Dai, Seow Qi Ng, Nayana Prabhu, Dennis Kappei, Wai Leong Tam. Applying cellular thermal shift assays to uncover novel regulators of epithelial to mesenchymal transition in triple negative 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 211.
Abstract 6050: Targeting KRAS G12D mutant tumors with the PROTAC degrader RP03707
Authors: Xiang Ji, Huanping Li, Gang Wu, Qiguo Zhang, Xiaolin He, Yanpeng Wu, Bing Zong, Xiaojin Xu, Chao Liang, Beibei Wang, Yuwei Zhang, Qingyao Hu, Jiaxin Zhou, Weihui Guo, Bing Bai, Lin Wang, Jinchao Ai, Leduo Zhang, Honggui Zhou, Shihao Sun, Yijie Wang, Youhong Wang, Qiming Fan, Dawei Chen, Tianlun Zhou, Jiasheng Lu
Journal: Cancer Research (2024)

Abstract RAS oncogene mutations are prevalent in approximately 19% of cancer patients, with the most frequent alteration occurring in codon 12 of the KRAS gene, resulting in a variety of G12X oncoproteins. Recent advances in drug discovery have yielded several KRAS G12C inhibitors currently in clinical use, benefiting a subset of patients. However, addressing the high-prevalence G12D mutation remains a substantial unmet medical need. Targeted protein degradation using PROTAC molecules offers a promising approach for treating KRAS G12D-associated tumors, potentially providing superior efficacy and mitigating the development of resistance, a challenge frequently observed with KRAS G12C inhibitors in clinical settings. In the present study, we report a PROTAC compound RP03707 that efficiently induces the degradation of the KRAS G12D mutant protein and inhibits tumor growth. Treatment of AsPc-1 cells with RP03707 results in significant degradation of the KRAS G12D protein, with a DC50 value in the sub-nanomolar range. Within 24 hours, the compound eliminates over 90% of G12D proteins and effectively suppresses downstream cellular MAPK signaling. Additional in vitro experiments demonstrate that RP03707 inhibits cell proliferation in multiple KRAS G12D mutant cell lines, surpassing the anti-tumor efficacy of enzyme inhibitors. In a mouse GP2d xenograft tumor model, a single intravenous administration of RP03707 at 10 mpk results in excellent compound penetration and retention in tumor tissues, followed by 90% reduction of G12D protein levels for 7 days. Profound inhibition of tumor growth is observed not only in mouse GP2d xenograft but also in other mouse KRAS G12D tumor models, even when the compound is administered in low and infrequent doses. Moreover, RP03707 exhibits high selectivity for degrading the KRAS G12D protein and possesses favorable drug-like properties. RP03707, therefore, meets the criteria for advancing into drug development and represents a valuable therapeutic option for treating KRAS G12D-associated tumors. Citation Format: Xiang Ji, Huanping Li, Gang Wu, Qiguo Zhang, Xiaolin He, Yanpeng Wu, Bing Zong, Xiaojin Xu, Chao Liang, Beibei Wang, Yuwei Zhang, Qingyao Hu, Jiaxin Zhou, Weihui Guo, Bing Bai, Lin Wang, Jinchao Ai, Leduo Zhang, Honggui Zhou, Shihao Sun, Yijie Wang, Youhong Wang, Qiming Fan, Dawei Chen, Tianlun Zhou, Jiasheng Lu. Targeting KRAS G12D mutant tumors with the PROTAC degrader RP03707 [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 6050.
Abstract 3019: Dissecting <i>in vivo</i> functions of R-Loops in <i>Brca1</i>-associated DNA replication stress and mammary tumorigenesis
Authors: Huai-Chin Chiang, Leilei Qi, Yanfen Hu, Rong Li
Journal: Cancer Research (2024)

Abstract Germ-line BRCA1 mutations are associated with a significantly increased incidence of breast cancer in women. Although BRCA1-associated breast tumors are basal-like and estrogen receptor α negative (ERα−), they originate from luminal progenitor cells. At the molecular level, BRCA1 is best known for its roles in resolution of DNA replication stress and promotion of homologous recombination (HR)-based double strand break (DSB) repair. In addition, BRCA1 is implicated in reduction of R-loops, a DNA-RNA hybrid structure and transcriptional byproduct associated with genome instability and transcriptional regulation. Our published findings suggest that BRCA1-dependent R-loop mitigation contributes to luminal cell-specific transcription and differentiation (Zhang et al, 2017, Nature Communications, 8:15908), which could in turn suppress Brca1-associated tumorigenesis. Using cell type-specific mouse genetics, we investigate a direct impact of R-loop removal on Brca1-associated mammary epithelial tumor formation. R-loop formation in mammary epithelial cells is efficiently reduced by over-expression of RNase H1, an R-loop-specific ribonuclease. R-loop removal does not affect mammary duct development or function. However, it drastically increases ɣH2AX foci in proliferating BRCA1-deficient epithelial cells without external DNA damage. This suggests a role of R-loops in attenuating elevated DNA replication stress caused by the loss of Brca1. While R-loop removal does not appear to affect the overall Brca1-associated mammary tumor incidence, it promotes cell differentiation from ERα− luminal progenitor cells to ERα+ mature luminal cells. Accordingly, unlike their counterparts, a significant percentage of Brca1-associated mammary tumors with RNase H1 overexpression tend to be ERα+. Thus, our findings provide in vivo evidence for a previously unappreciated role of R-loop dynamics on Brca1-associated DNA replication stress and tumor development in mammary epithelium. Citation Format: Huai-Chin Chiang, Leilei Qi, Yanfen Hu, Rong Li. Dissecting in vivo functions of R-Loops in Brca1-associated DNA replication stress and mammary tumorigenesis [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 3019.
Abstract 7359: Priority targets in pancreatic cancer
Authors: Zeribe Chike Nwosu, Marina Pasca di Magliano, Costas Lyssiotis
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a drug resistant and lethal cancer. To better understand this disease, we separately analyzed five published human PDAC microarrays, determined the differential genes in each dataset and defined a gene as ‘consistent’ if it is ‘upregulated’ or ‘downregulated’ in &amp;gt;4 datasets (adjusted P&amp;lt;0.05). We identified 2,010 consistently upregulated- and 1,928 downregulated genes, over 50% of which were previously uncharacterized in PDAC. These genes span multiple processes, including cell cycle, immunity, transporters, metabolism, signaling, transcription factors and epigenetics. - with cell cycle and glycolysis being the most altered. Many consistent genes correlated with tumor subtype, proliferation, metastasis, and ~41% predicted survival, notably, OGN, PLOD2, DIAPH3, C2orf40, ADM, UPP1, ZNF189, DCBLD2, PLAG1, and glycolysis genesALDOA, GAPDH, PKM and LDHA. We identified 451 high priority targets, including 185 upregulated genes (notably in cell cycle and glycolysis) whose knockdown suppressed PDAC cell growth in prior RNAi screen studies. Our results represent an important milestone in the quest for mechanisms, drug targets and biomarkers and could enable the discovery of novel mechanisms and therapies in PDAC. Citation Format: Zeribe Chike Nwosu, Marina Pasca di Magliano, Costas Lyssiotis. Priority targets in pancreatic 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 7359.
Abstract 4919: AI-enabled hit selection of drug screening on human pancreatic cancer organoids
Authors: Zhisong Tong, Angeline Lim, Marine Meyer, Maria Clapes, Oksana Sirenko, Nathalie Brandenberg
Journal: Cancer Research (2024)

Abstract Cancer remains one of the leading causes of death in the 21st century. Despite the latest advances in oncology, most cancer patients lack tailored therapeutic approaches with lasting benefit. Measuring the impact of anticancer compounds and their combinations is only possible on ex vivo assays. To this end, patient-derived organoids (PDOs) have been proposed as viable and efficient models for ex vivo testing. PDOs show long-term expansion potential while retaining tumor histopathology as well as cancer gene mutations. However, the translation of organoids in screening applications has so far been hampered by the lack of homogeneity and difficulties in handling and automation. Moreover, organoids are typically randomly distributed across the culture which complicates imaging and images analyses. To overcome these challenges, we set up a compound screening workflow with PDOs using Gri3D platform, comprising plates with micro-cavities suitable for high-throughput and reproducible organoid culture. Based on a standard 96 microtiter plate, each well contains a microwell array patterned in a cell repellent hydrogel. On Gri3D®, organoids are robustly generated in the microwells and are located in the same imaging plane. This greatly facilitates quantitative analyses in high content image-based screens. Furthermore, the pipetting port enables automation of cell seeding, media exchange and compound incubation with liquid-handlers, thus increasing assay reproducibility. In the presented work, we exposed human pancreatic cancer PDOs to a panel of anti-cancer compounds at different doses and followed their response to the drugs using viability dyes Calcein AM (live stain) and Ethidium Homodimer-1 (dead stain) with high-content confocal imaging. Using an AI-based approach, we efficiently detected each single organoid and extracted phenotypic features from all three channels (TL, live stain and dead stain) which correlate with cytotoxicity. The extracted features (more than 100) were first dimensionally reduced to 3 components using either PCA or UMAP, the treatments were then visualized in 3D scatter plots, ranked and clustered using machine learning. The data suggests that the compound treatment Palbociclib 50uM has significant cytotoxicity effects similar to the positive control, which is consistent with the traditional live/dead analysis. The AI approach demonstrates feasibility to perform drug screening in a robust and un-biased data analysis approach. Citation Format: Zhisong Tong, Angeline Lim, Marine Meyer, Maria Clapes, Oksana Sirenko, Nathalie Brandenberg. AI-enabled hit selection of drug screening on human pancreatic cancer organoids [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 4919.