tbuckley/cabot-search huggingface dataset:
Abstract 1565: USP13 influences metastatic features in fallopian tube-originated high-grade serous carcinoma
Authors: Boram Mok, Juntae Kwon, Jinmin Zhang, Samuel Allsup, Hyeongjwa Choi, Cecil Han
Journal: Cancer Research (2024)

Abstract High-grade serous ovarian carcinoma (HGSOC), originating from the fallopian tube, stands as a formidable challenging gynecologic malignancy with the highest mortality rate worldwide. Ubiquitin-specific peptidase 13 (USP13) has garnered attention due to the highly frequent USP13 gene copy amplification in human ovarian cancer. However, its precise pathological role in ovarian cancer remained elusive. To uncover the underlying role of USP13 in HGSOC, we developed a novel genetically engineered mouse model (GEMM) of HGSOC. Ovgp1-iCreERT2;Trp53flox/flox;Ptenflox/flox mouse (OPT) was crossed with Rosa26−LSL-Usp13 knockin mouse model (U), generating Ovgp1-iCreERT2;Trp53flox/flox;Ptenflox/flox ; Rosa26−LSL-Usp13 mouse model (OPTU). Usp13 overexpression with loss of p53 and Pten was induced specifically in fallopian tube secretory epithelial cells in OPTU mice. OPTU mice demonstrated the development of STIC and early HGSOC in the fallopian tube as well as invasive metastatic HGSOC. While OPT tumors largely retained mucinous and HGSOC subtypes, displaying limited metastatic behavior, OPTU tumors exhibited more complex ovarian tumor subtypes, including mucinous, HGSOC, and Mixed Mesodermal Mullerian Tumor (MMMT) histology. Furthermore, OPTU tumors showed invasive and metastatic phenotypes, characterized by an increased incidence of ovary invasion, metastasis to distant organs, and ascites development. Importantly, OPTU-driven HGSOC tumors closely resemble human HGSOC histology features, making the OPTU model a valuable tool for exploring fallopian tube-originated ovarian cancer. Primary ovarian cancer cells established from ascites of the OPTU mouse reproduced metastatic HGSOC tumorigenesis in the syngeneic mouse study. Stable USP13 knockdown in OPTU cells exhibited reduced cell proliferation and metastatic abilities in 2D and 3D cultures. In summary, this study underscores the pivotal role of USP13 in facilitating metastasis in fallopian tube-originated HGOSC. Our findings may provide a promising avenue for future therapeutic strategies aimed at mitigating the aggressive nature of USP13-amplified fallopian tube-originated HGOSC. Citation Format: Boram Mok, Juntae Kwon, Jinmin Zhang, Samuel Allsup, Hyeongjwa Choi, Cecil Han. USP13 influences metastatic features in fallopian tube-originated high-grade serous 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 1565.
Abstract 1246: Erg-driven prostate cancer emerges from a basal subset of cells with luminal transcriptomic features
Authors: Erik Ladewig, Weiran Feng, Christina Leslie, Charles Sawyers
Journal: Cancer Research (2024)

Abstract Translocations of the ETS family transcription factor ERG are found in nearly 150,000 newly diagnosed prostate cancers (PCas) each year in the United States underscoring the importance of defining the mechanism by which ERG promotes prostate epithelial transformation. A consequence of nearly all ERG translocations is the aberrant expression of ERG in prostate luminal cells under transcriptional control of TMPRSS2. Multiple lines of evidence implicate ERG translocations as an initiating event in prostate cancer. ERG expression is seen in prostatic intraepithelial neoplasia (PIN) and proliferative inflammatory atrophy; expression in cancers is typically uniform; and, in the context of PI3K pathway activation, ERG is sufficient to induce cancers in mice. Yet, despite extensive research the mechanism by which ERG initiates prostate cancer is unclear. To gain insight into how ERG translocations cause prostate cancer, we performed both transcriptional profiling (scRNA-seq) and chromatin accessibility via Assay for Transposase-Accessible Chromatin using sequencing (snATAC-seq) in single cells of an autochthonous mouse model at an early stage of disease initiation. Surprisingly, we observed in prostate epithelial cells broadly expressing ERG enhanced proliferation primarily in a hybrid subpopulation of cells having basal identity but with luminal morphology and cytokeratin expression. Through a series of lineage tracing and primary prostate epithelial transplantation experiments, we confirmed tumor initiating activity resided within a subpopulation of basal cells expressing luminal genes (e.g., Tmprss2 and Nkx3-1). A trajectory analysis from single-cell Chromatin accessibility indicated Erg+ cells began to lose basal (Trp63) accessibility and gained in STAT/NFAT TFs while retaining the ability to rapidly differentiate into luminal cells that reflect the lineage of ERG-positive cancers. These findings help resolve a preexisting debate about the cell of origin of ERG-driven prostate cancer and narrow the focus for future mechanistic studies to a basal-luminal subpopulation of tumor initiating cells. Citation Format: Erik Ladewig, Weiran Feng, Christina Leslie, Charles Sawyers. Erg-driven prostate cancer emerges from a basal subset of cells with luminal transcriptomic features [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 1246.
Abstract 7093: Prediction of overall survival in stage II and III colon cancer through machine learning of rapidly-acquired proteomics
Authors: Kailun Xu, Xiaoyang Yin, Tiannan Guo, Shu Zheng, Yingkuan Shao
Journal: Cancer Research (2024)

Abstract The use of adjuvant therapy in stage II-III colon cancer (CC) has been controversial for decades. No markers or models now is satisfactory enough to be adopted widely by the medical community. Here, we analyzed the proteomics of paraffin-embedded tissue (FFPE) biopsy samples from 230 CC patients (stages II-III) with up to 10 years of survival by using pressure cycling technology (PCT) and data-independent acquisition (DIA) mass spectrometry. Using machine learning, we established a novel and practical protein-based clinical classification system for CC prognosis which was further verified in an independent validation cohort. Using the nine protein-based clinical model, we improved the area under the curve (AUC) value to 0.926 in the training cohort and 0.872 in the validation cohort. Our promising model will be a potential approach to prognostication to aid in rational follow-up schedule-making and risk-adaptive individualized therapies. Citation Format: Kailun Xu, Xiaoyang Yin, Tiannan Guo, Shu Zheng, Yingkuan Shao. Prediction of overall survival in stage II and III colon cancer through machine learning of rapidly-acquired proteomics [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 7093.
Abstract 7113: Targeting the repair of DNA-protein crosslinks induced by bifunctional alkylating agents
Authors: Cole Turner, Hailey Cerrato, Victoria Melehov, Charlotte Healy, Kevin P. Rice
Journal: Cancer Research (2024)

Abstract Bifunctional alkylating agents, such as nitrosoureas, platinum-based therapeutics, and chloroethylhydrazines, have demonstrated clinical successes against cancer by inducing cytotoxic interstrand or intrastrand DNA crosslinks. However, the less well-characterized capacity of these agents to couple DNA to chromosomally-associated proteins may also contribute to these compounds’ observed cytotoxicities. Bulky DNA-protein crosslinks (DPCs) could obstruct the DNA metabolism critical to cancer proliferation, thus contribute to genomic instability and cell death. To endogenously repair DPCs, human cells often utilize a DPC-specific proteolytic mechanism dependent on the metalloprotease SPRTN. Complementary approaches for quantifying DPCs, generated ex vivo, to assess the capacity of several bifunctional alkylating agents to induce these lesions in cultured human leukemia cells are presented here. In the first approach, proteins were isolated from lysates of drug-treated cells and protein-bound DNA was quantified as a ratio to the total DNA present in the lysates. In the complementary approach, DNA was extracted from lysates of drug-treated cells using a modified ‘STAR’ assay in which genomic DNA is isolated and the DNA-bound proteins were quantified by fluorescein isothiocyanate labeling. Micromolar concentrations of the nitrogen mustard mechlorethamine and nitrosourea lomustine induced significant DPC formation while more modest DPC formation was observed using similar concentrations of the chloroethylating agents carmustine and laromustine, as well as cisplatin. Bifunctional alkylating agents dependent on epoxide functionality, including dianhydrogalacticol and diepoxybutane, required drug concentrations of at least one order of magnitude larger to produce similar DPC yields measurable by these techniques. A strategy to interfere with the DPC repair pathway via SPRTN knockdown and assess increased sensitivity of cancer cells to bifunctional alkylating agents is also presented. Chemotherapeutic sensitization by targeting SPRTN could suggest a therapeutic strategy to improve effectiveness of several DNA-targeted anticancer agents, especially if extended to other therapeutics that trap DPCs such as inhibitors of topoisomerase and poly(ADP-ribose) polymerase. Further, identifying structure-function relationships with respect to bifunctional alkylating agents and DPC formation could inform the future development and clinical utilization of these chemotherapies. Citation Format: Cole Turner, Hailey Cerrato, Victoria Melehov, Charlotte Healy, Kevin P. Rice. Targeting the repair of DNA-protein crosslinks induced by bifunctional alkylating agents [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 7113.
Abstract 1336: Verification of the effect of human allogeneic iPS cell-derived gene-engineered NK cells (eNK cells HLCN061) on mesothelioma
Authors: Seiji Matsumoto, Yoshiko Fujita, Kumiko Goto, Yuka Sato, Fusako Nishigaki, Yasuyuki Higashi, Hironobu Kimura, Kouichi Tamura
Journal: Cancer Research (2024)

Abstract Malignant pleural mesothelioma is a malignant tumor that is caused by exposure to asbestos. Because it is a rare cancer, there are few drugs that can be used to treat it. Healios is developing iPSC-derived NK cells (eNK cells) (HLCN061) engineered with NKG2D, DAP10, IL-15, CD16, CCL19, and CCR2B genes for the treatment of refractory solid tumors. This study evaluated the antitumor effect of eNK cells against human malignant pleural mesothelioma cell lines.(Method) The antitumor effect of eNK cells on human malignant pleural mesothelioma cell lines in vitro was evaluated using the Viability/Cytotoxicity Multiplex Assay Kit (WST-8/LDH).In vivo, immunodeficient mice were subcutaneously inoculated with human malignant pleural mesothelioma cell lines. After subcutaneous tumor formation, eNK cells were inoculated into or near the tumor, the size of the subcutaneous tumor was measured, and the tumor volume was compared with that of an untreated group. After the study was completed, the tumors were removed and the tumors in the untreated group and the eNK cell-administered group were analyzed using RNA-seq.(Results) The antitumor effect of eNK cells against human malignant pleural mesothelioma cell lines was confirmed in vitro. In a mouse subcutaneous tumor model, the eNK cell treatment group suppressed tumor growth compared to the untreated group (p≦0.05). RNA-seq showed increased expression of granulysin, IL2RB, cathepsin W, etc. in subcutaneous tumors treated with eNK cells. Citation Format: Seiji Matsumoto, Yoshiko Fujita, Kumiko Goto, Yuka Sato, Fusako Nishigaki, Yasuyuki Higashi, Hironobu Kimura, Kouichi Tamura. Verification of the effect of human allogeneic iPS cell-derived gene-engineered NK cells (eNK cells HLCN061) on mesothelioma [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 1336.
Abstract 7100: Quantitative proteomics reveal the mechanism of TTFields therapy for glioblastoma
Authors: Qi Mei, Yanmei Gao, Rong Li, Chenxu Wang, Guangyuan Hu, He Huang
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is a highly malignant brain tumor, and conventional treatments such as surgical resection and chemotherapy have limited effectiveness, with a high rate of recurrence and poor prognosis for patients. In 2011, the FDA approved a novel therapy for recurrent GBM known as Tumor Treating Fields (TTFields). TTFields use alternating intermediate-frequency (200 kHz) and low-intensity (1-3 V/cm) electric fields to interfere with tumor cells, inducing apoptosis and inhibiting tumor growth. This study aimed to explore the molecular mechanisms of TTFields therapy at the systems biology level using quantitative proteomics technology. We analyzed U87 cells before and after TTFields treatment using quantitative proteomics and identified a total of 7679 proteins. Among them, 804 proteins were significantly upregulated after TTFields treatment, and 1141 proteins were significantly downregulated. Pathway enrichment analysis of differentially expressed proteins showed that upregulated proteins were mainly associated with cell proliferation, cell cycle, and transcription, possibly representing compensatory responses to the TTFields treatment. Further analysis revealed a significant upregulation of the tumor proliferation key protein PARP1, which was validated by protein immunoblotting experiments. Based on this analysis, we hypothesized that combining TTFields with Olaparib (a PARP1 inhibitor) might enhance the sensitivity of TTFields. Subsequently, we performed cell proliferation experiments to evaluate the concomitant application strategy, and the results demonstrated that Olaparib in combination with TTFields treatment significantly reduced the survival rate of U87 cells compared to single-drug treatment. In conclusion, using quantitative proteomics, this study revealed the biological processes underlying the inhibitory effects of TTFields on GBM proliferation. Under TTFields intervention, the expression of PARP1 was upregulated, and the use of a PARP1 inhibitor in combination significantly increased the sensitivity of TTFields. Therefore, this study not only elucidated the molecular mechanisms of TTFields therapy for GBM treatment at the systems biology level, but also provided support for further enhancing the efficacy of TTFields. Citation Format: Qi Mei, Yanmei Gao, Rong Li, Chenxu Wang, Guangyuan Hu, He Huang. Quantitative proteomics reveal the mechanism of TTFields therapy for glioblastoma [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 7100.
Abstract 7111: Homoharringtonine is effective in treating acute lymphoblastic leukaemia via WEE1 downregulation and inducing DNA damage
Authors: Chun-fung Sin, Kei-ching Yuen, Anan Jiao, Bai-lin Li, Hau-wai Yu
Journal: Cancer Research (2024)

Abstract Acute lymphoblastic leukaemia (ALL) is an aggressive haematolymphoid malignancy that originated from clonal mutations in lymphoid precursors. The prognosis is poor in adult patients and relapse/refractory disease is not uncommon which carries dismal prognosis. There is an urgent need to develop novel therapeutics. Homoharringtonine (HHT) is a plant alkaloid which can bind to ribosomal A-site and thus inhibit protein synthesis. It was used to treat acute myeloid leukaemia in China during 1980s. Herein, we conducted a study to explore the therapeutic efficacy and mechanism of action in ALL. T-ALL (DND-41, PEER) and B-ALL (PALL-2, SUP-B15) cell lines were treated with HHT for 24 and 72 hours. Cell viability was reduced at a time and dose-dependent manner in all cell lines we tested, with increased in percentage of apoptosis. Western blot showed upregulation of p53, with PARP and caspase 3 cleavages upon treating with HHT for 24 hours. Moreover, we observed WEE1 downregulation which allowed cell cycle progression through G2/M with damaged DNA. Comet assay showed evidence of DNA damage. Proteomics study by label-free protein quantitation showed downregulation of proteins involving in homologous recombination-mediated DNA repairing machinery, including BRCA1 and RAD51. The findings not only showed therapeutic efficacy of HHT in ALL, but also demonstrated the first evidence of DNA damage induced by HHT which might account for its therapeutic effects. Further studies will be conducted for delineating the mechanisms of DNA damage and its relationship with therapeutic efficacy. Citation Format: Chun-fung Sin, Kei-ching Yuen, Anan Jiao, Bai-lin Li, Hau-wai Yu. Homoharringtonine is effective in treating acute lymphoblastic leukaemia via WEE1 downregulation and inducing DNA damage [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 7111.
Abstract 2007: Neurolysin: A novel architect of the prostate cancer microenvironment and therapeutic resistance
Authors: Choushi Wang, Ping Mu
Journal: Cancer Research (2024)

Abstract Introduction: Prostate cancer is the second leading cause of cancer-related death in American men, primarily driven by its ability to evade therapeutic interventions. This study uncovers a novel paradigm where neurolysin, a peptidase previously ascribed to neuronal function, orchestrates the tumor microenvironment (TME) by interfacing with cellular motor proteins. This interaction precipitates a series of events that not only fortify the cancer cells' survival but also underpin the resistance to antiandrogen therapies. Experimental Procedures: We deployed advanced prostate cancer models to delve into the extra-neuronal influence of neurolysin, probing its role in the orchestration of the TME. An exhaustive suite of transcriptomic and proteomic analyses, complemented by comprehensive patient cohort studies, laid the foundation for unraveling the complex interplay between neurolysin, motor proteins, and the TME dynamics. Results: Our data elucidates that neurolysin's depletion correlates with an altered TME, conducive to cancer proliferation and resilience against targeted therapies. This shift is mediated through neurolysin's interaction with cellular motor proteins, a liaison that appears to be a cornerstone in TME modulation. A significant subset of prostate cancer cases exhibits a neurolysin deficiency, paralleling more aggressive disease and therapeutic defiance, highlighting its role as a critical biomarker and a novel target for intervention. Conclusions: Neurolysin steps into the limelight as a pivotal modulator of the TME, operating through mechanisms distinct from its known neuronal functions. Its interplay with motor proteins opens a novel avenue in prostate cancer biology, providing a unique perspective on the regulation of the TME and subsequent therapeutic resistance. Targeting this newly discovered regulatory axis presents a promising therapeutic strategy that could potentially redefine the clinical approach to managing prostate cancer and may have implications for other malignancies driven by similar TME alterations. Citation Format: Choushi Wang, Ping Mu. Neurolysin: A novel architect of the prostate cancer microenvironment and therapeutic resistance [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 2007.
Abstract 7117: Convection enhanced delivery of a novel ATR inhibitor synergizes with systemic lomustine for improved treatment of glioblastoma
Authors: Alexander Josowitz, Teresa Lee, Ranjini K. Sundaram, Jinal Pothupitiya, Eric J. Brown, Amrita Sule, Jason Beckta, Yongheng Wang, Joseph Vacca, Oren Gilad, Ranjit S. Bindra, W Mark Saltzman
Journal: Cancer Research (2024)

Abstract Developing effective strategies for treating glioblastoma (GBM), the most common and aggressive form of brain cancer, has been a long-standing challenge. Despite rigorous treatment regimens including surgical resection with concomitant radiotherapy and chemotherapy, the prognosis for this disease remains poor, largely due to tumor recurrence, resistance to conventional therapeutics, pharmacokinetic and brain delivery challenges, and dose-limiting toxicities of existing therapies. The DNA damage response and DNA repair mechanisms such as the ataxia telangiectasia and Rad3-related (ATR) pathway are key mediators of therapeutic responses, and recent studies have shown that targeting DNA repair proteins alongside standard-of-care options is a promising anti-tumor strategy. Here, we employ a combination approach using a next-generation macrocyclic ATR inhibitor, ATRIN-333, to sensitize GBM tumors to alkylators. We establish the potency of ATRIN-333 and report a robust synergistic interaction between it and the alkylator lomustine in GBM cell-based assays and in a murine flank tumor model. This combinatorial treatment was then applied to a mouse intracranial tumor model, where we utilized a convection enhanced delivery (CED) system combined with nanoparticle technology for direct intracranial administration of ATRIN-333. ATRIN-333 was successfully encapsulated into a novel polymeric nanoparticle formulation using poly(ethylene glycol)-co-poly(ethylene brassylate-co-dioxanone) (PEG-EB-co-DO). CED of both free and encapsulated ATRIN-333 potently sensitized intracranial GBM tumors to low-dose (5 mg/kg) systemically-delivered lomustine, reducing tumor size and conferring a substantial survival benefit compared to cohorts treated with lomustine or the ATR inhibitor alone. The combination approach was well tolerated by the mice, with no hematological toxicity observed as assessed by bone marrow analysis and blood cell counts. Our results demonstrate that ATR inhibitor/lomustine combination therapy, used in conjunction with a CED platform, is a powerful avenue for GBM treatment and a viable option for potential clinical implementation. Note: AJ and TL contributed equally to this work. Citation Format: Alexander Josowitz, Teresa Lee, Ranjini K. Sundaram, Jinal Pothupitiya, Eric J. Brown, Amrita Sule, Jason Beckta, Yongheng Wang, Joseph Vacca, Oren Gilad, Ranjit S. Bindra, W Mark Saltzman. Convection enhanced delivery of a novel ATR inhibitor synergizes with systemic lomustine for improved treatment of glioblastoma [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 7117.