bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B007: New generation mTOR blocker sensitizes prostate cancer models to AR-targeting therapy
Authors: Li Shuang , La Manna Federico , Chouvardas Panagiotis , Thalmann George , Kruithof-de Julio Marianna 
Published: June 2023

Abstract
Advanced stage prostate cancers (PCa) can develop bone metastasis, a lethal feature of castration-resistant prostate cancer (CRPC) for which no curative options are currently available. Androgen deprivation therapy (ADT) is the main therapeutic strategy for treating advanced PCa; patients with bone metastasis, however, are frequently developing resistance to ADT, progressing to CRPC. Dysregulation of the mTOR pathway has been linked with AR reactivation and with progression to CRPC, and mutations in targets of the PI3K/Akt/mTOR pathway are frequently found in CRPC patients. This study investigates the effect of synergistic AR and mTOR pathways blockade on therapy resistance in advanced PCa in vitro and in vivo. LNCaP and LAPC4 cells were treated in vitro with AR blockers (apalutamide, enzalutamide), mTOR blockers (rapamycin, everolimus, MLN0128 or Rapalink-1) or a combination of both blockers. Viability was measured in a timecourse from 1 to 10 days after drug administration using CellTiter Acqueous 96. To mimick ADT in vitro, cells were cultured for 7 days in charcoal-stripped serum in medium without dihydroxytestosterone or phenol red before the drug screening. Two already established PDX models of bone-metastatic PCa, BM18 and LAPC9 respectively androgen-dependent and -independent, were used to assess the effect of combined ADT and mTOR-targeting therapy in vivo. Both LNCaP and LAPC4 models showed a higher sensitivity to MLN0128 and Rapalink-1 compared to rapalogs, LAPC4 cells in particular were more sensitive than LNCaP cells to mTOR inhibitors. AR blockers were moderately effective and only at concentrations between 10 and 100 µM, when used alone. However, treatment with sublethal doses of Rapalink-1 (0.001-0.01 µM) sensitized both cell lines to 2- to 3-log fold lower concentrations of apalutamide. In vivo, treatment with Rapalink-1 alone significantly reduced the growth rate of LAPC9 PDX, while co-treatment with ADT and Rapalink-1 resulted in regression in this CRPC model, a result not achievable by either treatment alone. Treatment with Rapalink-1, while effectively reducing cell viability in vitro already when used alone, could sensitize the tested models to AR blockers, at clinically relevant concentrations. In vivo treatment with Rapalink-1 was well-tolerated and sufficient to control the growth of the BM18 PDX model. When used in combination with ADT, it could induce regression of the CRPC model LAPC9.
Citation Format: Shuang Li, Federico La Manna, Panagiotis Chouvardas, George Thalmann, Marianna Kruithof-de Julio. New generation mTOR blocker sensitizes prostate cancer models to AR-targeting therapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B007.
Abstract B013: KLF5 drives basal cell identity to promote prostate cancer lineage plasticity
Authors: Pitzen Samuel P. , Qiu Yinjie , Munro Sarah , Dehm Scott M. 
Published: June 2023

Abstract
The purpose of this study was to characterize the phenotypes and drivers of therapy-induced lineage plastic castration resistant prostate cancer (CRPC). Since the majority of primary prostate cancer presents with a luminal cell identity, which relies on androgen receptor (AR) signaling for growth and survival, AR-targeted therapies have become an effective method of slowing progression. However, CRPC cells can develop resistance through reduced or lost dependence on AR. These cells can transition their identity to neuroendocrine CRPC (NEPC), which lacks AR and expresses neuroendocrine lineage specific markers like chromogranin A. More frequently, these cells display transition to a cell identity that lacks AR and neuroendocrine markers and has been termed double-negative CRPC (DNPC). Identifying effective therapeutic targets to treat or prevent DNPC remains a significant clinical challenge. By utilizing prostate cancer cell lines, patient derived xenografts (PDX), and publicly available data from clinical CRPC specimens, we have identified an upregulation in basal cell identity in a subset of CRPC in response to AR-targeted therapies. Additionally, we show that the stem cell transcription factor KLF5, which is highly expressed in healthy prostate basal cells, is uniquely upregulated in CRPC subtypes displaying basal cell identity. In a cell line model of DNPC, we found that knockdown of KLF5 decreased the expression of genes that define basal cell identity. From these results, we conclude that AR-targeted therapies, while effective at targeting luminal-like adenocarcinoma, promote upregulation of KLF5 which can drive a basal cell identity and AR independence. These studies nominate KLF5 signaling as a potential therapeutic target to block the emergence of basal identity, inhibit prostate cancer lineage plasticity, and increase the durability of AR-targeted therapies.
Citation Format: Samuel P. Pitzen, Yinjie Qiu, Sarah Munro, Scott M. Dehm. KLF5 drives basal cell identity to promote prostate cancer lineage plasticity [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B013.
Abstract B018: Loss of androgen receptor-mediated repression leads to EphA2 overexpression that promotes cellular dedifferentiation and castration resistance of prostate cancer through noncanonical signaling
Authors: Lingerak Ryan , Wang Bingcheng 
Published: June 2023

Abstract
As a member of Eph subfamily receptor tyrosine kinases, EphA2 has been extensively studied in cancer. It is frequently overexpressed in many different types of human cancer, which is often correlated with tumor progression. We reported recently that EphA2 has diametrically opposite roles in regulating PCa cell differentiation, proliferation, migration, and invasion. In the presence of ligands called ephrin-As, EphA2 canonical signaling inhibits Ras/ERK and PI3K/Akt pathways and suppressed cell proliferation and migration. In contrast, in the absence of ligands EphA2 mediates noncanonical signaling, which promotes chemotactic migration and invasion and accentuates the tumor cell stem properties. Interestingly the ligand-independent noncanonical signaling is correlated with phosphorylation of EphA2 on serine 897 (S897). S897A mutation abolished this ligand-independent effect on cell differentiation and migration and suppressed tumor development in PC3 xenograft model. In mouse prostate, EphA2 is expressed in the stem cell niche together with its cognate ephrin-A ligands in the peri-urethra region but is repressed in AR-positive, differentiated prostate epithelial cells. During progression toward CRPC, ephrin-ligand expression is reduced while EphA2 is overexpressed, facilitating ligand-independent noncanonical signaling by EphA2. Consistent with the negative roles of AR in regulating EphA2 expression, treatment with anti-AR enzalutamide promotes EphA2 expression. In contrast, activating AR with DHT strongly suppressed EphA2 expression. Knockout of EphA2 in the AR+ LAPC4 cells, delayed progression towards castration resistance in vivo. Our results unveiled the previously unknown functional crosstalk between AR and EphA2, and the important role of EphA2 in the malignant progression of prostate cancer.
Citation Format: Ryan Lingerak, Bingcheng Wang. Loss of androgen receptor-mediated repression leads to EphA2 overexpression that promotes cellular dedifferentiation and castration resistance of prostate cancer through noncanonical signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B018.
Abstract B026: PIM kinases regulates tumor associated macrophage survival and inflammatory signaling
Authors: Clements Amber N. , Warfel Noel A. 
Published: June 2023

Abstract
Prostate tumors are highly infiltrated by immunosuppressive tumor associated macrophages (TAMs). TAMs secrete various factors that promote tumor progression and suppress antitumor immunity, making them a promising therapeutic target. PIM kinases are serine/threonine kinases that are overexpressed in several tumor types including prostate cancer. PIM regulates many signaling pathways that promote cell proliferation and cell survival. However, the role of PIM in macrophages is not well understood. Macrophages express NLRP3, a cytosolic innate immune sensor, that forms a complex with ASC and caspase-1 termed the inflammasome. Activation of the inflammasome leads to release of proinflammatory cytokines including IL-1β and induces pyroptotic cell death. We hypothesize that PIM promotes macrophage survival by suppressing inflammasome activation. To test our hypothesis, we treated mouse bone marrow derived macrophages (BMDMs) with PIM447, a pan-PIM kinase inhibitor, and activated the inflammasome via lipopolysaccharide (LPS) and ATP stimulation. Preliminary data demonstrates that PIM inhibition in BMDMs promotes increased inflammasome activation as indicated by increased cleaved caspase-1 and increased IL-1β secretion. Recent studies have demonstrated that PIM kinases promote immune evasion through the modulation of both tumor cells and immune cells within the tumor microenvironment. We hypothesize that PIM kinase promotes TAM survival leading to increased immunosuppression and immunotherapy resistance in prostate cancer. We treated immunocompetent mice injected with MyC-Cap prostate cancer cells with PIM447. PIM inhibition decreased tumor growth and decreased the presence of tumor associated macrophages. In summary, the results of these studies suggest that PIM plays an important role in regulating macrophage survival and inflammatory signaling. Furthermore, PIM may be a potential target to enhance the efficacy of immunotherapies for the treatment of prostate cancer.
Citation Format: Amber N. Clements, Noel A. Warfel. PIM kinases regulates tumor associated macrophage survival and inflammatory signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B026.
Abstract B037: Elevated mitochondrial activity is a targetable signature of prostate cancer bone metastases
Authors: Su Shang , Liu Ke , Xing Jing , Zhao Yawei , Liu Ruihua , Chen Bin , Li Xiaohong 
Published: June 2023

Abstract
Prostate cancer (PCa) patients’ 5-year survival is only ~30% when metastases develop. Most PCa metastases happen in bone. We seek to identify gene signatures unique for bone-metastatic PCa cells and explore potential drug candidates to specifically target PCa bone metastases (bone met). Using public RNA-Seq datasets, we defined differentially expressed genes (DE) intrinsic to PCa bone met by analyzing the DE between bone mets (MET500) and primary tumors (TCGA) and filtering out the genes shown as the DE between normal bone marrow and prostate (GTex). Similarly, we got DE intrinsic to liver met. These two intrinsic DE were further compared and functional annotation for bone met only DE was performed. We found that the bone met only up-regulated DE were significantly enriched for mitochondrial OXPHOS and electron transport chain (ETC). In contrast, no mitochondria-related terms were enriched in PCa liver met, PCa lymph node met or breast cancer bone met, suggesting unique elevated mitochondrial activities in PCa bone met. We further performed RNA-Seq analyses and determined the DE unique in intratibial xenografts (mimicking bone mets), compared to C4-2B PCa primary tumors, i.e., orthotopic or subcutaneous xenografts. OXPHOS was also positively enriched in the intratibial DE, suggesting that pre-clinical animal models recapitulate functional signatures of PCa patients and can be used for drug testing. Therefore, we hypothesized that inhibiting mitochondrial OXPHOS or ETC complex blocks PCa bone metastases. Excitingly, we found that mitochondrial ETC complex I inhibitor, IACS-010759, showed high potency and specificity in suppressing PCa cell growth without affecting osteoblasts in vitro, and significantly inhibited metastatic development of PCa cells in vivo. In summary, elevated mitochondrial activity appears to be a unique signature and phenotype for PCa bone met and mitochondria-interrupting drugs selectively suppress the growth of PCa cells without affecting normal cells in the bone microenvironment such as osteoblasts. Blocking mitochondria hyperactivation is a potential approach against PCa bone met.
Citation Format: Shang Su, Ke Liu, Jing Xing, Yawei Zhao, Ruihua Liu, Bin Chen, Xiaohong Li. Elevated mitochondrial activity is a targetable signature of prostate cancer bone metastases [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B037.
Abstract B040: Novel immunotherapy strategies targeting PTEN and TP53 defects in advanced prostate cancer
Authors: Shi Wei , Wang Yin , Zhao Yuehui , Zhao Di 
Published: June 2023

Abstract
Prostate cancer is the most diagnosed cancer in men worldwide and the leading cause of cancer death in men worldwide. Genetic inactivation of PTEN and TP53 are common in advanced prostate cancers. Checkpoint immunotherapy has yielded meaningful responses across many cancers but shown modest activity in advanced prostate cancer. Prior studies showed that overexpression of immune checkpoint B7-H3 (CD276) correlates with the increased risks of clinical recurrence, disease spread, and poor outcomes in various cancer types, including prostate cancer. However, the roles of B7-H3 in prostate cancer development and its tumor microenvironment remain unclear, partially due to the lack of tissue-specific deletion mouse models. This gap in knowledge hinders the application of immunotherapy targeting B7-H3 in prostate cancers. To identify PTEN- and p53-associated immune checkpoints, we performed multi-omics analyses of expression patterns of 51 checkpoint molecules in human prostate cancer samples and found that B7-H3 is one of the most significantly overexpressed immune checkpoints in prostate tumors containing PTEN and TP53 genetic inactivation. Mechanistically, we found that the PTEN-AKT pathway co-operates with p53 pathway in modulating B7-H3 expression in cancer cells. In Pten/Trp53 genetically engineered mouse (GEM) models, prostate-specific deletion of Cd276 resulted in markedly delayed tumor progression and reversed immunosuppression in the tumor microenvironment. Furthermore, we developed and evaluated novel combinatorial immunotherapy strategies targeting B7-H3 in advanced prostate cancer with PTEN and TP53 deficiencies.
Citation Format: Wei Shi, Yin Wang, Yuehui Zhao, Di Zhao. Novel immunotherapy strategies targeting PTEN and TP53 defects in advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B040.
Abstract B044: Exosomal cancer-type SLCO1B3 and ABCC3 as potential biomarkers of castration resistant prostate cancer
Authors: Beatson Erica L. , Lee Kristi Y. , Knechel Martina A. , Sommer Elijah R. , Depaz Roger , Risdon Emily N. , Leon Andres F. , Strope Jonathan D. , Price Douglas K. , Chau Cindy H. , Figg William D. 
Published: June 2023

Abstract
Extracellular vesicles (EVs) provide a minimally invasive source of tumor-specific markers for liquid biopsy that can be utilized for cancer detection, diagnosis, or monitoring progression. Our laboratory has previously demonstrated the endogenous expression of all transporter systems in the common prostate cancer cell lines (LNCaP, 22Rv1, PC3, DU-145) using a medium throughput TaqMan-based qRT-PCR assay. We identified the two most differentially expressed transporter genes in castration-resistant prostate cancer cells (CRPC) as the cancer-type solute carrier organic anion transporter family 1B3 (ct-SLCO1B3) and the ATP Binding Cassette Subfamily Member C (ABBC3). Both transporters have been investigated as EV-derived tumor markers; however, their detection in prostate cancer-derived EVs remains to be determined. This study aims to investigate whether ct-SLCO1B31B3 and ABCC3 mRNA exists in prostate cancer-derived EVs and can be further detected using plasma specimens. We isolated EVs from prostate cancer (LNCaP, 22Rv1, PC3, DU-145) cell line supernatant and extracted exosomal RNA for qPCR analyses. Both ct-SLCO1B3 and ABBC3 transcripts were only detected in CRPC-derived EV cells vs androgen-responsive prostate cancer cells. To explore the possibility that both transcripts in CRPC-derived EVs can be detected in plasma, we isolated plasma EVs derived from human prostate cancer xenograft mice, and then performed digital droplet PCR analysis. We demonstrated that ct-SLCO1B3 and ABBC3 are detectable in the DU-145 xenograft mouse model, both in tissues and in plasma-derived EVs. Our results provide evidence that ct-SLCO1B3 and ABCC3 exist in EVs and can be detected (at least) in mouse plasma, potentially supporting their roles as novel, plasma-based biomarkers for monitoring prostate cancer progression.
Citation Format: Erica L. Beatson, Kristi Y. Lee, Martina A. Knechel, Elijah R. Sommer, Roger Depaz, Emily N. Risdon, Andres F. Leon, Jonathan D. Strope, Douglas K. Price, Cindy H. Chau, William D. Figg. Exosomal cancer-type SLCO1B3 and ABCC3 as potential biomarkers of castration resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B044.
Abstract B045: Single cell proteomics as a method to analyze circulating tumor cells in prostate cancer patients
Authors: Horrmann Alec , Sychev Zoi , Drake Justin M. 
Published: June 2023

Abstract
The purpose of this study was to develop a single-cell proteomic protocol capable of analyzing single circulating tumor cells (CTCs). Despite the numerous benefits possible from the analysis of CTCs they have not migrated into clinical use due to difficulty of purification and their minute numbers. Combined, this results in only miniscule amounts of sample, if any, for analysis. Most clinical assays primarily focus on genomic and/or transcriptomic assays, while only a select number of proteomic assays are used and these analyze a handful of targets at most. Recent developments in single-cell proteomics using liquid chromatography tandem mass spectrometry (LC-MS/MS) promise to solve this latter issue and increase the depth of proteome coverage. To analyze CTCs we adapted previously developed single-cell methodologies to be amenable for the analysis of CTCs. Our novel method uses a separately prepared carrier channel as opposed to traditional methods which rely on a large pool of the single-cells of interest. This is necessary since collected CTC’s will not have a large pool of similar cells to draw upon to form a carrier. As the carrier is prepared in bulk it allows for improved quality control measurements to be implemented. This is critical as for clinical use these metrics will be vital for ensuring repeatability and reliability of results. Using our developed protocol, we are able to analyze hundreds of proteins from each simulated CTC. Additionally, we demonstrate that a separately prepared carrier composed of cells from a different lineage still permits the identification of a wide array of proteins within single-cells as well as allows for better quality control over the digestion and TMT labeling efficiencies. In conclusion, our protocol demonstrates its capability to detect and quantify hundreds of proteins from individual cells. If this method was applied towards the analysis of CTCs it would represent by far the most comprehensive method for analysis of the proteome of single CTCs. Together, this provides a foundation for translating proteomic analysis of single CTCs towards guiding individualized cancer treatment in the clinic.
Citation Format: Alec Horrmann, Zoi Sychev, Justin M. Drake. Single cell proteomics as a method to analyze circulating tumor cells in prostate cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B045.
Abstract B064: ONECUT2 inhibition, a potential treatment for lethal prostate cancer
Authors: Gallent Brad , Qian Chen , Chatterjee Avradip , Katiki Madhusudhanarao , Murali Ramachandran , Freeman Michael R 
Published: June 2023

Abstract
Prostate cancer (PCa) is the most common cancer and the second most lethal cancer in men, claiming over 30,000 lives each year in the US alone. These PCa patient deaths are typically due to castration-resistant PCa (CRPC) which is resistant to androgen deprivation therapy, androgen receptor signaling inhibitors, and chemotherapies. Our group and others have shown that the transcription factor ONECUT2 (OC2) is a critical driver of CRPC. We have discovered a low molecular weight inhibitor of OC2 (OC2i), known as CSRM617, which inhibits metastatic PCa in cell culture (IC50 of 5-15 uM depending on cell line used) and effectively treats xenograft CRPC tumors in mouse models. We have developed a large series of these OC2i based on the CSRM617 scaffold. A thorough understanding of how these OC2i bind to and inhibit OC2 function are imperative to developing them into a clinically viable treatment option. Our recent work shows CSRM617 binds Fe and that this Fe:CSRM617 complex is necessary in order to inhibit OC2 binding of DNA. We have solved the crystal structure of OC2 bound to its conjugate DNA response element, demonstrating their atomic-level interactions. We are working towards solving a crystal structure of these OC2i bound to OC2 in order understand their specific interactions and make rational modifications to the chemical scaffold for improvements in binding affinity and pharmacokinetic properties.
Citation Format: Brad Gallent, Chen Qian, Avradip Chatterjee, Madhusudhanarao Katiki, Ramachandran Murali, Michael R Freeman. ONECUT2 inhibition, a potential treatment for lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B064.