tbuckley/cabot-search huggingface dataset:
Abstract 391: Role of NRF2 in HIF-2α-mediated cancer stem cell phenotype
Authors: Mi-Kyoung Kwak, Steffanus P. Hallis
Journal: Cancer Research (2024)

Abstract The acquisition of cancer stem cell (CSC) properties is influenced by the microenvironment, with tumor hypoxia playing a pivotal role. Elevated levels of nuclear factor erythroid 2-like 2 (NRF2), a redox balance-maintaining transcription factor, have been linked to enhanced tumor growth and therapy resistance. This study investigates the potential role of NRF2 in hypoxia-inducible factor-2α (HIF-2α) regulation in cancers. First, in a model of a 72-hour hypoxic incubation, chronic hypoxia led to CSC characteristics, including increased expression of KLF4 and OCT4, heightened cancer migration, and spheroid growth, which are associated with HIF-2α accumulation. NRF2 inhibition mitigated these effects, while NRF2 activation enhanced chronic hypoxia-induced CSC traits. Mechanistically, NRF2/miR181a-2 signaling emerged as a regulator of HIF-2α-mediated CSC phenotypes in chronic hypoxic conditions. Second, in clear cell renal cell carcinoma (ccRCC), characterized by pVHL gene mutation and constitutive HIF-2α elevation, the role of NRF2 in aggressive cancer phenotypes was explored. Silencing of NRF2 impaired aggressive phenotypes in multiple ccRCC cell lines with a reduction in HIF-2α expression. Promoter analysis elucidated that NRF2 directly upregulates HIF-2α expression through antioxidant response elements in the human HIF-2α gene. Collectively, our study suggests the involvement of NRF2/miR181a-2 signaling in the development of HIF-2α-mediated CSC phenotypes in sustained hypoxic environments and also proposes NRF2 as a promising target for mitigating HIF-2α-mediated CSC traits in ccRCC. Citation Format: Mi-Kyoung Kwak, Steffanus P. Hallis. Role of NRF2 in HIF-2α-mediated cancer stem cell phenotype [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 391.
Abstract 4673: Genome-scale metabolic models identify gene targets that enhance drug response of drug-resistant breast cancer cells
Authors: Hae Deok Jung, JinA Lim, Han Suk Ryu, Yoosik Kim, Hyun Uk Kim
Journal: Cancer Research (2024)

Abstract Adaptive drug resistance poses a significant therapeutic challenge in treatment of breast cancer patients. Metabolic reprogramming in cancer cells is one of the major mechanisms associated with drug resistance. In this study, we aim to identify gene targets that enhance the drug response of drug-resistant breast cancer cells through downregulation. We hypothesized that metabolic perturbation in drug-resistant breast cancer cells could revert their metabolic features to those of drug-sensitive cells. To predict such gene targets, we used a computational model known as a genome-scale metabolic model (GEM). A GEM simulates the entire metabolic reaction fluxes of a cell under varying genetic and/or environmental conditions. We specifically targeted two engineered MCF7 breast cancer cell lines: one resistant to doxorubicin and the other to paclitaxel. First, we generated proteome data from drug-sensitive and drug-resistant MCF7 cell lines, and used them to construct the cell-specific GEMs. Subsequently, single-gene knockout simulation was conducted using these cell-specific GEMs. The initial list of the gene knockout targets was subjected to pathway analysis involving proteome and metabolome data to finalize the gene targets. The final gene targets were expected to lead to metabolic features similar to those of drug-sensitive MCF7 upon the downregulation. In vitro experiments using inhibitors were conducted to validate these predicted gene targets. This study provides a computational approach that can also be applied to other types of drug-resistant cancer cells. Citation Format: Hae Deok Jung, JinA Lim, Han Suk Ryu, Yoosik Kim, Hyun Uk Kim. Genome-scale metabolic models identify gene targets that enhance drug response of drug-resistant breast 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 4673.
Abstract 5751: Ultrasound responsive injectable hydrogels for on-demand drug delivery
Authors: Li Xiang, Gulsu Sener, Adem Yildirim
Journal: Cancer Research (2024)

Abstract In this work, we developed ultrasound-responsive and injectable hydrogels for local and on-demand release of chemotherapeutics to solid tumors. Injectable hydrogels were prepared by using a zwitterionic monomer, sulfobetaine methacrylate (SBMA), without using any crosslinker. Gelation was performed at -20 oC using APS/TEMED as initiator, allowing the formation of strong electrostatic interactions between poly(SBMA) chains to physically crosslink the hydrogels. Monomer and initiator concentrations were carefully optimized to achieve injectable hydrogels with mechanical and thermal stability. To render ultrasound responsivity to the hydrogels, we loaded the hydrogels with hydrophobically (dodecyl) modified mesoporous silica nanoparticles (hMSNs) with sizes around 50 nm. When insonated with low-intensity focused ultrasound (LIUS), the hMSNs incept acoustic cavitation (i.e., growth and collapse of microsized bubbles), which in turn generates mechanical effects in the hydrogels such as shock waves or water jets. We found that loading the hydrogels with hMSN did not affect their injectability, and they remained mechanically stable at 37 °C for more than a week. hMSN-loaded hydrogels demonstrated strong ultrasound responsivity even at low particle concentrations (0.1 mg/mL) and ultrasound powers (25 W, 0.02% duty cycle). Finally, we loaded the hydrogels with a chemotherapy drug, doxorubicin (DOX, 0.2 mg/mL). DOX-loaded hydrogels demonstrated minimal release without LIUS treatment (&amp;lt;20% in a day). Application of LIUS (150 W, 1% duty cycle) for 5 min resulted in almost complete mechanical disintegration of the hydrogels, resulting in a burst DOX release. We also showed that the amount of released DOX could be controlled by tuning the LUIS power and its duration. In summary, we developed injectable hydrogels with strong ultrasound responsivity. These hydrogels hold great promise for local and on-demand drug delivery to solid tumors, which is currently under investigation in our laboratory. Citation Format: Li Xiang, Gulsu Sener, Adem Yildirim. Ultrasound responsive injectable hydrogels for on-demand drug delivery [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 5751.
Abstract 5754: Targeting miR-92b with peptide-modified liposomes for glioblastoma treatment
Authors: Annelis Odette Sánchez-Álvarez, Fatima Valiyeva, Pablo E. Vivas-Mejia
Journal: Cancer Research (2024)

Abstract Focusing on enhancing drug delivery to the brain, we aim to optimize a nanocarrier system with a specific focus on glioblastoma (GBM). This involves the utilization of spherical nucleic acids (SNAs) enclosed in peptide-modified liposomes, a configuration previously proven to effectively penetrate the blood-brain barrier (BBB) in a GBM mouse model. Our objective is to enhance the nanocarrier's treatment load by optimizing the attachment of oligonucleotide-modified gold nanoparticles (OMI) to the SNAs. MicroRNAs (miRNAs) play crucial roles in GBM pathogenesis, with miR-92b identified as overexpressed in various cancers, including GBM. Previous research from our lab implicated miR-92b in targeting proteins (FBXW7 &amp; SKP2) in the ubiquitination pathway. RNA sequencing confirmed the significance of these pathways. RNA sequencing of miR-92b inhibition in the U87 GBM cell line revealed impacts on cell cycle, apoptosis, DNA repair, and multiple cancer-related pathways. We successfully modified the gold nanoparticle size from 15 nm to 5 nm, increasing the surface area and improving OMI attachment efficiency from less than 5% to 50%. This alteration significantly enhances drug loading in the nanocarrier, providing a promising platform for clinical applications. Characterization of the optimized peptide-modified liposomes reassured the retention and potential improvement of original features related to nanoparticle size and internalization in cell cultures. Future in vivo experiments, utilizing a GBM mouse model, will assess the therapeutic effect of inhibiting miR-92b using peptide-modified liposomes as a drug delivery system. Our multifaceted approach, involving nanocarrier optimization and miR-92b inhibition, holds promise for developing an effective treatment strategy against GBM. The presented results highlight the potential translational impact of our research in addressing the challenges associated with GBM therapy. Citation Format: Annelis Odette Sánchez-Álvarez, Fatima Valiyeva, Pablo E. Vivas-Mejia. Targeting miR-92b with peptide-modified liposomes for glioblastoma treatment [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 5754.
Abstract 5746: Tris(4-methoxyphenyl) methanol conjugates of triptorelin as cell-penetrating anti-cancer prodrugs
Authors: Ryan Beni, William Boadi, Jawzah Alnakhli, Samiyah Alhamed
Journal: Cancer Research (2024)

Abstract Triptorelin® (TRP) is an anti-cancer drug used for the treatment of a wide range of hormone-responsive cancers, including prostate cancer. The increase in testosterone levels, known as the flare effect, is a major side effect of cancer chemotherapy when TRP is used in a combination regimen. Reports indicate that enhancing the cellular uptake and retention of TRP can improve its biological activity. In this study, TRP conjugates of tris(4-methoxyphenyl) methanol derivatives (TPMs) with optimized hydrophobicity were synthesized by reacting 2-substituted methoxybenzenes with 1,3,5-trioxane, followed by conjugation with TRP and sebacic acid to produce TRP-TPMs derivatives. The hydrophobicity of TRP was optimized by using the appropriate hydrophobic linker attached to the respective TPM to improve cellular uptake. The aim of the current studies was to evaluate the respective antiproliferative effects of the newly synthesized TRP-TPMs, physical mixtures of TPMs and TRP using different cell lines. Our hypothesis was that exposure of cells to TRP-TPMs derivatives can enhance the antiproliferative activities in cells in comparison to respective the physical mixtures and TRP. Antiproliferative studies in human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse preadipocytes (3T3-L1) were carried out following exposure to the respective compounds. Our findings indicate that TRP-TPMs conjugates, at a concentration of 50 µM, significantly inhibited cell proliferation in CCRF-CEM, SK-OV-3, and 3T3-L1 cells by 21-37%, 24-73%, and 37-56%, respectively, following 72-hour incubation in comparison to the respective physical mixtures and TRP. Conjugation of TRP with the respective derivative of TPMs enhanced antiproliferative activities in all the cells (with no significant differences in cytotoxicity) compared to the physical mixtures of TPMs and TRP. The findings in the current studies suggest that TRP-TPMs can be used as potential prodrugs, to enhance the cells biological activity, and cellular uptake of TRP. Citation Format: Ryan Beni, William Boadi, Jawzah Alnakhli, Samiyah Alhamed. Tris(4-methoxyphenyl) methanol conjugates of triptorelin as cell-penetrating anti-cancer prodrugs [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 5746.
Abstract 7524: Targeting siglec-7/9 glyco-immune checkpoints in prostate cancer for enhanced immune responses and tumor suppression
Authors: Ru Wen, G Edward Marti, Jessica Stark, Fernando Jose Garcia Marques, Nick Riley, Abel Bermudez, Hongjuan Zhao, Carolyn Bertozzi, Sharon Pitteri, James Brooks
Journal: Cancer Research (2024)

Abstract Prostate cancer is one of the leading causes of death in men worldwide. Despite significant advancements in the fight against cancer, immune checkpoint inhibitors have limited effectiveness in treating prostate cancer. Evidence shows that disrupting the interactions between Siglec-7/9 and sialic acids can enhance immune responses and effectively inhibit tumor growth in several cancers. However, the understanding of Siglec-7/9-sialic acid interactions in prostate cancer remains limited. Here, we found that tumor-infiltrating immune cells derived from prostate cancer patients exhibited high levels of Siglec-7 and Siglec-9. TCGA data analysis suggests that high levels of Siglec-7/9 are correlated to worse patient survival. Elevated levels of Siglec-7/9 ligands were found in prostate tumor tissues compared to adjacent normal tissues. Prostate cancer cell lines exhibited significant expression levels of Siglec-7 and Siglec-9 ligands, and cell surface sialic acids. Proteomic analysis suggests that increased sialylation was observed in tumor tissues in comparison to adjacent normal tissues. Disrupting interactions between Siglec-7/9 and sialoglycans enhanced T cell-mediated cytotoxicity against prostate cancer cells. Treatment with anti-Siglec-7/9 antibodies effectively suppressed the growth of PC3 and 22Rv1 tumors in a humanized mouse model. Immunohistochemistry analysis of tumor tissues showed that PC3 and 22Rv1 tumors treated with anti-Siglec-7/9 exhibited reduced proliferation, decreased vascularization, increased apoptosis, and enhanced immune cell infiltration. The CRISPR screen and mass spectrometry analysis suggested CD59 as a potential ligand for Siglec-9. Knockout of CD59 in prostate cancer cells decreased their binding activity of Siglec-9-Fc chimera proteins and promoted T cell-mediated killing ability. These findings provide valuable insights into the potential therapeutic strategy of targeting Siglec-7/9 and their ligands for prostate cancer treatment. Citation Format: Ru Wen, G Edward Marti, Jessica Stark, Fernando Jose Garcia Marques, Nick Riley, Abel Bermudez, Hongjuan Zhao, Carolyn Bertozzi, Sharon Pitteri, James Brooks. Targeting siglec-7/9 glyco-immune checkpoints in prostate cancer for enhanced immune responses and tumor suppression [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 7524.
Abstract 5741: siteDAR, complete antibody drug conjugate, ADC characterization
Authors: Warham L. Martin, Michael Senseney, Bhaskar Kusuma, Julien Dugal-Tessier, Nareshkumar Jain
Journal: Cancer Research (2024)

Abstract Antibody drug conjugate characterization currently extends to the global determination of the drug -to- antibody ratio (DAR). However, there can be confounding batch variability in pharmacological outcome from ADCs of the same drug, antibody, and DAR. Previously, DAR was obtained by quantifying the extent of modification of the intact antibody or its protein subunits. The coupling chemistry is used to infer which type of amino acids were modified but generally no specific sites of modification are identified and if identification is obtained, it is not quantitative. Borrowing the rigorously reproducible proteolytic digestion methods from multi-atribute mapping (MAM) used in monoclonal antibody manufacture, and compiling a comprehensive quantitative assignment of every abundant peptide in the ADC digest we can both calculate a DAR from the ion volume ratios and a quantitative map of the specific modified sites. This method, termed “siteDAR”, is applied here to both commercial Kadcyla® (ado-trastuzumab emtansine) and in-house preparations of ado-trastuzumab emtansine. We show that preparations of Kadcyla® with the same DAR can have significantly different quantitative maps of modification sites. We use siteDAR analysis in our ADC design cycle to characterize an ADC, and have developed an ADC synthesis method that was quantitatively verified, and had increased biosimilarity with commercially available Kadcyla®. siteDAR for commercial Kadcyla siteDAR for initial in-house Kadcyla Initial biosimilarity Citation Format: Warham L. Martin, Michael Senseney, Bhaskar Kusuma, Julien Dugal-Tessier, Nareshkumar Jain. siteDAR, complete antibody drug conjugate, ADC characterization [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 5741.
Abstract 6556: Targeting mesenchymal tumor cell-intrinsic factors sensitizes refractory tumors to immune checkpoint blockade therapy
Authors: Kimaya M. Bakhle, Caitie H. Sams, Anushka Dongre
Journal: Cancer Research (2024)

Abstract Immune checkpoint blockade (ICB) therapy has emerged as a promising approach for treating breast cancer, however, only a fraction of patients derives clinical benefit and the underlying reasons for heterogeneous responses remain elusive. The epithelial-to-mesenchymal transition (EMT) enables these carcinomas to metastasize and acquire resistance to chemotherapy. We have recently demonstrated that the EMT program also confers resistance to immunotherapies. Specifically, epithelial tumors recruit CD8+ T-cells to the tumor microenvironment and are sensitive to anti-CTLA4 ICB. In contrast, mesenchymal tumors assemble an immunosuppressive tumor microenvironment and are resistant to the same treatment. Furthermore, mesenchymal tumors express multiple immunosuppressive paracrine factors relative to their epithelial counterparts. Of these, abrogation of CSF1 or SPP1 from mesenchymal cancer cells generates partial responses to ICB therapy. Strikingly, abrogation of CD73 from mesenchymal carcinoma cells completely sensitizes otherwise refractory tumors to immunotherapy. While targeting cancer cell-intrinsic factors can sensitize mesenchymal tumors to ICB, the mechanisms that dictate partial versus complete responses are unclear. Furthermore, whether abrogation of CD73 can also sensitize mesenchymal tumors to other forms of ICB remains unknown. By performing immunofluorescent analysis of tumor sections, we observed that knockout of CD73 promoted the greatest infiltration of both CD4+ and CD8+ T-cells in response to anti-CTLA4 ICB compared to tumors knocked out for CSF1 and SPP1, which showed only intermediate levels of infiltration. Moreover, treatment of mesenchymal tumor-bearing mice with anti-CD73 generated synergistic responses with anti-CTLA4 ICB, but not with anti-PD1, or combinations of anti-CTLA4 and anti-PD1. In conclusion, our results demonstrate that the EMT program in cancer cells is predictive of responses to ICB. Targeting CD73 in mesenchymal breast tumors promotes an influx of both CD4+ and CD8+ T-cells and potentiates the efficacy of anti-CTLA4 ICB. Through mining of canine mammary tumor RNA sequencing data, we have found that canine tumors associated with EMT have increased expression of CD73, which suggests that these mechanisms of immune evasion may translate across species. These findings could promote therapies for both animals and humans that sensitize highly refractory populations of more-mesenchymal cancer cells. Citation Format: Kimaya M. Bakhle, Caitie H. Sams, Anushka Dongre. Targeting mesenchymal tumor cell-intrinsic factors sensitizes refractory tumors to immune checkpoint blockade therapy [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 6556.
Abstract 554: Determining the role of <i>PROX1</i> in prostate cancer neuroendocrine trans-differentiation
Authors: Sonam Raj, Brian Capaldo, Joel Bowman, Margaret White, Xavier Moore, Berkley Gryder, Aian N. Alilin, David Takeda, Kathleen Kelly
Journal: Cancer Research (2024)

Abstract Nonbiased mutational screening to identify essential genes and pathways in cancer is a powerful approach for understanding underlying biology as well as the identification of potential therapeutic targets. Epigenetic (EPI) and transcriptional factors (TF) play an important role in the change of phenotype and lineage plasticity from adenocarcinoma to castration resistant prostate cancer (CRPC), double negative (DN) or treatment-induced neuroendocrine prostate cancer (NEPC). When RB1 loss occurs in combination with TP53 alterations, stemness and lineage plasticity increase with one consequence being differentiation to a neuroendocrine (NE) lineage. Here, we are identifying and testing the functional role of epigenetic and transcription factors required for the viability of CRPC, DN and NEPC relative to a matrix of genotypic and phenotypic characteristics. We applied CRISPR-CAS9 dropout screens in prostate organoids and cell lines to identify gene/s associated with CRPC, DN and NEPC viability. We successfully CRISPR-engineered LNCaP clones of single (LNCaP-TP53-SKO, LNCaP-RB1-SKO) and double (LNCaP-TP53-RB1-DKO) gene knockouts, which were subsequently characterized for immuno-phenotype and transcriptome. Our dropout screens, targeting all TFs and EPIs, identified 117 TF and 40 EPI genes responsible for the viability of DN, NEPC and LNCaP models. We found known genes such as FOXA1 and ASCL1, as well as novel genes including PROX1 and KLF3, which were validated through guide RNA competition assays. Our results showed PROX1 is essential for cell viability in a DN organoid model, and its expression is associated with increased aggressiveness, indicating PROX1 has role in stemness/lineage plasticity in treatment resistant adenocarcinoma. RNA-seq analysis following overexpression of PROX1 in the LNCaP-TP53-RB1 null adenocarcinoma model, with and without enzalutamide, identified pathways enriched for cell proliferation, differentiation, neuronal development, and prostate gland development. In summary, our study has suggested an important role for PROX1 in the growth and differentiation of poorly differentiated prostate cancer, which may lead to the identification of potential therapeutic targets. Citation Format: Sonam Raj, Brian Capaldo, Joel Bowman, Margaret White, Xavier Moore, Berkley Gryder, Aian N. Alilin, David Takeda, Kathleen Kelly. Determining the role of PROX1 in prostate cancer neuroendocrine trans-differentiation [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 554.