tbuckley/cabot-search huggingface dataset:
Abstract 2469: PROTAC mediated NR4A1 degradation as a novel strategy for cancer immunotherapy
Authors: Lei Wang, Yufeng Xiao, Yuewan Luo, Rohan Master, Jiao Mo, Myung-Chul Kim, Yi Liu, Chandra Maharjan, Urvi Patel, Xiangming Li, Donald Shaffer, Guertin Kevin, Haoyang Zhuang, Emily Moser, Keiran Smalley, Daohong Zhou, Guangrong Zheng, Weizhou Zhang
Journal: Cancer Research (2024)

Abstract An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple cell types in the TME and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti-cancer immune responses and offers a new avenue for treating various types of cancer such as melanoma. Citation Format: Lei Wang, Yufeng Xiao, Yuewan Luo, Rohan Master, Jiao Mo, Myung-Chul Kim, Yi Liu, Chandra Maharjan, Urvi Patel, Xiangming Li, Donald Shaffer, Guertin Kevin, Haoyang Zhuang, Emily Moser, Keiran Smalley, Daohong Zhou, Guangrong Zheng, Weizhou Zhang. PROTAC mediated NR4A1 degradation as a novel strategy for cancer immunotherapy [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 2469.
Abstract 4026: The combination of DLL4/VEGF-a blockade and immunomodulation can eliminate MHC class I negative tumors in mice
Authors: Diana I. Albu, Rachael Duffy, Amy Daniel Ulumben, Jason Kong, Jessica Zolotarevsky, Melissa Brundin, Mei Su, Ruturaj Jadhav, Kris F. Sachsenmeier, Bing Gong, Thomas J. Schuetz, Alberto Visintin
Journal: Cancer Research (2024)

Abstract CTX-009 is a bispecific antibody targeting VEGF-A and DLL4 which is undergoing clinical investigation in patients with multiple tumor types, including biliary tract and colon cancers. In biliary tract cancers, checkpoint inhibitor therapy has been shown to improve outcomes when combined with chemotherapy. In an effort to increase the breadth and duration of response of CTX-009, we set out to investigate the combined anti-tumor efficacy of this bispecific antibody and immunotherapy in preclinical models. Here we report the evaluation of the combination of the mouse surrogates of CTX-009 and CTX-471, an agonistic anti-mouse CD137 antibody, or monoclonal antibodies that disrupt the PD-1/PD-L1 signaling axis. Coupling VEGF-A/DLL4 targeting with either CD137 agonism or PD-1/PD-L1 blockade markedly increased the anti-tumor efficacy of the individual treatments alone in multiple syngeneic mouse tumor models. Tumor growth inhibition was accompanied by pharmacodynamic evidence consistent with enhancement of anti-tumor immunity. Notably, the combination of CTX-009 and CTX-471 retained potent anti-tumor activity even in a tumor line (MC38) which was made MHC I deficient through the deletion of the beta 2 microglobulin gene. This system may model the clinically relevant unmet need characterized by tumor escape through the loss of antigen presentation machinery such as HLA LOH. Interestingly, the model cell lines CT26 and MC38 failed to thrive in the B2M-deficient setting and depletion of NK cells markedly increased their ability to grow. This implies that NK cells might be involved in controlling tumor growth in this setting, and that the combined action of CTX-471 and CTX-009 in the tumor stroma enhances NK cell activity. The findings presented here suggest that CTX-009 may provide enhanced clinical benefit when combined with immunomodulatory agents, such as agonistic anti-CD137 antibodies or PD-1/PD-L1 blockers in tumors where immune checkpoint inhibitors have failed. Citation Format: Diana I. Albu, Rachael Duffy, Amy Daniel Ulumben, Jason Kong, Jessica Zolotarevsky, Melissa Brundin, Mei Su, Ruturaj Jadhav, Kris F. Sachsenmeier, Bing Gong, Thomas J. Schuetz, Alberto Visintin. The combination of DLL4/VEGF-a blockade and immunomodulation can eliminate MHC class I negative tumors in mice [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 4026.
Abstract 5397: Characteristics of cancer associated fibroblasts isolated from refractory colorectal cancer using RNA sequence
Authors: Hiroaki Kasashima, Yasuhiro Fukui, Ken Yonemitsu, Kisyu Kitayama, Yuichiro Miki, Mami Yoshii, Tatsunari Fukuoka, Tatsuro Tamura, Masatsune Shibutani, Takahiro Toyokawa, Shigeru Ree, Masakazu Yashiro, Kiyoshi Maeda
Journal: Cancer Research (2024)

Abstract Primary tumor location of colorectal cancers (CRCs) is emerging as an important prognostic factor owing to distinct biological features. In fact, the patients with right-side CRCs (R-CRCs), in which primary tumors were resected in our department and followed by systemic chemotherapy, have a poorer prognosis in 2-year overall survival and progression-free survival than those with left-side CRCs (L-CRCs). Furthermore, cancer-associated fibroblasts (CAFs) promote tumor malignancy, but the precise transcriptional mechanisms regulating the acquisition of the CAF phenotype are not well understood. Here, we isolated the CAFs and normal counterparts from 10 CRCs which were performed radical resection, including 5 L-CRCs and 5 R-CRCs, and analyzed transcriptomic profile of CAFs by RNA-sequencing. Gene Set Enrichment Analysis (GSEA) was performed and inflammatory signatures, such as "HALLMARK IL2 STAT5 SIGNALING"(NOM p-value&amp;lt;0.001, FDR q-value=0.146), "HALLMARK IL6 JAK STAT3 SIGNALING"(NOM p-value=0.014, FDR q-value=0.162), "HALLMARK INTERFERON GAMMA RESPONSE"(NOM p-value=0.032, FDR q-value=0.1726), were enriched in the CAFs isolated from R-CRCs (R-CAFs). In addition to sidedness of CRCs, based on gene expression profiles from bulk tumors, CRCs were classified into four consensus molecular subtypes (CMS1-4). Among them, The fibrotic CMS4 subtype portends poor relapse-free survival. We identified 4 CMS4-CRCs, which have the characteristics of stromal activation and the worst prognosis among other CRCs. GSEA showed that the signature of "HALLMARK TNFA_SIGNALING_VIA_NFKB" (NOM p-value=0.023 FDR q-value=0.207), "HALLMARK GLYCOLYSIS" (NOM p-value=0.036 FDR q-value=0.239) were upregulated in the CAFs isolated from CMS4-CRCs. These results indicated that CAFs isolated from refractory CRCs have unique phenotypes and the elucidation of these mechanisms might lead to a promising treatment for refractory CRCs. Citation Format: Hiroaki Kasashima, Yasuhiro Fukui, Ken Yonemitsu, Kisyu Kitayama, Yuichiro Miki, Mami Yoshii, Tatsunari Fukuoka, Tatsuro Tamura, Masatsune Shibutani, Takahiro Toyokawa, Shigeru Ree, Masakazu Yashiro, Kiyoshi Maeda. Characteristics of cancer associated fibroblasts isolated from refractory colorectal cancer using RNA sequence [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 5397.
Abstract 5393: Characterization of small ubiquitin-like modifier (SUMO) protein complex expression in human cancer cells to identify novel therapeutic targets
Authors: Mohammed Abdullah Mohammed Salih, Ritchie Williamson, Sriharsha Kantamneni
Journal: Cancer Research (2024)

Abstract SUMOylation is a post-translational modification where a number of small ubiquitin-like modifier proteins (SUMO) are conjugated to lysine residues of the target proteins and contribute to various cellular functions essential for cancer cell survival and proliferation. The unique behaviors, phenotypic and molecular adaptations found in the naked-mole rat (NMR) suggest a high stability and effective functioning of the molecular machinery that counteracts damage accumulation in its genome. NMR can reach 32 years, shows no signs of ageing, and possesses a very efficient mechanism of resistance to cancer. This study aims to investigate the regulation of SUMOylation machinery between NMR tissues in comparison to human cancer cells, to find novel targets for cancer therapy. Gene expression of SUMO isoforms between NMR and humans, were investigated through qRT-PCR. The data suggests a significant low expression level for most SUMO machinery (except PIAS4) in NMR brain and intestine tissues compared to MCF-7, DLD-1, SH-SY5Y, and MCF-10A cells. Western blotting analysis also revealed high protein expression of PIAS4 in NMR compared to SENP1 and Ubc9. Also, SUMO machinery expression levels from NMR are recapitulated in cancer cells either silencing (hUBE2I: shRNA, hSENP1: shRNA) or overexpression (Myc/hPIAS4: Exp). Further, cytotoxicity assay was analyzed in relevance to Doxorubicin in MCF-7, 5-Fluorouracil in DLD-1 and Methotrexate in SH-SY5. The functional assays such as clonogenic and invasion assays were performed including apoptotic mechanisms (Bcl-2, and BID). In conclusion, the data revealed important differences in SUMOylation machinery between NMR and human cancer cells, which provides a future therapeutic path for cancer treatment. Citation Format: Mohammed Abdullah Mohammed Salih, Ritchie Williamson, Sriharsha Kantamneni. Characterization of small ubiquitin-like modifier (SUMO) protein complex expression in human cancer cells to identify novel therapeutic targets [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 5393.
Abstract 2609: Vesicular LGALS3BP is a neuroblastoma biomarker and a therapeutic target for combination therapy with antibody-drug conjugate and checkpoint inhibitors
Authors: Gianluca Sala, Emily Capone, Ilaria Cela, Giulio Lovato, Alessia Lamolinara, Manuela Iezzi, Cosmo Rossi, Vincenzo De Laurenzi, Rodolfo Ippoliti, Stefano Iacobelli
Journal: Cancer Research (2024)

Abstract We have recently shown that targeting circulating LGALS3BP with a maytansinoid-based non-internalizing antibody-drug conjugate (ADC) resulted in tumor eradication of high-risk NMYC-amplified neuroblastoma patient-derived xenografts. LGALS3BP is a high molecular weight, hyperglycosylated and secreted protein which is enriched at the surface of cancer-derived extracellular vesicles (EVs). Here, using a neuroblastoma pseudometastatic preclinical model, we extended our previous work demonstrating that EVs-associated LGALS3BP strictly correlates with disease progression and dissemination. Moreover, to investigate whether LGALS3BP ADC, named 1959sss/DM4, possesses immune-modulating properties, we analyzed DM4 ability to induce immunogenic cell death (ICD). Interestingly, using NXS2 murine neuroblastoma cells, we found that DM4 induced a time-dependent surface expression of three different ICD marker, i.e. calreticulin, HSP70 and HSP90. As it was recently demonstrated that to limit immune surveillance NXS2 cells increase PD-L1 expression in response to IFNγ production in the tumor immune infiltrate, we evaluated potential synergism between LGALS3BP targeting ADC and an anti-PD1 immune check-point inhibitor. To this aim, we genetically manipulated NXS2 cells which resulted nearly negative for murine LGALS3BP expression. Therefore, using a lentivirus-based gene transduction system, we obtained NXS2 cells producing large amounts of vesicular human LGALS3BP. Of note, the vesicular LGALS3BP could be quantified by ELISA and imaged by confocal microscopy using 1959 antibody. Strikingly, while single agent treatment showed a limited antitumor activity in NXS2-LGALS3BP syngeneic model, the LGALS3BP ADC/anti-PD1 combination resulted in a marked inhibition of tumor growth, which was followed by a prolonged survival. In conclusion, our findings establish that vesicular LGALS3BP is a potential biomarker for liquid biopsy and reveals this protein as a suitable target for therapeutic strategy that combines 1959sss/DM4 ADC with immune checkpoint blockade for the treatment of LGALS3BP expressing neuroblastoma. Citation Format: Gianluca Sala, Emily Capone, Ilaria Cela, Giulio Lovato, Alessia Lamolinara, Manuela Iezzi, Cosmo Rossi, Vincenzo De Laurenzi, Rodolfo Ippoliti, Stefano Iacobelli. Vesicular LGALS3BP is a neuroblastoma biomarker and a therapeutic target for combination therapy with antibody-drug conjugate and checkpoint inhibitors [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 2609.
Abstract 2791: Establishment of immortalized endometrial cell lines using Sendai virus
Authors: Kohei Hikino, Hiroaki Komatsu, Genki Hichiwa, Kanako Kazuki, Yasuhiro Kazuki, Hiroyuki Kugoh, Masayo Okawa, Yuki Ida, Masayo Hosokawa, Mayumi Sawada, Akiko Kudoh, Shinya Sato, Fuminori Taniguchi
Journal: Cancer Research (2024)

Abstract Objective: To establish endometrial immortalized cell lines using the Sendai virus and analyze their characteristics. Methods: The study included patients with benign ovarian tumors and endometrioid carcinoma who had regular menstrual cycles. Endometrial cells were collected and separated into epithelial and non-epithelial cells using flowcytometry (FCM) (CD326 (EpCAM) antibody). Furthermore, the isolated cells were infected with Sendai virus carrying three immortalization genes (Bmi-1, hTERT, and SV40T) to create immortalized cell lines. The cells were characterized as epithelial cells by immunocytochemistry (ICC), and receptor expression was assessed by reverse transcription PCR (RT-PCR) and ICC. Non-epithelial cells from the patients with endometrial carcinoma were evaluated using ICC. Results: The immortalized cell lines were capable of more than 20 passages. Immortalized endometrial epithelial cells tested positive for anti-Keratin antibodies and negative for anti-Vimentin antibodies by ICC. Additionally, FCM detected these cells as positive for anti-EpCAM antibody, confirming that they were epithelial cells. RT-PCR confirmed mRNA expression of estrogen α-receptor and progesterone receptor after 20 passages and ICC confirmed protein expression of them after 10 passages, establishing an endometrial epithelial immortalized cell line. Non-epithelial cells isolated from patients with endometrial carcinoma tested positive for anti-α-smooth muscle actin and anti-Vimentin antibodies by ICC, indicating their characterization as cancer-associated fibroblasts. Conclusion: We successfully established an immortalized cell line of endometrial epithelial cells using Sendai virus and generated cancer-associated fibroblasts. Citation Format: Kohei Hikino, Hiroaki Komatsu, Genki Hichiwa, Kanako Kazuki, Yasuhiro Kazuki, Hiroyuki Kugoh, Masayo Okawa, Yuki Ida, Masayo Hosokawa, Mayumi Sawada, Akiko Kudoh, Shinya Sato, Fuminori Taniguchi. Establishment of immortalized endometrial cell lines using Sendai virus [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 2791.
Abstract 4516: Inhibiting YAP activity in cancers by targeted degradation of TEAD
Authors: Hui Chen, Artem Gridnev, Netanya Schlamowitz, Guangrong Zheng, Jyoti R. Misra
Journal: Cancer Research (2024)

Abstract The oncogenic transcriptional coactivators YAP/TAZ function as the terminal effectors of the Hippo signaling pathway and are dysregulated in many human cancers, where they promote cancer cell proliferation, survival, stemness, and resistance to targeted therapies, and thus provide a critical point for therapeutic targeting. YAP/TAZ activity is regulated by phosphorylation mediated by the kinase cascade of the Hippo signaling pathway, where phosphorylation causes cytoplasmic retention. Aberrantly activated Hypo/unphosphorylated YAP/TAZ translocates into the nucleus, where it exerts its oncogenic activity by associating with the TEAD1-4 transcription factors and inducing expression of genes encoding pro-proliferative and antiapoptotic factors. Since YAP/TAZ cannot be directly therapeutically targeted, its oncogenic transcriptional activity can be controlled indirectly by targeted degradation of TEAD. Here we report on the development of Proteolysis Targeting Chimeras that potently induces degradation of TEAD and inhibits YAP transcriptional activity and cell proliferation in YAP-dependent cancers. Citation Format: Hui Chen, Artem Gridnev, Netanya Schlamowitz, Guangrong Zheng, Jyoti R. Misra. Inhibiting YAP activity in cancers by targeted degradation of TEAD [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 4516.
Abstract 2601: Potent antitumor activity of anti-HER2 antibody-topoisomerase I inhibitor conjugate based on self-immolative dendritic dimeric-linker
Authors: Yulia Liubomirski, Galia Tiram, Anna Scomparin, Samer Gnaim, Sayantan Das, Sachin Gholap, Liang Ge, Eilam Yeini, Omri Shelef, Arie Zauberman, Nir Berger, Doron Kalimi, Mira Toister-Achituv, Christian Schröter, Stephan Dickgiesser, Jason Tonillo, Min Shan, Carl Deutsch, Stanley Sweeney-Lasch, Doron Shabat, Ronit Satchi-Fainaro
Journal: Cancer Research (2024)

Abstract Antibody-drug conjugates (ADCs) are a rapidly expanding class of anticancer therapeutics, with 14 ADCs already approved worldwide. We developed unique linker technologies for the bioconjugation of drug molecules with controlled-release applications. We synthesized cathepsin-cleavable ADCs using a dimeric prodrug system based on a self-immolative dendritic scaffold, resulting in a high drug-antibody ratio (DAR) with the potential to reach 16 payloads due to its dendritic structure, increased stability in the circulation and efficient release profile of a highly cytotoxic payload at the targeted site. Using our novel cleavable linker technologies, we conjugated the anti-human epidermal growth factor receptor 2 (anti-HER2) antibody, trastuzumab, with topoisomerase I inhibitors, exatecan or belotecan. The newly synthesized ADCs were tested in vitro on mammary carcinoma cells overexpressing human HER2, demonstrating a substantial inhibitory effect on the proliferation of HER2-positive cells. Importantly, a single dose of our trastuzumab-based ADCs administered in vivo to mice bearing HER2-positive tumors, showed a dose-dependent inhibition of tumor growth and survival benefit, with the most potent antitumor effects observed at 10 mg/kg, which resulted in complete tumor regression and survival of 100% of the mice. Overall, our novel dendritic technologies using the protease-cleavable Val-Cit linker present an opportunity for the development of highly selective and potent controlled-released therapeutic payloads. This strategy could potentially lead to the development of novel and effective ADC technologies for patients diagnosed with HER2-positive cancers. Moreover, our proposed ADC linker technology can be implemented in additional medical conditions such as other malignancies as well as autoimmune diseases that overexpress targets, other than HER2. Citation Format: Yulia Liubomirski, Galia Tiram, Anna Scomparin, Samer Gnaim, Sayantan Das, Sachin Gholap, Liang Ge, Eilam Yeini, Omri Shelef, Arie Zauberman, Nir Berger, Doron Kalimi, Mira Toister-Achituv, Christian Schröter, Stephan Dickgiesser, Jason Tonillo, Min Shan, Carl Deutsch, Stanley Sweeney-Lasch, Doron Shabat, Ronit Satchi-Fainaro. Potent antitumor activity of anti-HER2 antibody-topoisomerase I inhibitor conjugate based on self-immolative dendritic dimeric-linker [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 2601.
Abstract 2910: Targeting thioredoxin reductase 1 (TrxR1) suppresses TAZ-driven glioblastoma progression
Authors: Miaolu Tang, Kaitlyn Dirks, Soo Yeon Kim, Jessica Thorpe, Wei Li
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain malignancy in adults. Poor outcomes for traditional treatments demand targeted therapies based on identified mechanisms that drive tumor development and sustain its malignancy. Molecular pathology studies have classified GBM into subtypes differing in treatment responses and survival rates. Among these subtypes, the mesenchymal (MES) group is associated with the worst prognosis. The Hippo pathway transcriptional co-activator with PDZ-binding motif (TAZ) is one of the three transcriptional regulators that drive the GBM MES gene expression program. Studies from our lab and others have previously shown that TAZ activation is able to promote GBM MES differentiation and progression. Therefore, finding vulnerabilities of TAZ-driven tumors may help to develop targeted therapeutic methods for MES GBM. In an orthotopic GBM mouse model, we found that TAZ-driven tumors show increased expression of thioredoxin reductase 1 (TrxR1), which is responsible for catalyzing the reduction of thioredoxin and maintaining the cellular redox balance. In searching for the cause of increased expression of TrxR1, we found that glucose deprivation can induce TrxR1 expression, suggesting TrxR1 may be an adaptive mechanism for tumor cells to survive in glucose deprivation conditions. Indeed, either depleting TrxR1 genetically or inhibiting TrxR1 pharmacologically can promote tumor cell death under glucose deprivation. Furthermore, knockout TrxR1 in a TAZ-driven mouse GBM model significantly decelerated tumor progression. Collectively, our studies revealed that inhibition of the Trx redox system under glucose deprivation conditions leads to a synergistic cell death induction in GBM cells, therefore making targeting TrxR1 a potential therapeutic strategy for TAZ-driven MES GBM. Citation Format: Miaolu Tang, Kaitlyn Dirks, Soo Yeon Kim, Jessica Thorpe, Wei Li. Targeting thioredoxin reductase 1 (TrxR1) suppresses TAZ-driven glioblastoma progression [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 2910.