tbuckley/cabot-search huggingface dataset:
Abstract 4695: Effect of fully human anti-PTGFRN antibody drug conjugate on head neck cancer cells and patient derived xenografts
Authors: Jorge Marquez, Jianping Dong, Mitsuo Oshimura, Jun Hayashi, Ginette Serrero
Journal: Cancer Research (2024)

Abstract Prostaglandin F2 Receptor Negative regulator, or PTGFRN, also known as FPRP is a 175 kDa transmembrane protein associated with metastatic characteristics of certain cancer types and a member of the tetraspanin family. PTGFRN expression is undetectable to low in normal tissues whereas it is elevated in several cancers such as head and neck, mesothelioma and medulloblastoma. PTGFRN has also been reported to be upregulated in many different types of cancer, increasingly so in metastatic cancer cells, compared to their non-metastatic counterparts PTGFRN expression has been reported to be a poor prognostic factor for glioblastoma making it a potential novel cancer therapeutic target. We have previously shown that PTGFRN is an internalizable cell surface protein making it suitable for targeting by antibody drug conjugate (ADC). We have developed fully human monoclonal antibodies to PTGFRN by immunizing humanized transgenic TC mice with human PTGFRN. Within 60 days from the start of immunization we were able to select several fully human anti-PTGFRN monoclonal antibodies that were examined by several functional assays that included flow binding, internalization, affinity determination and cell killing as antibody drug conjugates. Several monoclonal antibodies were selected and evaluated for their ability to inhibit tumor formation in several cancers. Selected antibodies were then conjugated to duocarmycin by a cleavable linker. The present study proposed to examine the effect of one such anti-PTGFRN ADC on head and neck cancer cell lines and patient derived xenografts that had been analyzed for their PTGFRN expression by western blot analysis using anti-PTGFRN antibody. Cells lines and PDX that were positive for PTGFRN expression were used to examine the effect of anti-PTGFRN ADC on their in vitro and in vivo proliferation. The data show that anti-PTGFRN ADC inhibits tumor formation in a dose-dependent fashion. These data also establish PTGFRN as cancer druggable target and the selected fully human anti-PTGFRN antibody as an attractive antibody for the development of new antibody drug conjugate in Oncology. These data also emphasize the potential of humanized transgenic TC mice for the development of fully human monoclonal antibodies, thus bypassing the need for humanization and affinity maturation required by other humanized mice or phase display. Citation Format: Jorge Marquez, Jianping Dong, Mitsuo Oshimura, Jun Hayashi, Ginette Serrero. Effect of fully human anti-PTGFRN antibody drug conjugate on head neck cancer cells and patient derived xenografts [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 4695.
Abstract 3836: Mast cell leukemia provisional prognostic score
Authors: Philip A. Haddad, Sumasri Chennapragada
Journal: Cancer Research (2024)

Abstract Background Mast cell leukemia (MstCL) is a rare but aggressive variant of systemic mastocytosis (SM), defined by the presence of &amp;gt;20% atypical mast cells in the bone marrow. It is further classified into leukemic and aleukemic variants based on the presence or absence of &amp;gt;10% atypical mast cells in the peripheral blood, respectively. There is a wide variation in treatment regimens used to treat MstCL. Despite this, prognosis remains poor. While MstCL often follows an aggressive course, its outcomes vary considerably. We conducted this study to develop a provisional MstCL prognostic score (MCLPS) for this rare disease. Methods We used our constructed MstCL database, which contains retrospective data on 144 cases. Such data included demographics such as sex, age, and race. It also included disease presentation symptoms, duration of symptoms before diagnosis, site(s) of the disease, blood counts, coexisting comorbidities, disease immunohistochemical and molecular phenotype, types of treatment, and survival outcomes. Of the 144 cases, only 104 had complete survival and outcomes data, the sample chosen for this study. Cox proportional-hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on overall survival (OS). We included factors that statistically impacted OS and scored them by the impact of their hazard ratios. Results The median OS of the cohort was 9 months. The following dichotomous variables were identified as impactful prognostic factors in this cohort: Age&amp;lt;55 (6 vs. 15 months), Hgb&amp;lt;10g/dl (3 vs. 29 months), Plt&amp;lt;100K (3 vs. 23 months), leukemic phase (7 vs. 18 months), and complex cytogenetics (2.3 vs. 23 months). A prognostic model was devised using these variables to identify different levels of risk. Each variable was assigned a score of 1 when present for a maximum possible score of 5. In this exploratory cohort, low risk was assigned a score of 0, intermediate risk a score of 1-2, and high risk a score of 3-5. This prognostic score system led to our cohort's most optimal risk discriminatory model, where low, intermediate, and high risk had a median OS of 29, 8, and 2.4 months, respectively (p=0.0006). Conclusion This MCLPS is a promising new tool for risk-stratifying patients with MstCL. However, it still requires prospective validation. Citation Format: Philip A. Haddad, Sumasri Chennapragada. Mast cell leukemia provisional prognostic score [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 3836.
Abstract 4705: Repetitive membrane potential oscillations enhance metformin's antiproliferative effect in glioblastoma stem cells
Authors: Ivan Verduci, Gaetano Cannavale, Guido Rey, Francesca Cianci, Alessandro Fantin, Michele Mazzanti
Journal: Cancer Research (2024)

Abstract Glioblastoma (GB) is the most common and lethal brain tumor and there is a general agreement that GB stem cells (GSCs) are primarily responsible for its high aggressiveness and recurrence. It was recently reported that GSCs are enriched in the transmembrane form of CLIC1 protein (tmCLIC1) and its inhibition was shown to impair tumor growth both in vitro and in vivo. IAA94 hampers tmCLIC1 function but could not be used in clinics. However, tmCLIC1 is also sensitive to metformin, the most used drug to treat type-2 diabetes. Metformin has been demonstrated to have the same effect as IAA94 in in vitro experiments, resulting in an antitumoral action on cancer cells. Moreover, GB orthotopic mouse model treated with metformin shows a 50% survival compared to control animals, even if metformin concentration in the mice brain resulted in the nanomolar range. In this scenario, the main aim of this work is to enhance the effect of metformin able to reach the brain, improving its antitumoral activity in GB. The interaction between metformin and tmCLIC1 occurs only when this protein is in its open state. TmCLIC1 has the peculiarity of being a voltage-dependent ion channel that opens at depolarized voltages. Thus, our strategy is to apply electromagnetic field (EMF) stimulation to induce repetitive membrane depolarization, increasing metformin-tmCLIC1 binding. Our results show that EMF stimulation induces the close-to-open transitions of tmCLIC1, resulting in a 10-fold decrease of the operative concentration of Metformin. This was verified initially in vitro with GSC culture and spheroids model and afterward confirmed also in an in vivo model. The project’s long-term goal is to combine transcranial stimulation and metformin administration in patients as an adjuvant therapy able to target cells that are resistant to chemotherapy and drive tumor relapse. Citation Format: Ivan Verduci, Gaetano Cannavale, Guido Rey, Francesca Cianci, Alessandro Fantin, Michele Mazzanti. Repetitive membrane potential oscillations enhance metformin's antiproliferative effect in glioblastoma stem 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 4705.
Abstract 4674: Reserpine analog modulates transport function of ABCG2
Authors: Shinobu Ohnuma, Shoji Kokubo, Norihiko Sugisawa, Megumi Murakami, Yuuri Hatsuzawa, Minoru Kobayashi, Taiki Kajiwara, Hideyuki Suzuki, Hideaki Karasawa, Kazuhiro Watanabe, Takayuki Doi, Suresh V. Ambudkar, Takashi Kamei, Michiaki Unno
Journal: Cancer Research (2024)

Abstract Backgrounds: Reserpine is an agent that is used for the treatment of hypertension. ABCG2 also known as breast cancer resistance protein (BCRP) is a member of the ABC transporters associated with multidrug resistance (MDR). Our high-throughput screening assay has revealed that reserpine analog inhibits transport function of ABCG2. Aim: To investigate the effect of reserpine analog on ABCG2 function. Results: Flow cytometry assay showed that reserpine analog blocked the efflux of Pheophorbide a (PhA: fluorescent substrate of ABCG2) from ABCG2-expressing HCT-116/BCRP colon cancer cells in a concentration-dependent manner. Furthermore, cell proliferation assay (MTS assay) revealed that 5 and 10 μM reserpine analog sensitized HCT-116/BCRP cells to SN38 with IC50 value 0.61 + 0.12 μM and 0.22 + 0.036 μM, respectively. Finally, reserpine analog did not stimulate ABCG2-mediated ATP hydrolysis, but rather inhibited it (concentration required for 50% inhibition = 2.7 μM), suggesting that reserpine analog might prevent conformational changes required for ATP hydrolysis. Conclusion: Reserpine analog could be developed as a potent modulator to overcome ABCG2-mediated MDR in cancer cells. Citation Format: Shinobu Ohnuma, Shoji Kokubo, Norihiko Sugisawa, Megumi Murakami, Yuuri Hatsuzawa, Minoru Kobayashi, Taiki Kajiwara, Hideyuki Suzuki, Hideaki Karasawa, Kazuhiro Watanabe, Takayuki Doi, Suresh V. Ambudkar, Takashi Kamei, Michiaki Unno. Reserpine analog modulates transport function of ABCG2 [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 4674.
Abstract 161: Aged mice decelerate bone metastasis of prostate cancer by decreasing infiltration of M2 macrophages
Authors: Xiao Zhang, Wei Yu, Xin Huang, Yi Lu, Jian Zhang
Journal: Cancer Research (2024)

Abstract Bone metastasis is a major contributor to the mortality of patients with prostate cancer and results in the development of an immunosuppressive microenvironment in the bone marrow. While advanced age increases the risk of bone metastasis, effects of age-related changes on immune microenvironmental homeostasis are not yet clearly understood. To investigate interactions between cancer cells and the immune microenvironment in elderly individuals, we utilized murine-derived specific bone metastatic prostate cancer cells (RM1-BM), which we had previously isolated from bone metastatic mice and transfected with a luciferase-based reporter gene. We then injected the cells into the left ventricle of both 3‒6 months and 22‒24 months, male, wild-type mice to induce bone metastasis, using age-matched mice injected with PBS as a control. We employed in vivo imaging to compare the metastatic levels in both groups of mice every other day. On day 14, we extracted bone marrow cells for CyTOF analysis and femurs and tibias for Hematoxylin and Eosin staining. Interestingly, our preliminary results demonstrated that healthy aged mice exhibited a lower susceptibility to develop bone metastasis when compared to their younger counterparts. A further investigation of the immune subtypes revealed an increase in the percentage of macrophages in CD45+ immune cells in young mice that developed bone metastasis as opposed to age-matched controls. However, the percentage decreased in aged mice, going from 12.20% to 9.92% (p = 0.001). Lastly, macrophages were isolated from the bone marrow of 3‒6 months and 22‒24 months old mice and were co-cultured with ovalbumin-transfected RM1-BM cells (RM1-BM-ova) in vitro for 24 hours. The flow cytometry results indicated that both groups consist mainly of CD206+ (M2) macrophages. Nonetheless, those obtained from aged mice exhibited reduced ovalbumin presentation capability while maintaining a steady level of type I major histocompatibility complex (MHC-I). These findings suggested that increased infiltration of pro-inflammatory M2 macrophages within the tumor microenvironment may contribute to the bone metastasis of prostate cancer. Therefore, inhibiting M2 macrophages recruitment to the bone marrow microenvironment may prove a useful approach for treating patients with prostate cancer bone metastasis. This study was supported by the NSFC projects (81972420, 81972766, 82173336), and grants from the Shenzhen Science and Technology Innovation Commission (JCYJ20190809161811237, JCYJ20210324104214040). Citation Format: Xiao Zhang, Wei Yu, Xin Huang, Yi Lu, Jian Zhang. Aged mice decelerate bone metastasis of prostate cancer by decreasing infiltration of M2 macrophages [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 161.
Abstract 5758: Gold nanoparticles with graphene quantum dots as drug delivery platforms for anticancer applications
Authors: Fabiola M. Rosa Suárez, Gerardo Morell, Brad Weiner, Nataniel Medina, Wenndy Pantoja
Journal: Cancer Research (2024)

Abstract Cancer is a global health challenge that has a profound impact on the lives of people worldwide, either directly affecting individuals or their loved ones. Among the various types of cancer, prostate cancer stands out as one of the most prevalent in men. Prostate cancer is primarily identified by symptoms related to urinary health. Conventional medical approaches often rely on drug-based treatments to address this form of cancer. However, like many treatments, drug therapy comes with its own set of challenges. In our research project, we propose an alternative approach for managing prostate cancer. Our innovative idea centers around utilizing nanoparticles as a means of drug delivery. Specifically, we are investigating the use of Taxol, also known as Paclitaxel, as the drug of interest. Taxol possesses a significant challenge due to its hydrophobic nature, which hinders its circulation within the bloodstream. Its solubility is extremely low, at 0.00025 mg per milliliter. To overcome this limitation, we have undertaken the synthesis and integration of AuNPs (gold nanoparticles) with GQDs (graphene quantum dots). This combination enhances the drug's hydrophilic properties, making it more effective in transportation. Our research has led us to conduct experiments on prostate cancer cells (specifically the PC3 cell line). We aim to compare the IC50 value, which represents the drug concentration required to kill 50% of the cancer cells, when using the drug alone versus when using the drug in conjunction with the nanoparticles. Taxol's IC50 value is determined to be 5.73nM. In addition to assessing the impact on cancer cells, we have also examined how the nanoparticles interact with blood, and how this interaction influences the morphology of red blood cells. Furthermore, we have characterized the system using various analytical techniques, including FTIR, NMR, Fluorescence, and UV-Vis spectroscopy. To pinpoint the accumulation sites of the drug and delivery agents, we have employed confocal microscopy on the cancer cells. Our ultimate objective is to equip the drug with the necessary components to facilitate its entry into prostate cancer cells effectively. Citation Format: Fabiola M. Rosa Suárez, Gerardo Morell, Brad Weiner, Nataniel Medina, Wenndy Pantoja. Gold nanoparticles with graphene quantum dots as drug delivery platforms for anticancer applications [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 5758.
Abstract 46: Mechanisms and impact of bystander killing by CAR T cells
Authors: Joanna Chorazeczewski, Lishi Xie, Xiufen Chen, Sidney Wang, Justin Kline
Journal: Cancer Research (2024)

Abstract While CD19-directed chimeric antigen receptor (CAR) T cell therapy has improved outcomes of patients with relapsed/refractory diffuse large B cell lymphoma (r/r DLBCL), a majority will suffer disease relapse following CAR T cell infusion. Therefore, understanding mechanisms of CAR T cell killing is critical to enhance therapeutic efficacy. Cytolysis of CAR T cell targets presumably involves recognition of CD19 antigen by the CAR followed by activation of the granzyme/perforin axis. However, bystander elimination of CD19-negative lymphoma cells by CAR T cells has been reported, indicating that an alternative pathway may be required for optimal killing. Through in-depth phenotyping of a large panel of human DLBCLs and in vitro killing assays, we observed that CD19 expression levels on DLBCL cells and vulnerability to CAR T cell killing were weakly correlated. Conversely, cell surface expression of the death receptor, FAS, on DLBCL cells was strongly associated with susceptibility to CAR T cell killing. Although FAS expression across DLBCL cell lines varied, it could be broadly enhanced following exposure to IFNγ. Potent CAR T cell-mediated cytolysis of CD19-negative, Fas-positive murine DLBCL cells required the presence of CD19-positive lymphoma cells in the culture. CRISPR/Cas9 targeting was employed to delete FAS and/or CD19 in isogenic human DLBCL cells to generate CD19+FAS+, CD19+FAS−, CD19−FAS+, and CD19−FAS− subsets, which enabled us to define the extent to which CD19 engagement by the CAR was required to affect killing via FAS. When CAR T cells were co-cultured with equal numbers of the four gene-modified DLBCL cells described above, CD19+FAS+ DLBCL cells were killed most effectively, followed by CD19+FAS− DLBCL cells, and CD19−FAS+ DLBCL cells. Double-negative DLBCL cells were poorly killed. This result suggested that CD19 engagement by the CAR was required for optimal DLBCL cell killing via FAS, and that CD19 and FAS need not necessarily be engaged on the same target cell. Future studies will determine if Fas/FasL interactions can be exploited by overexpression of FasL in CAR T cells and examination of DLBCL killing in vitro and in vivo. Citation Format: Joanna Chorazeczewski, Lishi Xie, Xiufen Chen, Sidney Wang, Justin Kline. Mechanisms and impact of bystander killing by CAR T 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 46.
Abstract 3922: Quaking modulates anti-tumor immunity by regulating antigen processing and presentation in dendritic cells
Authors: Yating Li, Jian Hu, Cassian Yee
Journal: Cancer Research (2024)

Abstract Dendritic cells are essential players in anti-tumor immunity. One of their critical roles is to process and present tumor associated antigens to T cells, thereby inducing antigen-specific T cell response. However, cellular factors and molecular pathways regulating antigen processing and presentation by DCs are not fully understood.Here, we revealed a potential regulatory role of a transcriptional co-activator, Quaking (QKI), and its binding partner, PPARδ in antigen processing and presentation by DCs. Consistent with our previous studies in neural stem cells and microglia, we found QKI and PPARδ enhance phagocytosis in DCs by upregulating genes involved in the formation of phagosome and endosomes. QKI- or PPARδ-deficient DCs showed reduced CD8+ T cell priming capacity in vitro. In vivo tumor models suggested DC-specific knocking out of QKI or PPARδ promoted the tumor growth. Furthermore, ablation of QKI or PPARδ in DCs limited the effectiveness of immune checkpoint blockade in multiple tumor models.Together, these revealed a transcriptional regulation of antigen processing and presentation by DCs through QKI and PPARδ. Our data also suggested that perturbing this important function of DC would subvert their anti-tumor activity, highlighting the pivotal role of DCs in an effective anti-tumor immune response. Citation Format: Yating Li, Jian Hu, Cassian Yee. Quaking modulates anti-tumor immunity by regulating antigen processing and presentation in dendritic 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 3922.
Abstract 6118: Sex-related disparity in immune checkpoint inhibitor benefit for patients with esophageal squamous cell carcinoma: A systematic review and meta-analysis
Authors: Chaoqi Zhang, Peng Wu, Jingjing Liu, Dongyu Li, Nan Sun, Jie He
Journal: Cancer Research (2024)

Abstract Sex-related dimorphism in cancer incidence and immune response is widely recognized, yet the impact of an individual's sex on the effectiveness of Immune Checkpoint Inhibitors (ICIs) for patients with advanced esophageal squamous cell carcinoma (ESCC) remains poorly understood. In this study, we conducted a comprehensive meta-analysis to evaluate the heterogeneity of ICIs in patients with advanced ESCC. We collected studies from PubMed, MEDLINE, Embase, and Scopus, spanning from the inception of the databases to September 30, 2023. These studies focused on phase III randomized trials comparing first-line ICIs (PD-1/PD-L1) plus chemotherapy with chemotherapy alone for advanced or metastatic ESCC. Additionally, we reviewed abstracts and presentations from AACR, ASCO, ESMO, and WCLC. Inclusion criteria mandated the reporting of overall survival (OS) data stratified by sex and nonselective baseline PD-L1 expression. The study adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The analysis included 6 randomized clinical trials comprising 3603 ESCC patients, of whom 3090 (85.8%) were male and 513 (14.2%) were female. A significant OS benefit was observed for ICIs plus chemotherapy in all patients (HR, 0.68; 95% CI, 0.62-0.74; P &amp;lt; 0.001). Similarly, ICIs plus chemotherapy correlated with a significantly prolonged OS in males (HR, 0.67; 95% CI, 0.61-0.74, P &amp;lt; 0.001). However, there was no significant OS benefit observed in females with ICIs plus chemotherapy (HR, 0.79; 95% CI, 0.58-1.09; P = 0.148). Females had a tendency toward less benefit than males (pooled HR, 1.18; 95% CI, 0.89-1.57; P = 0.245). Our findings suggest that there is no statistically significant association between patient sex and the efficacy of ICIs for ESCC patients. Importantly, we report, for the first time, a lack of survival benefit with the ICI plus chemotherapy regimen in the first-line setting compared to chemotherapy alone in female ESCC patients. Citation Format: Chaoqi Zhang, Peng Wu, Jingjing Liu, Dongyu Li, Nan Sun, Jie He. Sex-related disparity in immune checkpoint inhibitor benefit for patients with esophageal squamous cell carcinoma: A systematic review and meta-analysis [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 6118.