tbuckley/cabot-search huggingface dataset:
Abstract 1278: Differential urinary microbiome and its metabolic footprint in bladder cancer patients following BCG treatment
Authors: Xuan-Mei Piao, Kyungchan Min, Young Joon Byun, Chuang-Ming Zheng, Seon-Kyu Kim, Seong-Hwan Park, Sungmin Moon, Kyeong Kim, Ho Won Kang, Won Tae Kim, Seok Joong Yun, Hansoo Park
Journal: Cancer Research (2024)

Abstract Introduction &amp; Objectives: Recent insights reveal a urinary microbiome, challenging prior beliefs about urine's sterility. Using 16S rRNA gene sequencing, a pivotal tool in mapping this microbiome, our study delves into the interplay between bladder cancer (BCa), BCG therapy, and the urinary microbiome. We analyzed bacterial profiles in benign and malignant samples, considering various clinical parameters. Materials &amp; Methods: A total of 88 patients participated in the study, comprising 30 individuals with benign diseases and 58 BCa patients. Urine samples were collected from patients with benign conditions and from BCa patients before and after BCG treatment. Malignant samples obtained before the completion of the intravesical BCG induction cycle were labeled 'Pre-BCG', while those collected after this cycle were termed 'Post-BCG'. Following collection, DNA was extracted and underwent 16S rRNA gene sequencing. The sequencing data was then utilized for bioinformatic analyses, which included metagenomic profiling and metabolic pathway inference. Results: Significant differences in bacterial compositions were observed between benign and malignant samples, with a metabolic signature suggesting toluene degradation pathway may mitigate bladder cancer development. In the post-BCG samples, we inferred elevations of 2-oxoglutarate, a BCG derivative, and L-methionine, which is associated with therapeutic benefits, compared to their pre-BCG counterparts. Furthermore, post-BCG samples showed microbial differences in responders and increased quinolone synthesis compared to non-responders. This is of significance due to quinolone's role in modulating DNA topoisomerase and mitochondrial functions, both pivotal in bladder cancer progression. Conclusions: Utilizing 16S rRNA gene sequencing, we drew comparisons between the urinary microbiomes of benign and malignant samples and suggested a potential pathway for bladder cancer occurrence. Following intravesical BCG treatment, certain microbial metabolic pathways seemed to offer therapeutic benefits to responders. Our study provides insights into the microbial influences on bladder cancer development and the varying responses to BCG treatment. Citation Format: Xuan-Mei Piao, Kyungchan Min, Young Joon Byun, Chuang-Ming Zheng, Seon-Kyu Kim, Seong-Hwan Park, Sungmin Moon, Kyeong Kim, Ho Won Kang, Won Tae Kim, Seok Joong Yun, Hansoo Park. Differential urinary microbiome and its metabolic footprint in bladder cancer patients following BCG 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 1278.
Abstract 4595: HSK41959-2: An oral MTA-cooperative PRMT5 inhibitor for MTAP deleted cancer
Authors: Pangke Yan, Ju Wang, Meilin Qian, Xiaojuan Yu, Yao Li, Haoliang Zhang, Lihua Tao, Rui Kou, Teng Hu, Pingming Tang, Hongjiao Dong, Aipin Wu, Maotao He
Journal: Cancer Research (2024)

Abstract Methylthioadenosine phosphorylase (MTAP) homozygous deletion occurs in 10-15% of all human cancers. Loss of MTAP result in methylthioadenosine (MTA) accumulation. PRMT5, which is a type II arginine methyltransferase that regulates multiple essential cellular functions via symmetric dimethylation of arginine (SDMA) in target proteins, was identified as a synthetic lethal target for MTAP del cancers. MTA-cooperative PRMT5 inhibitors may exhibit better safety profiling compared to first generation PRMT5i (which observe limiting heme-related toxicities in clinical), which preferentially inhibiting PRMT5 in MTAP del cancer cells to normal cells. HSK41959-2 is a MTA-cooperative PRMT5 inhibitor, which could selectively inhibits PRMT5 in the present of MTA with IC50 was 0.80 nM. In HCT116 MTAP Deleted cell line, HSK41959-2 significantly inhibits the cell proliferation with GI50 of 19.89 nM, which was around 45-fold selectivity in HCT116 cell line. In SDMA assay, HSK41959-2 also showed high potency in HCT116 MTAP-del cell line with IC50 was 3.39 nM, and much weaker in HCT116 MTAP-WT cell line with IC50 was 499 nM, around 147-fold selectivity. In vitro CD34+ Hematopoietic stem cell cell proliferation assay was used for evaluate the heme-related toxicities. HSK41959-2 weakly inhibited the cell proliferation with IC50 of 544 nM while the first generation PRMT5i with IC50 was 35.39 nM. This results indicated HSK41959-2 may has lower heme-related toxicities compared with the first generation PRMT5i. In the HCT116 MTAP-del xenograft model, daily orally administrated with 25 mpk and 100 mpk HSK41959-2 showed significant tumor growth inhibition, with TGI were 62% and 88%, and PRMT5-dependent SDMA protein inhibition were 89% and 95%, respectively. Meanwhile in the HCT116 MTAP-WT xenograft model, HSK41959-2 did not show tumor growth inhibition at 100 mpk. In conclusion, HSK41959-2 is a promising oral MTA-cooperative PRMT5 inhibitor, it was nominated as a development candidate. Citation Format: Pangke Yan, Ju Wang, Meilin Qian, Xiaojuan Yu, Yao Li, Haoliang Zhang, Lihua Tao, Rui Kou, Teng Hu, Pingming Tang, Hongjiao Dong, Aipin Wu, Maotao He. HSK41959-2: An oral MTA-cooperative PRMT5 inhibitor for MTAP deleted cancer [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 4595.
Abstract 702: Development of a radioresistant PDX prostate cancer model to evaluate potential radiosensitizing compounds
Authors: Maria Zeiler Alfsen, Maria Thaysen, Nikoline Nielsen, Michael Wick, Luke Piggott, Sebastian Gnosa, Carsten Haagen Nielsen
Journal: Cancer Research (2024)

Abstract Prostate cancer is the second most common cancer diagnosis worldwide and the fifth leading cause of cancer related death among men. Several treatment strategies are used including the FDA approved 177Lu-vipivotide tetraxetan (177Lu-PSMA-617) for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. However, not all patients respond to treatment due to tumor intrinsic resistance mechanisms. Therefore, the combination of targeted radionuclide therapy with inhibitors against e.g. DNA damage response, cell cycle progression or cell survival pathways are investigated to enhance the radiosensitivity of the tumor. Current models to study radioresistance in prostate cancer are based on cancer cell lines or cell-line derived xenograft models, but these models do not account for the heterogenous and complex biology of the disease. To overcome this issue, we have developed a radioresistant patient-derived xenograft (PDX) prostate cancer model (ST1273, XenoSTART), that is positive for PSMA. Resistance to radiation was initially established by sequential irradiation of the tumors with external beam radiation. Moreover, the model has proven to be resistant towards treatment with 30 MBq 177Lu-PSMA-617. Utilizing this radioresistant model we are now able to investigate the treatment response of 177Lu-PSMA-617 in combination with different drug inhibitor classes to evaluate their potential radiosensitizing effect. The PARP inhibitor, Olaparib, was administered at 50 mg/kg QDx48 alone or in combination with a single dose of 177Lu-PSMA-617 in radioresistant ST1273 tumor bearing NMRI nude mice. First results showed a prolonging treatment effect of Olaparib given in combination with 177Lu-PSMA-617 compared to 177Lu-PSMA-617 alone. Tumor relapse was observed 29 days after treatment with 177Lu-PSMA-617 alone, whereas it was observed 49 days after combination treatment. Olaparib given alone did not influence tumor growth. To further investigate the mechanism of resistance we are currently investigating the radiosensitizing potential of additional compounds and evaluating the tumors by RNA- and whole-exome- sequencing. Altogether, we successfully established a PSMA positive prostate cancer model resistant to PSMA targeted radionuclide therapy. With this model we are able to investigate the radiosensitizing effect of different drug classes. Citation Format: Maria Zeiler Alfsen, Maria Thaysen, Nikoline Nielsen, Michael Wick, Luke Piggott, Sebastian Gnosa, Carsten Haagen Nielsen. Development of a radioresistant PDX prostate cancer model to evaluate potential radiosensitizing compounds [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 702.
Abstract 704: Targeting hypoxic survival pathways to overcome radiotherapy-related treatment resistance
Authors: Claire Beckers, Lazaros Vasilikos, Alba Sanchez-Fernandez, Lorena Moor, Martin Pruschy
Journal: Cancer Research (2024)

Abstract Tumor cells undergo biological adaptations in order to survive stress conditions, such as hypoxia and nutrient deprivation. These biological adaptations include the activation of hypoxic survival pathways that play an important role in acquiring radioresistance which becomes most challenging with treatment regimens using high doses of radiation/fraction (e.g., hypofractionated radiotherapy). Therefore, inhibiting key regulators within these pathways and thereby exploiting these survival mechanisms, gives rise to new potential drug targets for combined treatment modalities. This novel strategy investigated in our laboratory relies on the concept of biological cooperation: while ionizing radiation kills primarily well-oxygenated cells, such inhibitors of survival kinases will drive quiescent tumor cells under hypoxia and/or nutrient deprivation either directly into cell death or into re-entry into a proliferative and thereby more ionizing radiation-sensitive state. One of the survival kinases we are investigating in combination with ionizing radiation (IR) is DYRK1B (dual-specificity tyrosine regulated kinase 1B). We demonstrated that the expression of DYRK1B was upregulated under serum-starvation and hypoxia, but not in response to IR. The small molecule DYRK1B inhibitor AZ191 and shRNA-mediated DYRK1B knockdown significantly reduced proliferative activity and clonogenicity of SW620 tumor cells alone and in combination with IR under serum-starved conditions, which correlated with increased ROS levels and DNA damage. Furthermore, AZ191 successfully targeted the hypoxic core of tumor spheroids while IR preferentially targeted normoxic cells in the rim of the spheroids. A combined treatment effect was also observed in patient-derived colorectal carcinoma organoids but not in healthy tissue organoids. This data shows that inhibition of DYRK1B in quiescent tumor cells could drive tumor cells on their own into crisis or into a more radiosensitive cell cycle phase and thus supports our strategy of biological cooperation. In the continuation of this project, we have performed a drug-screen with approx. 3’000 clinically relevant compounds in colorectal tumor cells lines under normoxic and hypoxic conditions in order to explore additional hypoxia-mediated survival pathways contributing to radioresistance. Thereby we aim to identify novel combined treatment modalities to overcome radiotherapy-induced hypoxia and hypoxia-related resistance mechanisms. Citation Format: Claire Beckers, Lazaros Vasilikos, Alba Sanchez-Fernandez, Lorena Moor, Martin Pruschy. Targeting hypoxic survival pathways to overcome radiotherapy-related treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 704.
Abstract 1130: Leveraging the IVIS imaging technologies for drug potency testing in orthotopic and metastatic tumor models
Authors: Jingqi Huang, Jing Jin, Hongchen Duan, Xueqin Yang, Wenhao Jin, Yiming Zhang, Lihui Zhang, Gaoyang Xu, Liya Xie, Wentao Li
Journal: Cancer Research (2024)

Abstract Assessing anti-tumor drug potency is significantly enhanced using orthotopic and metastasis mouse tumor models. These models imitate the tumor's native environment, biological complexities, and challenges of drug delivery via blood perfusion, thereby providing a high predictive value for clinical outcomes. In this poster, we demonstrate how the IVIS optical imaging technology is employed to determine the effects of two drugs on two tumor models: •The KRAS (G12C) inhibitor, AMG510, was evaluated on the luciferase-expressing Miapaca-2 pancreatic orthotopic model •The third-generation EGFR inhibitor, AZD9291, was tested on the luciferase-expressing NIC-H1975 intracranial metastatic model Both drugs showed significant anti-tumor activity. In addition to potency testing, each drug was administered in single doses for pharmacodynamic analysis, evaluating pERK/ERK and DUSP6 levels. The pERK levels decreased after treatment, which is in line with the mechanism of action of the inhibitors. Our research illustrates that IVIS imaging offers a robust method for monitoring anti-tumor activity of drugs in orthotopic and metastatic tumor models, empowering scientists to assess new drug candidates by using biologically relevant animal models. Citation Format: Jingqi Huang, Jing Jin, Hongchen Duan, Xueqin Yang, Wenhao Jin, Yiming Zhang, Lihui Zhang, Gaoyang Xu, Liya Xie, Wentao Li. Leveraging the IVIS imaging technologies for drug potency testing in orthotopic and metastatic tumor models [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 1130.
Abstract 6837: Prolonged effects of hypoxia in luminal breast cancer cells
Authors: Aidan Moriarty, Oihana Iriondo, Yonatan Amzaleg, Remi Klotz, Min Yu
Journal: Cancer Research (2024)

Abstract Metastasis is the main cause of tumor-related mortality in breast cancer patients. Improving our understanding of the metastatic cascade is imperative to improve patient outcomes. Prior research indicates cancer cells with increased metastatic potential have acquired adaptive properties induced by factors in the tumor microenvironment (TME), including hypoxia. However, previous hypoxia research has primarily focused on signaling changes that occur when cancer cells are in the hypoxic TME and does not account for long-term changes that may occur once cancer cells re-enter normoxia, such as when they metastasize. Our research in patient-derived circulating tumor cell (CTCs) lines and breast cancer cell lines indicates that certain transcriptional changes are maintained after cells leave hypoxia, and that these post-hypoxic cells maintain a higher metastatic potential compared to cells not exposed to hypoxia. Taking an un-biased approach to define changes in hypoxia-exposed breast cancer cells upon reoxygenation, we performed bulk RNA-Seq on post-hypoxic luminal breast cancer cell lines compared to normoxic controls cultured either in adherent or suspension conditions, the latter to mimic the physiological context of CTCs. We found that a subset of genes that were differentially expressed in hypoxic conditions were maintained as up- or down-regulated after cells were reoxygenated, indicating a “hypoxic memory”. Additionally, a subset of differentially expressed genes were unique to the post-hypoxic cells, demonstrating both prolonged and novel gene expression changes induced by hypoxia exposure. We also performed functional assays and observed that this post-hypoxic state is associated with a more aggressive phenotype. Current research in our lab is on-going to understand the epigenetic changes that may be responsible for this hypoxic memory. Overall, this research will improve our understanding of the prolonged consequences of hypoxia on CTC biology and metastasis. Citation Format: Aidan Moriarty, Oihana Iriondo, Yonatan Amzaleg, Remi Klotz, Min Yu. Prolonged effects of hypoxia in luminal 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 6837.
Abstract 4776: The role of angiogenesis in gastric tumorigenesis
Authors: Venu Akkanapally, SUJIT BASU
Journal: Cancer Research (2024)

Abstract Introduction: Gastric or stomach cancer remains one of the most lethal malignancies, with an estimated 1,089,103 new cases and 768,793 deaths worldwide in 2020. In the United States, it is estimated that there were 26,500 new cases and 11,130 deaths from stomach cancer in 2023. Unfortunately, despite improved treatment in recent years, ~65% of gastric cancer patients present with aggressive metastatic disease, and they die within one year of diagnosis. Therefore, the identification of newer and effective therapies to target the precancerous stages of the disease promises possibilities for the prevention of gastric cancer in patients harboring these lesions. Gastric metaplasia and dysplasia are precancerous lesions that often progress to gastric cancer. Since anti-VEGF-A anti-angiogenic agents have shown efficacy in advanced gastric cancer patients, we hypothesized that VEGF-A-mediated angiogenesis has a functional role in the pathogenesis of gastric metaplasia and dysplasia. Experimental Procedures: The Initial experiments were undertaken in human gastric metaplasia and dysplasia tissues and murine gastric metaplasia and dysplasia tissues collected from a well-established Helicobacter felis (H. felis) induced murine model of gastric tumorigenesis simulating human patients to detect angiogenesis (CD31/MVD) and identify angiogenic pathways using GeoMx DSP Spatial Proteomics and NanoString nCounter assay. Thereafter, further experiments were undertaken in the H. felis-induced murine model of gastric metaplasia and dysplasia, simulating human patients using VEGF-A hypo mice to determine the role of VEGF-A-induced angiogenesis in the progression of these lesions. Results and Conclusion: Although our results indicated angiogenesis and VEGF-A expression in both human and mouse gastric metaplasia and dysplasia, inhibition in the progression of the precancerous gastric lesions was observed in only 40% of the VEGF-A hypo mice, thereby suggesting that VEGF-A induced angiogenesis might not be the major angiogenic pathway in these precancerous lesions in every patient. A similar phenomenon is also seen in some gastric cancer patients. Citation Format: Venu Akkanapally, SUJIT BASU. The role of angiogenesis in gastric tumorigenesis [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 4776.
Abstract 6871: Tumor-infiltrating mregDC restrains anti-tumor immunity to promote cancer relapse in HCC
Authors: Zefan Zhang, Jian Zhou, Jia Fan, Yu Zhong, Liang Wu, Yunfan Sun
Journal: Cancer Research (2024)

Abstract Background and aims: Cancer relapse is one of the major causes of mortality in patients after curative resection of primary tumors. Furthermore, significant proportion of patients with recurrent tumor lack of effective treatments, thus novel therapeutic strategies are urgently needed. Although there have been several single-cell studies of primary tumor, functional roles and mechanism of tumor-infiltrating immune cells, especially those of myeloid cells in tumor relapse have remained to be elucidated. Methods: We analyzed the RNA profile of 16498 cells from 12 primary and 6 early-relapse HCC cases. Digital pathology, multiplex immunofluorescent staining and digital spatial profiling (DSP) of paired primary and relapsed tumors from 41 HCC patients were also performed as our validation set. The molecular mechanisms associated with DCs was further tested through ex vivo and in vivo experiments. Results: We performed single-cell clustering and visualized 3 DC clusters (cDC1, cDC2, and DC3). Compared with the other two subsets, the enrichment of DC3 in relapsed HCC was correlated with a higher second recurrence rate. Deeper inspections of the signature genes indicated this subset as ‘mregDC’, a DC subset enriched in maturation and regulatory molecules. Our results demonstrated that mregDC recruited CD161+CD8+ T cells that had an innate-like, low-cytotoxic, and low-clonal-expansion phenotype. CD161+CD8+ T cells secreted large amounts of TNF to activate non-canonical NF-κB pathway via tumor necrosis factor receptor 2 (TNFR2) and promoted the differentiation of immature DC into mregDC. This positive feedback loop between mregDC and CD161+CD8+ T cells shaped a dysfunctional anti-tumor immunity, facilitating cancer relapse in HCC. In vivo assay further indicated that therapy combining anti-TNFR2 and PD-L1 antibodies significantly inhibited HCC tumor growth via impeding the infiltration of mregDC compared with anti-PD-L1 monotherapy. We also found mregDC recruited FCN1+ monocyte, a MDSC-like cell population to create an immunosuppressive niche of relapsed HCC. Conclusions: We identified this population of mregDC with immunomodulatory function in recurrent HCC and demonstrated the role of these special DCs in shaping the immunosuppressive microenvironment of recurrent tumors. Our study suggests that mregDC may be a new target for the treatment of recurrent HCC in the future. Citation Format: Zefan Zhang, Jian Zhou, Jia Fan, Yu Zhong, Liang Wu, Yunfan Sun. Tumor-infiltrating mregDC restrains anti-tumor immunity to promote cancer relapse in HCC [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 6871.