tbuckley/cabot-search huggingface dataset:
Abstract IA002: Molecular subtypes of NMIBC
Authors: Sia V. Lindskrog
Journal: Clinical Cancer Research (2024)

Abstract Non-muscle-invasive bladder cancers (NMIBCs) show large variation in disease aggressiveness which is not fully explained by differences in clinical and pathological factors. It is therefore essential to increase our understanding of the molecular landscape of NMIBC to improve risk assessment and identify potential therapeutic targets. In 2021, we published the four transcriptomic UROMOL2021 classes of NMIBC: class 1, class 2a, class 2b and class 3 (Lindskrog et al., Nature Communications, 2021). Multiple other subtyping schemes for NMIBC have been published, including, among others, the Lund taxonomy (Marzouka et al., The Journal of Molecular Diagnostics, 2022), the stage-stratified subtypes from Leeds (Hurst et al., Cell Reports Medicine, 2021) and BRS1-3 from Rotterdam (de Jong et al., Science Translational Medicine, 2023). In my presentation, I will give an overview of the development and status of NMIBC subtypes and discuss clinical utility. Furthermore, I will present novel data from the UROMOL cohort, where we have now performed a comprehensive genomic characterization of tumors using whole exome sequencing (n=438) and shallow whole genome sequencing (n=362). Overall, we observe a large genomic variation within NMIBC that is associated with different gene expression profiles (UROMOL2021 classes). We performed integrative clustering analysis of somatic mutations, copy number alterations and gene expression data for 230 tumors and identified four “iClusters”, which were highly prognostic and went beyond the single-layer stratifications of tumors. Multi-omics subtyping may improve our understanding of differences in disease aggressiveness within NMIBC further, which could ultimately be used to improve risk assessment of patients and identify potential therapeutic targets. Citation Format: Sia V. Lindskrog. Molecular subtypes of NMIBC [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA002.
Abstract A012: <i>Kmt2c/d</i> loss primes urothelium for tumorigenesis and redistributes Menin to bivalent promoters
Authors: Naitao Wang, Mohini Pachai, Dan Li, Cindy Lee, Sarah Warda, Makhzuna Khudoynazarova, Woo Hyun Cho, Guojia Xie, Fengshen Kuo, Sagar Shah, Li Yao, Cheng Qian, Elissa Wong, Juan Yan, Fanny Tomas, Wenhuo Hu, Sizhi Gao, Alison Smith, Ming Han, Dong Gao, Kai Ge, Haiyuan Yu, Sarat Chandarlapaty, Gopakumar Iyer, Jonathan Rosenberg, David Solit, Hikmat AI-Ahmadie, Ping Chi, Yu Chen
Journal: Clinical Cancer Research (2024)

Abstract Urothelial carcinoma arises from a “field” of precancerous but histologically normal urothelium. The KMT2C/D-KDM6A complexes known to bind and activate enhancers are frequently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using a genetically engineered mouse model, we demonstrate that knockout of Kmt2c and/or Kmt2d induced a histologically normal, pre-tumorigenic state characterized by impaired differentiation from basal state and by augmented responses to growth and inflammatory stimuli. This sensitized the urothelium to transformation by known oncogenic drivers in urothelial carcinoma. Mechanistically, Kmt2d localized to both active enhancers and a small group of CpG-poor promoters and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which together led to downregulation of the urothelial differentiation program. We further observed that Menin distributed extensively to Kmt2d localized enhancers and Kmt2c/d knockout led to redistribution of Menin to CpG-high and particularly bivalent promoters, resulting in transcriptional de-repression of bivalent genes. Blockade of Kmt2a/b-Menin interaction partially rescued the transcriptional changes that induced by Kmt2c/d deletion. Therapeutically, Kmt2c/d knockout maintained a basal state that upregulated EGFR signaling and conferred vulnerability to EGFR inhibitors. Together, our data posits that functional loss of Kmt2c/d licenses a molecular “field effect” priming histologically normal urothelium for oncogenic transformation and leading to therapeutic vulnerabilities to EGFR signaling pathway inhibition. Citation Format: Naitao Wang, Mohini Pachai, Dan Li, Cindy Lee, Sarah Warda, Makhzuna Khudoynazarova, Woo Hyun Cho, Guojia Xie, Fengshen Kuo, Sagar Shah, Li Yao, Cheng Qian, Elissa Wong, Juan Yan, Fanny Tomas, Wenhuo Hu, Sizhi Gao, Alison Smith, Ming Han, Dong Gao, Kai Ge, Haiyuan Yu, Sarat Chandarlapaty, Gopakumar Iyer, Jonathan Rosenberg, David Solit, Hikmat AI-Ahmadie, Ping Chi, Yu Chen. Kmt2c/d loss primes urothelium for tumorigenesis and redistributes Menin to bivalent promoters [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A012.
Abstract IA013: Current state of the art: Bladder-preserving trimodality therapy for muscle-invasive bladder cancer
Authors: Jason A. Efstathiou
Journal: Clinical Cancer Research (2024)

Abstract Many muscle-invasive bladder cancer (MIBC) patients are not getting curative treatment, there remains an undertreated/underserved population and a huge unmet need. Some are not good surgical candidates and others decline a radical cystectomy given concerns regarding its morbidity. Trimodality therapy (TMT), comprising of a maximal transurethral resection of bladder tumor (TURBT) followed by chemoradiation (with salvage cystectomy reserved for those that incur a muscle-invasive recurrence), has emerged as a viable bladder-preserving alternative to radical cystectomy for selected patients. In clinically-matched cohorts, survival is comparable to radical cystectomy in the modern era. More than 85% of contemporary patients keep their own native bladder and long-term quality of life after bladder preservation is good. Salvage cystectomy is feasible and can be curative for those with MIBC recurrences. TMT is now supported by numerous clinical guidelines, including NCCN (category 1 recommendation for stage II and IIIA). There are opportunities to continue to optimize clinical staging of disease (e.g. MRI), delivery of RT (e.g. image guidance, adaptive delivery, dose escalation, hypofractionation, field design) and systemic therapies (e.g. concurrent, neoadjuvant and adjuvant, including possibly immunotherapy) to improve outcomes. Ongoing trials (such as SWOG/NRG 1806 which recently closed to accrual) will inform the addition of immunotherapy to TMT. Validation of biomarkers in independent cohorts and in prospective trials is necessary to further guide bladder preservation therapy for MIBC and for personalized treatment selection. Ultimately, MIBC patients should be seen in a multidisciplinary environment where informed decision making by the patient is key. Citation Format: Jason A. Efstathiou. Current state of the art: Bladder-preserving trimodality therapy for muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA013.
Abstract A003: Characterization of circulating tumor cells from patients with metastatic bladder cancer
Authors: Zeqi Niu, Molly Kozminski, Kathleen C. Day, Luke Broses, Marian L. Henderson, Sophia Merajver, Aaron Udager, Phillip L. Palmbos, Sunitha Nagrath, Mark L. Day
Journal: Clinical Cancer Research (2024)

Abstract Assessing the molecular profile of bladder tumors from patients with metastatic disease is crucial for implementing personalized treatment. Current standards are based on highly invasive biopsies. Alternatively, liquid biopsies of tumor cells, proteins, and nucleic acids allows longitudinal profiling in a less invasive manner. Circulating tumor cells (CTCs) isolated from blood are a key analyte of liquid biopsy. In this study, we developed a protein and transcriptomic co-analysis workflow for bladder cancer CTCs utilizing the graphene oxide (GO) microfluidic chip conjugated with antibodies against both EpCAM and EGFR to isolate CTCs from blood of patients with metastatic bladder cancer. Following CTC capture, protein and mRNA were analyzed using immunofluorescent staining and ion-torrent whole transcriptome sequencing. This is the first time that whole transcriptome sequencing was used in a downstream application for the GO microfluidic platform. We found that elevated CTC counts were significantly associated with patient disease status at the time of blood draw and that greater than 2 CTCs per mL were associated with shorter overall survival. Invasive markers, including EGFR, HER-2, CD31, and ADAM15, were detected in subpopulations of CTCs. Targeted whole transcriptome sequencing showed distinct expression profiles from patients with metastatic burden at the time of blood draw. In these patients, we found significant upregulation of several metastasis-related and chemotherapy-resistant genes demonstrating the capability of identifying tumor-related RNA signatures from circulating CTCs using immune-affinity GO chip-based assays. In addition, this workflow highlights the prognostic potential of CTCs in metastatic bladder cancer patients. Citation Format: Zeqi Niu, Molly Kozminski, Kathleen C. Day, Luke Broses, Marian L. Henderson, Sophia Merajver, Aaron Udager, Phillip L. Palmbos, Sunitha Nagrath, Mark L. Day. Characterization of circulating tumor cells from patients with metastatic bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A003.
Abstract B009: Targeting bladder cancer-macrophage interactions by SPARC peptides
Authors: Mariam Diab, Neveen Said
Journal: Clinical Cancer Research (2024)

Abstract Bladder cancer is one of the privileged cancers treated with two modalities of immune therapeutics: intravesical Bacille Calmette-Guérin (BCG) for non-muscle invasive disease and immune checkpoint inhibitors for advanced metastatic muscle invasive disease. However, recurrence, intolerance and adverse events are encountered in both modalities with limited second and third line treatment options. Clinical data indicated that pretreatment infiltration of bladder tumors with tumor associated macrophages (TAMs) is associated with BCG failure, resistance to standard of care chemo- and immune-therapy and poor disease outcome. Preclinical studies indicated that macrophage infiltration is the forerunner of carcinogen-induced preneoplastic bladder lesions and progresses throughout overt neoplastic and metastatic disease. Thus, TAMs represent a plausible therapeutic target for bladder cancer. Capitalizing on our earlier report that SPARC, as tumor suppressor of BCa, we developed peptides mapping the biologically active domains of SPARC and investigated their direct effect on tumor cell malignant phenotype. In tandem, we determined the effect of SPARC-peptides on macrophage differentiation, polarization, and anti-tumor effects. We identified a potent inhibitory effect of our peptides on a panel of bladder cancer cell survival and invasiveness in 2D and 3D cultures. Using macrophage cell lines as well as bone marrow-derived myeloid cells, we found these peptides induced an M1 phenotype in response to cytokine stimulation, with enhanced phagocytic activity and macrophage-induced tumor cell killing in vitro. Moreover, SPARC-peptides inhibited macrophage polarization to M2 phenotype. Our data strongly suggest that SPARC-peptides are promising therapeutic candidates for bladder cancer. Citation Format: Mariam Diab, Neveen Said. Targeting bladder cancer-macrophage interactions by SPARC peptides [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B009.
Abstract A014: PIK3CA mutation might confer resistance to an FGFR inhibitor, erdafitinib, in urothelial cancer cells
Authors: Seiji Arai, Tatsuhiro Sawada, Akira Ohtsu, Mai Onose, Yuta Maeno, Yoshitaka Sekine, Kazuhiro Suzuki
Journal: Clinical Cancer Research (2024)

Abstract Objective: Metastatic urothelial carcinoma (mUC) has a poor prognosis. In the United States, an FGFR inhibitor (erdafitinib) was approved for mUC patients with FGFR2/3 alterations. Significantly, FGFR3 mutations are associated with favorable outcomes in UC but might also be associated with less sensitivity to immune checkpoint inhibitors, especially in metastatic upper tract UC (mUTUC). Therefore, erdafitinib can be an optimal candidate for mUTUC with FGFR3 mutations before treatment with immune checkpoint inhibitors. However, the duration of response for erdafitinib is limited in many patients. Hence, this study aimed to elucidate the resistance mechanism of erdafitinib and develop a new treatment for mUC. Methods: UC cell lines with FGFR3 alterations were exposed to erdafitinib for an extended period to create resistant cell lines. We assessed genetic modifications in the resistant lines. We also investigated the susceptibility to specific therapeutic agents for cancer-associated gene mutations in vitro and in vivo. [Results] Whole exome sequencing demonstrated PIK3CA gene mutations in two resistant lines. Significantly, a PI3K inhibitor showed apoptosis in resistant cells in vitro. Moreover, alpelisib showed a statistically significant growth inhibitory effect on erdafitinib-resistant UC tumors in vivo compared to control or erdafitinib treatment. Conclusions: PIK3CA gene mutations may be one of the resistant mechanisms to erdafitinib and can also be targetable with a commercially available PI3K inhibitor in mUC. Citation Format: Seiji Arai, Tatsuhiro Sawada, Akira Ohtsu, Mai Onose, Yuta Maeno, Yoshitaka Sekine, Kazuhiro Suzuki. PIK3CA mutation might confer resistance to an FGFR inhibitor, erdafitinib, in urothelial cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A014.
Abstract B021: Targeting nucleotide excision repair in non-muscle invasive bladder cancer
Authors: Dongbo Xu, Li Wang, Kyle Wieczorekl, Zhiyu Tian, Qiang Li
Journal: Clinical Cancer Research (2024)

Abstract Background: Previous studies demonstrated that nucleotide excision repair (NER) plays a critical role in cisplatin-based chemotherapy response in muscle-invasive bladder cancer (MIBC), and that spironolactone (SP) is a potent NER inhibitor. We sought to investigate the role of SP in enhancing the response to mitomycin chemotherapy in non-muscle invasive bladder cancer (NMIBC). Materials and Methods: KU1919 cells (NER proficient) were used for chemotherapy response to mitomycin. Cell viability was examined using CellTiter-Glo. IC50 concentrations were calculated using a four-parameter sigmoidal model and plots generated by GraphPad Prism 9. Drug combination indexes (CI) of chemotherapy and SP were calculated using Chou-Talalay method. Cell cycle and apoptosis analysis were measured by assay and Annexin V apoptosis detection kit. DNA damage response and apoptosis signaling were examined by Western blot of gamma-H2AX, cleaved Caspase-3, and cleaved PARP. Results: Combinations of mitomycin and SP (2 μM: 40 μM, CI = 0.09) resulted in strong synergies in KU1919 cells. Mitomycin combined with SP led to more cells with a sub-G1 phase DNA content (9.43% vs. 4.69%, P &amp;lt; 0.01) and apoptosis (55.85% vs. 13.11% P &amp;lt; 0.01) than treatment with mitomycin alone. Western blot analyses showed that the addition of SP to mitomycin treatment induced increased protein expression of DNA damage response genes (gamma-H2AX) and activation of apoptosis (cleaved Caspase-3 and cleaved PARP). Conclusion: Targeting the NER pathway with SP in NMIBC enhances mitomycin-induced DNA damage signaling and subsequent cell apoptosis. These findings offer proof of concept and rationale for combining NER inhibitors with intravesical chemotherapy in NMIBC. Citation Format: Dongbo Xu, Li Wang, Kyle Wieczorekl, Zhiyu Tian, Qiang Li. Targeting nucleotide excision repair in non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B021.
Abstract B020: Development of novel Src-targeting strategies to block bladder cancer invasive progression
Authors: Nicole A. Jerome, Yin Wang, Marian L. Henderson, Luke Broses, Kathleen C. Day, Mark L. Day, Matthew B. Soellner, Phillip L. Palmbos
Journal: Clinical Cancer Research (2024)

Abstract Background: Treatment of muscle-invasive bladder cancer remains challenging and, BCG, one of the few treatments that prevents progression of high-risk non-muscle invasive tumors to invasive metastatic disease, is difficult to obtain. Thus, development of new treatment approaches to block progression to muscle invasive disease is essential. We find that TRIM29 (tripartite motif containing 29, also known as ATDC), drives bladder cancer invasive progression through modulation of focal adhesions containing FAK and c-Src (Src). Despite this, literature has reported conflicting effects of Src knockdown and Src kinase inhibition on migration, perhaps due to separable pro- and anti-invasive functions of Src in bladder cancer. Hypothesis: Src drives bladder cancer invasive progression specifically through its tyrosine kinase activity within focal adhesions. Methods: We used 2D live cell migration assays and 3D spheroid invasion assays to test dasatinib, highly specific, novel conformation inhibitors of Src, a novel Src PROTAC, and siRNA against Src on bladder cancer migration and invasion. Results: Dasatinib and our novel conformation-specific inhibitors inhibited Src kinase activity and both siRNA and the novel PROTAC reduced total Src expression in vitro. Neither dasatinib, conformation inhibitors, siRNA, nor the PROTAC impacted bladder cancer cell viability in UM-UC5, UM-UC9 or UM-UC14 cell lines. Interestingly, we found that inhibiting Src’s kinase activity with either dasatinib or conformation-specific inhibitors abrogated bladder cancer migration. Conclusion: These results point to the selective importance of Src in regulating bladder cancer migration and invasion. They also suggest that novel Src targeting agents have potential clinical utility in the prevention of bladder cancer invasive progression. Citation Format: Nicole A. Jerome, Yin Wang, Marian L. Henderson, Luke Broses, Kathleen C. Day, Mark L. Day, Matthew B. Soellner, Phillip L. Palmbos. Development of novel Src-targeting strategies to block bladder cancer invasive progression [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B020.
Abstract IA012: Novel approaches to the management of non-muscle invasive bladder cancer
Authors: Ashish M. Kamat
Journal: Clinical Cancer Research (2024)

Abstract Non-muscle invasive bladder cancer (NMIBC) is a prevalent disease with a high recurrence rate and the potential to progress to muscle-invasive stages. While transurethral resection and bacillus Calmette-Guerin (BCG) immunotherapy remain the mainstay of treatment, limitations exist, particularly for high-grade and BCG-unresponsive NMIBC. This necessitates the exploration of novel therapeutic strategies. This talk will explore promising avenues in NMIBC management, including combination intravesical therapies, enhanced delivery methods for existing treatments, and emerging fields like gene therapy, targeted therapy, immunotherapy variants, and photodynamic therapy. These approaches hold the potential to improve bladder preservation rates, reduce recurrence, and ultimately enhance patient outcomes across the entire spectrum of NMIBC disease. Citation Format: Ashish M. Kamat. Novel approaches to the management of non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA012.
Abstract A015: Novel genetic driver for the genesis of muscle invasion in bladder cancer
Authors: Sreenidhi Mohanvelu, Poorvi Subramanian, Sabir Salim, Dinesh Babu Somasundaram, Sheeja Aravindan, Natarajan Aravindan
Journal: Clinical Cancer Research (2024)

Abstract Non-muscle invasive bladder cancer (NMIBC) is a heterogeneous type of urothelial carcinoma with a substantial risk (&amp;gt;50%) of tumor progression and muscle invasion. Our sequential studies uniquely unveiled the availability of Retinal Degeneration Protein 3 (RD3) in human adult/fetal tissues and recognized its functional significance in tumor evolution. Herein, we investigated the relevance of RD3 in coordinating de novo MIBC from NMIBC. Compared to the low-grade tumor, RD3 is significantly lost (mRNA, qPCR; protein, ELISA) in grade III and IV patient derived NMIBC cells. In a cohort of (n=55) NMIBC patients, RD3-loss associated with increased tumor invasive potential (complete loss in highly invasive T4), metastasis (vs. primary tumors), therapy pressure (insignificant levels in progressive disease that defies therapy), disease recurrence, and death (custom archived TMA with automated RD3 IHC).Crucially, we observed a significant low-is-worse association to overall survival (p=7.30E-03, hazard ratio (HR) of 5.161), relapse-free survival (p=4.464E-02, HR = 2.328), and progression-free survival (p=7.00E-0.4, HR = 3.264). Further, radio-resistant cells exposed to fractionated irradiation (FIR, 2Gy/Day for 5 days) to a total dose of 10 or 20Gy displayed a dose dependent loss of RD3 recognizing an ongoing acquisition of RD3-loss with therapy pressure. More interestingly, Grade I or III bystander cells (BSE) co-cultured with FIR-exposed cells displayed anew acquisition of RD3-loss and displayed tumor grade-dependent increase (vs. mock-irradiated) in NFkB transcriptional activity (EMSA) and the activation of NFkB trans-activated pro-survival molecules (QPCR profiling of 89 NFkB targets). Together, these results clearly depict that RD3 regulates NMIBC disease pathogenesis, dissemination, acquired loss of RD3 with therapy pressure and further implies its role in the evolution of de novo MIBC from NMIBC. Funding: DOD CA-210339, OCAST-HR19-045, NIH-P20GM103639, NIH-NCI-P30CA225520 and TSET-R23-03. Citation Format: Sreenidhi Mohanvelu, Poorvi Subramanian, Sabir Salim, Dinesh Babu Somasundaram, Sheeja Aravindan, Natarajan Aravindan. Novel genetic driver for the genesis of muscle invasion in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A015.