tbuckley/cabot-search huggingface dataset:
Abstract B024: Development of HM-001 as a therapeutic drug for non-muscle invasive bladder cancer
Authors: Shinji Mima, Monta Sakaki, Noriaki Kiya, Atsunari Kawashima, Norio Nonomura, Chihaya Kakinuma
Journal: Clinical Cancer Research (2024)

Abstract HM-001 is a drug containing sodium chlorite as the active ingredient that is being developed as a drug for non-muscle invasive bladder cancer (NMIBC), and is currently undergoing physician-led clinical trials. It has been discovered that sodium chlorite generates radicals in an acidic environment, and phosphatidylserine on the surface of tumor cells acts as a Lewis acid to generate radicals. HM-001, like other anticancer drugs and BCG, is intended to be injected into the bladder, retained, and then excreted. GLP studies using the same administration method has been completed, and no toxic changes have been observed in human trial doses. The efficacy of HM-001 against NMIBC was evaluated using an orthotopic transplantation model of UM-UC-3, a bladder cancer cell line. In the model, cells were transplanted into the bladder of SCID mouse after epithelial removal with trypsin, 600, 800, 1,600, and 3,200 ppm of HM-001 were administered once a week, and the weight of the excised bladder was calculated. After 4 weeks, the tumor weight was calculated and the tumor weight suppression rate in the control group was evaluated. As a result, the medicinal efficacy was confirmed at concentrations of 800ppm or higher. On the other hand, the UM-UC-3 model is a commonly used model, but it mimics CIS (carcinoma in situ) and can only partially mimic NMIBC. That is, other models are needed to evaluate efficacy for low- and high-grade NMIBC other than CIS. Therefore, we established high-grade and low-grade PDX and evaluated the effectiveness of HM-001 against low- and high-grade PDX through ex vivo testing. First, patient-derived tissue was transplanted into SCID mice, allowed to grow, and then removed. After extraction, they were cut into 2 mm3 pieces, exposed to HM-001 at 800, 1600, and 3200 ppm for 2 hours, and then transplanted into SCID mice. As a result of comparing the tumor size after transplantation with the control group, a dose-dependent tumor regression effect was confirmed in high-grade and low-grade PDX. NMIBC is divided into low-, medium-, and high-risk categories, with different treatment methods and drugs used for each. In particular, low-grade forms are restricted to low- and intermediate-risk groups. The results of this study show that HM-001 is effective not only for high-risk (including CIS) NMIBC but also for low- and intermediate-risk (low-grade) NMIBC. Citation Format: Shinji Mima, Monta Sakaki, Noriaki Kiya, Atsunari Kawashima, Norio Nonomura, Chihaya Kakinuma. Development of HM-001 as a therapeutic drug for 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 B024.
Abstract IA005: Y chromosome loss in cancer drives growth by evasion of adaptive immunity
Authors: Dan Theodorescu
Journal: Clinical Cancer Research (2024)

Abstract Loss of the Y chromosome (LOY) is observed in 10-40% of bladder cancers, but its clinical and biological significance is unknown. We will present genomic and transcriptomic studies that show LOY correlates with poor prognoses in patients. We performed studies of murine bladder cancer cells with LOY as well as those with deletion of Y chromosome by CRISPR/Cas9 and compared them to cells with and intact Y chromosome as controls. Y+ and Y- tumors grew similarly in vitro, while Y- tumors grew faster than Y+ tumors in immune competent hosts in a T cell-dependent manner. Flow cytometric analyses demonstrated that Y- tumors promote exhaustion of CD8+ T cells in the tumor microenvironment. These findings were supported by data obtained from single-nuclei RNA sequencing and spatial proteomic evaluation of human bladder cancers. Compared to Y+ tumors, Y- tumors exhibited a superior response to anti-PD-1 therapy in mice. In bladder cancer patients those with LOY tumors have better prognosis than those with Y+ tumors. This is the first evidence demonstrating that LOY in tumors alters T cell function by promoting T cell exhaustion and sensitizes them to PD-1-targeted immunotherapy. This work provides novel insights into basic LOY biology as well as the potential for the development of biomarkers for improved cancer immunotherapy. Citation Format: Dan Theodorescu. Y chromosome loss in cancer drives growth by evasion of adaptive immunity [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 IA005.
Abstract B010: Tumor B8T expression stratifies overall survival in high risk muscle invasive urothelial carcinoma
Authors: Roy Elias, Adam K. Aragaki, Jean H. Hoffman-Censits, Noah M. Hahn, David J. McConkey, Burles A. Johnson
Journal: Clinical Cancer Research (2024)

Abstract Background and Objective: Determining novel biomarkers to identify patients that benefit and do not benefit from immune checkpoint inhibitor (ICI) therapy is critical to avoid overtreatment. Circulating tumor DNA (ctDNA) has emerged as a biomarker that associates with overall survival (OS) benefit to ICI in patients with muscle invasive urothelial carcinoma (MIUC). However, few studies have examined whether existing immune based biomarkers stratify OS within the high risk, ctDNA(+) population. Methods: To address this, we interrogated ctDNA and RNA sequencing data from the IMvigor010 dataset of patients with high risk MIUC after cystectomy who were randomized to adjuvant atezolizumab versus observation. We correlated OS with ctDNA positivity and expression of a B cell and CD8 T cell gene signature (B8T). Key Findings: In patients who were ctDNA(+), high tumor expression of a B cell gene signature (BCGS) associated with significantly higher OS when compared with patients with low tumor BCGS, regardless of whether patients were treated with atezolizumab. In ctDNA(+) patients with high tumor expression of both BCGS and CD8 T cell gene signature (CD8TGS), e.g. B8T high/high, atezolizumab did not associate with OS benefit. Conversely, in patients with B8T high/low tumors, receipt of adjuvant atezolizumab associated with significantly increased OS (p &amp;lt; 0.001), and this benefit remained significant in multivariable analyses (p = 0.047). Notably, benefit with atezolizumab occurred in patients with B8T high/low tumors who were either ctDNA(+) (p = 0.057) or ctDNA(-) (p = 0.034). Conclusions and Clinical Implications: While tumor B8T high/high expression is a prognostic biomarker for OS in ctDNA(+) patients with high risk MIUC, these results suggest B8T high/low is a predictive biomarker for benefit from ICI. Moreover, in a small subset of patients who are ctDNA(-), tumor B8T high/low associates with benefit to ICI. This supports the utility of the B8T biomarker as a prognostic identifier in high risk MIUC, its ability to identify patients who will benefit from ICI regardless of ctDNA status, and for the first time ascertains a potential cohort of patients who are ctDNA(-) yet benefit from ICI. Citation Format: Roy Elias, Adam K. Aragaki, Jean H. Hoffman-Censits, Noah M. Hahn, David J. McConkey, Burles A. Johnson III. Tumor B8T expression stratifies overall survival in high risk muscle invasive urothelial carcinoma [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 B010.
Abstract A001: Urine-based liquid biopsy test for the detection of residual bladder cancer in radical cystectomy patients
Authors: Philip H. Abbosh, Henkel Valentine, Rhea Arya
Journal: Clinical Cancer Research (2024)

Abstract One commonly employed management strategy for muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy (RC) and urinary diversion. Approximately 35% of patients achieve a pathologic complete response (pCR) when evaluated from RC specimens. RC with urinary diversion is a life-altering operation with high complication rates and therefore determining who are complete responders would improve quality of life and could decrease costs and still achieve a high cure rate via RC avoidance. Unfortunately, current methods cannot accurately identify complete responders. Our lab has developed a urine-based liquid biopsy test in which DNA isolated from urine and germline is isolated and subjected to panel exome sequencing for enumeration of somatic variants. This occurs under the premise that tumor DNA identified (as mutant alleles) is a marker of residual disease while the absence of tumor DNA (meaning the absence of mutant alleles) can indicate a pCR. A 60 gene panel was designed to be used for exonic sequencing of urinary DNA (uDNA) to identify mutations indicative of bladder cancer or therapeutic targets. We have shown that most mutations in tumor tissue (Mt) are detectable as mutations in urine (Mu). We also showed that the presence or absence of residual Mu after completion of chemotherapy strongly associates with residual disease or pCR at the time of RC, respectively. Therefore, this test could be used after neoadjuvant therapy to better identify patients for RC avoidance. We optimized this test by studying pre-analytical factors affecting the yield, purity, and integrity of uDNA and the quality of sequencing data using prospectively collected samples from patients with MIBC. We are also in the process of testing commercial and novel preservatives to optimize DNA integrity, yield, and mutation detection accuracy to enable temporary ambient temperature storage without compromising mutation detection, permitting shipping/centralized testing. Lastly, we are comparing two library preparation approaches. Study of these preanalytical factors has increased the number of Mu that can be detected and were applied to a cohort of patients who underwent bladder sparing curative-intent treatment in a prospective clinical trial. Studies described herein will enable liquid biopsy tests to accurately identify patients with pCR after neoadjuvant therapy and might safely avoid radical cystectomy. Citation Format: Philip H. Abbosh, Henkel Valentine, Rhea Arya. Urine-based liquid biopsy test for the detection of residual bladder cancer in radical cystectomy patients [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 A001.
Abstract IA019: Lessons from glioblastoma diversity, heterogeneity, and beginnings
Authors: Luis F. Parada
Journal: Clinical Cancer Research (2024)

Abstract Glioblastoma (GBM) is a dire disease with poor prognosis and survival outcomes have changed little over the past two decades. Various genomic studies have emphasized the heterogeneity of GBM yet a consensus on the causes and its role in tumor recurrence has not been reached. Multiple studies using genetic and patient-derived xenograft (PDX) mouse models have demonstrated an inverse relationship between differentiation state and tumor initiation efficiency with neural stem and progenitor cells as the most efficient. However, other studies have proposed that well differentiated cells like neurons and astrocytes can form tumors. In addition, bioinformatic analyses of human primary GBM have reported that plasticity allows for mobility among cell states exist. Regardless of transcriptional modulation in GBM cells, to achieve progress in understanding and addressing clinical recurrence, the outstanding goal remains to identify and isolate the GBM cell type(s) responsible for therapy resistance and recurrence. To achieve this, we have employer autochthonous GBM models as well as orthotopic patient derived xenografts to in parallel examine tumor heterogeneity, cell of origin, and functional consequences. Citation Format: Luis F. Parada. Lessons from glioblastoma diversity, heterogeneity, and beginnings [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 IA019.
m<sup>6</sup>A modification of lncRNA PHKA1‐AS1 enhances Actinin Alpha 4 stability and promotes non‐small cell lung cancer metastasis
Authors: Qiao‐Ru Guo, Guo‐Bin Zhang, Wen‐Min Zhou, Yu Lu, Xin‐Zhu Chen, Zhuo‐Fen Deng, Jin‐Shuo Li, Hong Bi, Ming‐Sheng Wu, Ming‐Ran Xie, Yan‐Yan Yan, Jian‐Ye Zhang
Journal: MedComm (2024)

Abstract Cancer is a disease with molecular heterogeneity that is closely related to gene mutations and epigenetic changes. The principal histological subtype of lung cancer is non‐small cell lung cancer (NSCLC). Long noncoding RNA (lncRNA) is a kind of RNA that is without protein coding function, playing a critical role in the progression of cancer. In this research, the regulatory mechanisms of lncRNA phosphorylase kinase regulatory subunit alpha 1 antisense RNA 1 (PHKA1‐AS1) in the progression of NSCLC were explored. The increased level of N6‐methyladenosine (m 6 A) modification in NSCLC caused the high expression of PHKA1‐AS1. Subsequently, high‐expressed PHKA1‐AS1 significantly facilitated the proliferation and metastasis of NSCLC cells, and these effects could be reversed upon the inhibition of PHKA1‐AS1 expression, both in vivo and in vitro. Additionally, the target protein of PHKA1‐AS1 was actinin alpha 4 (ACTN4), which is known as an oncogene. Herein, PHKA1‐AS1 could enhance the protein stability of ACTN4 by inhibiting its ubiquitination degradation process, thus exerting the function of ACTN4 in promoting the progress of NSCLC. In conclusion, this research provided a theoretical basis for further exploring the potential mechanism of NSCLC metastasis and searching novel biomarkers related to the pathogenesis and progression of NSCLC.
Abstract A019: TRIM29 enhances the invasion of bladder cancer cells by modulating the intermediate filament network and focal adhesions
Authors: Yin Wang, Nicole A. Jerome, Allan Kelleher, Marian L. Henderson, Mark Day, Pierre A. Coulombe, Phillip L. Palmbos
Journal: Clinical Cancer Research (2024)

Abstract Background: Bladder cancer patient treatment and outcomes are determined by the tumor’s ability to invade and metastasize. Our previous work has shown that TRIM29, also known as ATDC, is regulated by TP63 in basal bladder cancers, where it promotes cancer invasion and metastasis. We also observe that TRIM29 predominately localizes to intermediate filaments in invasive bladder cancer cells. Hypothesis: TRIM29 promotes the invasive progression of bladder cancer by regulating K14-containing intermediate filaments and focal adhesions. Methods: To test this hypothesis, we utilized cell culture models of bladder cancer, live cell imaging and 2D and 3D invasion assays to examine the role of TRIM29 in the regulation of K14, focal adhesions and the migration and invasion and bladder cancer cells. Results: We observed a physical interaction between TRIM29 and K14 filamentous structures in bladder cancer cells. We also found that TRIM29 and K14 regulate focal adhesion stability during bladder cancer invasion. Finally, we found that both K14 and the focal adhesion protein, zyxin (ZYX), are essential for bladder cancer migration and invasion, acting downstream of TRIM29. Conclusions: Our findings highlight a novel role for TRIM29 in regulating the cytoskeleton and focal adhesion dynamics during tumor cell invasion and suggest a potential therapeutic pathway for treating bladder cancer. Citation Format: Yin Wang, Nicole A. Jerome, Allan Kelleher, Marian L. Henderson, Mark Day, Pierre A. Coulombe, Phillip L. Palmbos. TRIM29 enhances the invasion of bladder cancer cells by modulating the intermediate filament network and focal adhesions [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 A019.
Abstract B013: Novel prognostic score for patients with metastatic bladder cancer on immunotherapy
Authors: Vishwani Chauhan, Sofia Silva Diaz, Pablo Jara, Denis Efovi, Ayushma Gurung, Matthew Young, Connor Wells, Elizabeth Nally, Bernadett Szabados, Thomas Powles, Francesca Jackson-Spence
Journal: Clinical Cancer Research (2024)

Abstract Background: Some patients with metastatic bladder cancer (mBC) have durable responses to immune checkpoint inhibitors (ICIs); others progress early while suffering from autoimmune toxicity. Currently there is no prognostic score or tumour marker to predict who will benefit from ICIs in bladder cancer. We designed a novel prognostic score to stratify response to ICIs in patients with mBC. Methods: We analysed data from patients with mBC receiving ICIs as second- or later-line treatment between 2013–2023. We assessed key patient characteristics and their impact on progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier and Cox-regression methods (retained if p&amp;lt;0.05). Variables independently correlated with OS and PFS on multivariate analysis were selected to create a new scoring model. Radiological response to ICIs was assessed. C-statistic was calculated to assess the model’s fit. Results: 149 patients with mBC were identified as having received second- or later-line ICIs. Median OS was 9.3 months and PFS 2.5 months. On multivariate analysis, absent liver and bone metastases, haemoglobin≥100g/L, ALP≤130 unit/L, NLR&amp;gt;5, and time from last therapy ≥6 months were independently associated with improved OS and PFS. Using these variables, we created a 3-tier model that strongly correlated with OS (HR 2.0, 95% CI 1.4–2.4, p&amp;lt;0.001) and PFS (HR 1.7, 95% CI 1.2–2.0, p&amp;lt;0.001). Median OS for patients with 0-1, 2 and 3-5 risk factors was 24.2, 6.7, and 2.4 months, respectively. Complete or partial response was seen in 45.8%, 21.2%, and 6.5%, respectively. Disease control was seen in 62.5%, 39.4%, and 10.9% respectively. This model achieved a C-statistic of 0.70 (95% CI 0.65-0.75). Conclusions: ICIs with enfortumab vedotin will become first-line therapy for most patients with mBC. We used routinely available metrics to develop a new 3-tier model that strongly stratifies outcomes of patients with mBC receiving second- or later-line ICIs. The model requires external validation. Citation Format: Vishwani Chauhan, Sofia Silva Diaz, Pablo Jara, Denis Efovi, Ayushma Gurung, Matthew Young, Connor Wells, Elizabeth Nally, Bernadett Szabados, Thomas Powles, Francesca Jackson-Spence. Novel prognostic score for patients with metastatic bladder cancer on immunotherapy [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 B013.
Oxygen Self‐Supplied Nanoplatform for Enhanced Photodynamic Therapy against <i>Enterococcus Faecalis</i> within Root Canals (Adv. Healthcare Mater. 13/2024)
Authors: Jiawen Chen, Hong Zhang, Tiancong Zhao, Yiyan Yu, Jiazhuo Song, Yuanhang Zhao, Hamed Alshawwa, Xinying Zou, Zhimin Zhang
Journal: Advanced Healthcare Materials (2024)
Pump‐Less, Recirculating Organ‐on‐Chip (rOoC) Platform to Model the Metabolic Crosstalk between Islets and Liver (Adv. Healthcare Mater. 13/2024)
Authors: Aleksandra Aizenshtadt, Chencheng Wang, Shadab Abadpour, Pedro Duarte Menezes, Ingrid Wilhelmsen, Andrea Dalmao‐Fernandez, Justyna Stokowiec, Alexey Golovin, Mads Johnsen, Thomas M. D. Combriat, Hanne Røberg‐Larsen, Nikolaj Gadegaard, Hanne Scholz, Mathias Busek, Stefan J. K. Krauss
Journal: Advanced Healthcare Materials (2024)
A Modular Microfluidic Organoid Platform Using LEGO‐Like Bricks (Adv. Healthcare Mater. 13/2024)
Authors: Daniel J. Carvalho, Anna M. Kip, Andreas Tegel, Matthias Stich, Christian Krause, Mírian Romitti, Carlotta Branca, Bart Verhoeven, Sabine Costagliola, Lorenzo Moroni, Stefan Giselbrecht
Journal: Advanced Healthcare Materials (2024)
Incorporation of Decidual Stromal Cells Derived Exosomes in Sodium Alginate Hydrogel as an Innovative Therapeutic Strategy for Advancing Endometrial Regeneration and Reinstating Fertility (Adv. Healthcare Mater. 13/2024)
Authors: Yuxiang Liang, Qizhi Shuai, Xiao Zhang, Shanshan Jin, Yuqian Guo, Zhaowei Yu, Xinrui Xu, Ruifang Ao, Zhiwei Peng, Huimin Lv, Sheng He, Chunfang Wang, Guohua Song, Zhizhen Liu, Hong Zhao, Qilong Feng, Ruochen Du, Bin Zheng, Zhaoyang Chen, Jun Xie
Journal: Advanced Healthcare Materials (2024)
Abstract IA003: Molecular subtypes and clinical benefit from neoadjuvant chemotherapy: A ten-year update
Authors: David J McConkey
Journal: Clinical Cancer Research (2024)

Abstract Ten years ago TCGA and two private groups reported that muscle-invasive bladder cancers (MIBCs) could be grouped into basal and luminal molecular subtypes that shared features with the corresponding subtypes of breast cancer. These and earlier studies by the group at Lund University demonstrated that molecular subtype membership was prognostic: patients whose tumors were assigned to basal/squamous subtypes had shorter survival than did patients whose tumors were assigned to the luminal subtypes, and these relationships were confirmed in subsequent studies. In addition, one of the studies included tumors from patients treated with neoadjuvant cisplatin-based combination chemotherapy (NAC), where patients whose tumors were infiltrated with smooth muscle cells and fibroblasts (the MD Anderson p53-like subtype) had the lowest response rates. Parallel comparisons of patients who either did or did not receive NAC concluded that patients with basal tumors derived the most clinical benefit in terms of disease-specific or overall survival. Thus, in addition to being prognostic, there was a suggestion that molecular subtypes might also be used to predict resistance to NAC. This work led to the design of two large collaborative projects that were designed to validate these observations and the conclusion that inactivating mutations in several DNA damage and repair (DDR) genes were also associated with response. One leveraged the S1314 Phase-2 “CoXEN” trial that was designed to prospectively validate another gene expression-based biomarker, and the other exploited pretreatment samples from the CALGB/Alliance 90601 Phase-3 trial of gemcitabine/cisplatin with or without bevacizumab in patients with advanced or metastatic disease. Comparisons of response rates as a function of molecular subtype membership in S1314 failed to validate the original link between the MD Anderson p53-like subtype and resistance, and patients with basal/squamous tumors in 90601 did not have better outcomes than did patients with luminal tumors. Thus, while the prognostic value of molecular subtype membership was confirmed, the predictive value was not. Developing biomarkers to predict response to chemotherapy remains a challenge not only for bladder cancer but also for other solid and hematopoietic malignancies. It seems likely that success will require the integration of measurements using multiple platforms, including liquid biopsies and others. The exciting results of the EV-302 clinical trial of enfortumab vedotin plus pembrolizumab have shifted the focus of biomarker work to these and other novel agents. Citation Format: David J McConkey. Molecular subtypes and clinical benefit from neoadjuvant chemotherapy: A ten-year update [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 IA003.