tbuckley/cabot-search huggingface dataset:
Treatment Efficacy and Molecular Dynamics of Neoadjuvant Durvalumab and Olaparib in Resectable Urothelial Bladder Cancer: The NEODURVARIB Trial
Authors: Juan F. Rodríguez-Moreno, Guillermo de Velasco, Carlos Álvarez-Fernández, Ricardo Collado, Ricardo Fernández, Sergio Vázquez, Juan A. Virizuela, Pablo Gajate, Albert Font, Nuria Lainez, Elena Sevillano-Fernández, Osvaldo Graña-Castro, Luis Beltrán, Rodrigo Madurga, Cristina Rodríguez-Antona, Pedro Berraondo, Sergio Ruiz-Llorente, Jesús García-Donas
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Neoadjuvant treatment of bladder cancer is evolving, with immunotherapy demonstrating promising activity. PARP inhibition combined with immune activation has been proposed as a synergistic strategy. We conducted a comprehensive molecular characterization of tumors treated with this combination in the neoadjuvant setting to provide crucial results for rational development. Patients and Methods: A phase II clinical trial was designed to evaluate the combination of anti-PDL1 inhibitor durvalumab and PARP inhibitor olaparib, focusing on biomarker dynamics in both pre- and post-treatment settings. A total of 29 patients were enrolled. Genomic and transcriptomic profiling, as well as analyses of immune cell populations, was conducted at baseline and at the time of cystectomy. Results: Of the 29 patients treated, a pathologic complete response was observed in 13 cases (44.8%). No major safety concerns were associated with the treatment, and 26 patients (90%) underwent cystectomy. Mutational patterns, tumor mutation burden, and homologous recombination deficiency remained stable throughout treatment and were not predictive of outcomes. However, a shift toward stromal phenotypes and increased expression of epithelial–mesenchymal transition signatures were observed following therapy, particularly in resistant tumors. Moreover, an increase in circulating CD4+ CD27− CD28− T cells was noted among responders. Conclusions: The combination of neoadjuvant durvalumab and olaparib shows therapeutic activity in bladder cancer. Resistance mechanisms seem to be driven by transcriptional adaptations rather than the emergence of new mutations.
Abstract 2901: Targeting <i>miR-19b</i>/PPP2R5E regulatory axis to enhance alkylating agent efficacy: a new avenue to counteract temozolomide resistance in recurrent glioblastomas
Authors: Erik Vassella, Elham Kashani
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM), the most aggressive primary brain tumor, notorious for its inevitable recurrence despite standard of care, presents a pressing need for novel treatment paradigms. Temozolomide (TMZ), a frontline DNA alkylating agent, induces extensive DNA damage. However, TMZ response is counteracted by intricate or acquired survival mechanisms. Through functional TMZ-resistance screens using microRNAs, we uncovered a novel mechanism involving the miR-19b target, PPP2R5E, a subunit of PP2A serine-threonine phosphatase, in TMZ response. Specifically, the induced expression of PPP2R5E, resulting from miR-19b attenuation, triggers genotoxic stress, priming GBM cell lines and primary GBM cells for heightened TMZ cytotoxicity. Elevated DNA damage in PPP2R5E-overexpressing cells is attributed to increased nuclear and mitochondrial ROS production, which is accompanied by enhanced ROS-mediated senescence and ferroptosis. Of note, all these phenotypes are reversed in GBM cells with concomitant miR-19b and PPP2R5E attenuation, indicating that miR-19b exerts its role in TMZ resistance by targeting PPP2R5E. In line with this finding, our orthotopic human-derived GBM stem cell xenograft model confirmed that PPP2R5E attenuation not only decreases TMZ cytotoxicity in the brain, but also at the spinal metastatic location. Consistently, treating cells with the PP2A-activating drug FTY720 or knocking down endogenous PP2A-inhibiting proteins mirrors the effects of miR-19b attenuation in enhancing TMZ cytotoxicity. This intricate interplay between miR-19b and PPP2R5E underscores a novel strategy to modulate the TMZ response, highlighting promising results in our pre-clinical models. Intriguingly, PP2A inhibiting proteins CIP2A and ANP32A (PHAP1) are upregulated in TMZ-resistant GBM cells and recurrent GBM tumors following TMZ treatment, suggesting a role of the PPP2R5E axis in TMZ resistance. In conclusion, our findings advocate for the therapeutic targeting of the miR-19b/PPP2R5E axis as a promising strategy to overcome TMZ resistance in GBM, indicating a potential novel strategy in the pursuit of effective therapeutic interventions for the formidable recurrent GBM tumors. Citation Format: Erik Vassella, Elham Kashani. Targeting miR-19b/PPP2R5E regulatory axis to enhance alkylating agent efficacy: a new avenue to counteract temozolomide resistance in recurrent glioblastomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2901.
Abstract 784: Cardiovascular disease mortality surpasses cancer mortality in patients with renal cell carcinoma: A U.S. population-based cohort study
Authors: Zhengyi Deng, Minji Jung, Jinhui Li, Mingyi Li, Marvin E. Langston, Benjamin I. Chung
Journal: Cancer Research (2025)

Abstract Background: Cardiovascular disease (CVD) is the leading cause of non-cancer death among patients diagnosed with renal cell cancer (RCC). There is limited evidence on how CVD and RCC death rates change over time since RCC diagnosis, and evidence on potential risk factors associated with short-term and long-term CVD and RCC deaths. Methods: This population-based cohort study used data from the Surveillance, Epidemiology, and End Results Program (SEER, 2004-2020). We included adult patients (aged ≥18 years) diagnosed with a first malignant RCC from 2004 to 2019, who survived at least one year since their cancer diagnosis. Poisson regression with natural cubic spline was used to model the trends in RCC and CVD death rates over a 16-year follow-up period and to determine the crossover time where the two curves intersected. Fine and Gray competing risk models were implemented to evaluate time-dependent associations of sociodemographic and clinical characteristics with CVD and RCC deaths at 1, 5, 10, and 16 years of follow-up. Results: Among 116, 836 RCC patients, CVD death rate overtook RCC death rate at 13.7 (95% confidence interval: 12.0-15.4) years after cancer diagnosis. The crossover time occurred earlier in patients who were ≥75 years, female, unmarried, Non-Hispanic Black, or had a RCC of stage I, tumor size ≤7 cm, grade I, or chromophobe histology, compared to others (crossover time ranged from 3.0 to 9.0 years). In contrast, CVD death rate did not exceed RCC death rate in patients with a RCC of stage III/IV, tumor size &amp;gt;7cm, or those receiving chemotherapy/radiotherapy during the study period. Age, sex, and papillary histology were time-dependently associated with RCC deaths, and stage and grade were time-dependently associated with CVD deaths. Conclusion: In RCC patients, CVD death became dominant over RCC death during survivorship, with patterns varying according to different sociodemographic and clinical characteristics. These findings underscore the need for integrated management strategies addressing both cancer and CVD in RCC patients. Citation Format: Zhengyi Deng, Minji Jung, Jinhui Li, Mingyi Li, Marvin E. Langston, Benjamin I. Chung. Cardiovascular disease mortality surpasses cancer mortality in patients with renal cell carcinoma: A U.S. population-based cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 784.
Abstract 836: A phase Ib/II study of PARPi Mefuparib Hydrochloride (CVL218) in combination with PD-1 inhibitor plus chemotherapy in metastatic or recurrent triple-negative breast cancer (TNBC)
Authors: Jian Zhang, Rujiao Liu, Steve Shen
Journal: Cancer Research (2025)

Abstract Background: BRCA 1 and /or BRAC 2 mutation accounts for about 15% of all TNBC and remains poor outcomes. Mefuparib hydrochloride (CVL218) is a second generation in PARPi with low hematological toxicity and high ability to cross the blood-brain barrier. This study is to explore efficacy and safety of CVL218 combined with PD-1antibody and paclitaxel nanoparticle albumin-bound in patients with TNBC who have failed previous first-line treatment. Methods: This open- labeled, phase Ib/II clinical study NCT06078670 explores efficacy and safety of three drugs combination . 500mg BID CVL218 was administered orally in combination with toripalimab 240 mg on Day 1 of every 21-day cycle and paclitaxel nanoparticle albumin-bound 125 mg/m2 on Day 1 of every 21-day cycle. Patients in cohort A were advanced TNBC with either CPS ≥ 1 or HRD gene pathogenic variants. Results: From July 2023 to 15 July 2024 data, 6 subjects were enrolled in Phase Ib and 5 subjects were enrolled in Phase II. In phase Ib, The RP2D of CVL218 was identified as 500 mg BID. The preliminary efficacy was perfomed every 6 weeks in the first half a year and then once every 12 weeks thereafter in both phase Ib and II by RECISTv 1.1. Among 11 patients, ORR was 72.7% (8 PR, 2 SD), and DCR (Disease Control Rate) was 90.9%. The most common Grade 3 or higher treatment-related AEs (TRAEs) were hepatic function injury (2.6%), adynamia (1.8%), creatinine increased (0.8%), neutrophils decreased (0.8%), white blood cell decreased (0.8%), exanthema (0.8%), and peripheral sensory nerve disorder (0.8%), No Grade 5 TRAE. A total of 9 treatment-related SAEs in 6 patients (54.5%) were observed, including 2 aspartate aminotransferase increased, 2 alanine aminotransferase increased, 1 creatinine increased, 1 liver function injury, 1 adynamia, 1 neutrophils decreased, 1 fever, and 1 ventricular premature beats. All these SAEs recovered after symptomatic treatment. Conclusion: CVL218 combined with PD-1 antibody and chemotherapy appears to be well tolerated and has good preliminary efficacy in TNBC patients. Citation Format: Jian Zhang, Rujiao Liu, Steve Shen. A phase Ib/II study of PARPi Mefuparib Hydrochloride (CVL218) in combination with PD-1 inhibitor plus chemotherapy in metastatic or recurrent triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 836.
Abstract 1972: Utilization of flow cytometry for the characterization of mesenchymal and embryonic properties of circulating tumor cells
Authors: Tamás Ricárd Linkner, Zsófia Brigitta Nagy, Nikolett Szakállas, Eszter Farkas, Fruzsina Bányai, István Takács, Béla Molnár
Journal: Cancer Research (2025)

Abstract Background: Circulating tumor cells break off from the primary cancer tissue and enter into the bloodstream, where they reach the distant parts of the body where they can form metastases. The tumor cell could lose its adhesive properties and takes on a mobile, mesenchymal phenotype and they undergo epithelial-mesenchymal transition (EMT). The detection of these circulating tumor cells carries great diagnostic potential. Their identification is based on specific cellular markers such as cytokeratin or vimentin expression, which are key molecules in EMT, or SOX9 which plays a prominent role in the development of stem cell-like properties of tumor cells and carries therapy resistance potential. Aims: The aim of our study was to develop and optimize a technique suitable for the detection of circulating tumor cells and cells undergoing epithelial-mesenchymal or embryonic transition from blood. Materials and Methods: Magnetic cell separation technique (autoMACS Pro, Miltenyi) was performed in order to deplete CD45 immune cells from blood. Additionally, flow cytometry technique was used to detect fluorescent antibody labeled circulating tumor cells. CD45-AF700, CD15-PeVio770, CK-FITC, Vimentin-APC, SOX9-PE labeled antibodies were utilized. Peripheral whole blood of colorectal carcinoma patients (CRC) were analyzed, four of the patients were classified with grade II and grade III. Data was compared to healthy controls. Results: After the depletion of CD45 positive immune cells from the blood 5CTC/100000 counted cell were characterized as cytokeratin positive cell. Moreover, 50CTC/100000 counted cell was observed as vimentin positive cells. Additionally, SOX9 positive cells (6CTC/100000) were also detected from patients. These results indicates the presence of cancer cells with mesenchymal and stem cell characteristics in the circulation of cancer patients. Conclusion: Overall, magnetic separation is suitable technique for the enrichment of circulating tumor cells from whole blood. Moreover, flow cytometry is a key method for the detection of circulating tumor cells and cancer stem cells that have undergone embryonic transformation. With the sorting of these cells we hope that we can create the base of future diagnostic analysis of cancer patients. Citation Format: Tamás Ricárd Linkner, Zsófia Brigitta Nagy, Nikolett Szakállas, Eszter Farkas, Fruzsina Bányai, István Takács, Béla Molnár. Utilization of flow cytometry for the characterization of mesenchymal and embryonic properties of circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1972.
Abstract 384: IPS-06061, a novel TPD molecular glue degrader targeting KRAS G12D
Authors: Incheol Kang, Seungoh Seo, Seong Hyeok Cho
Journal: Cancer Research (2025)

Abstract We have discovered a novel KRAS G12D-degrading Molecular Glue using IPS's cutting-edge ProGlu AI-based drug discovery platform and PPIExplorer, an IPS-Chip based Proteomics technology. ProGlu accurately predicts PPI between E3 ligase and KRAS G12D through MD simulation, enabling de novo design of MG degraders. One such degrader, namely IPS-06061, was successfully synthesized and confirmed a strong anti-tumor efficacy using a xenograft animal model. These data demonstrate that KRAS MG will be a promising new therapeutic modality for the treatment of PDA, CRC, and NSCLC. Citation Format: Incheol Kang, Seungoh Seo, Seong Hyeok Cho. IPS-06061, a novel TPD molecular glue degrader targeting KRAS G12D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 384.
Abstract 405: Discovery of GLR203101, a selective and orally bioavailable PROTAC of SMARCA2 for the treatment of SMARCA4 mutant tumors
Authors: Xiaoguang Li, Siyu Gu, Yongzheng Ding, Jing Cheng, Kanghua Wang, Weiwei Yu, Wenmin Chen, Fuming Xu
Journal: Cancer Research (2025)

Abstract The SWI/SNF (mammalian SWItch/Sucrose Non-Fermentable) helicase SMARCA4 is frequently mutated in cancer. Its inactivation results in a cellular dependence on its paralog, SMARCA2, for survival. Therefore, SMARCA2 constitutes an attractive therapeutic synthetic lethality target. However, the co-deletion of Smarca2 and Smarca4 in adult mice was lethal, highlighting the necessity for designing molecules that target SMARCA2 selectively. This objective is rather challenging due to the high homology of SMARCA2/4. Few SMARCA2 selective compounds have entered clinical trials, including PROTAC molecule PRT-3789 administered by intravenous injection in phase 2 clinical trials. Herein, we report the discovery of a selective and orally bioavailable SMARCA2 PROTAC degrader, GLR203101. Notably, our lead compound GLR203101 possesses a favorable molecular weight (&amp;lt; 650), contributing to excellent physical and chemical properties. GLR203101 exhibited robust degradation of SMARCA2 (DC50 &amp;lt; 10 nM, Dmax &amp;gt; 80%) over SMARCA4 (Dmax &amp;lt; 10%) in Hela cell line using HiBiT assay. The degradation selectivity was also validated by western blot in several SMARCA4 wild-type cell lines, including Hela, MV-4-11, LNCaP and SW1573. GLR203101 also selectively inhibited the viability of SMARCA4-deficient cancer cells with low nanomolar IC50 values, showing &amp;gt;1000-fold selectivity over SMARCA4 wild-type cell lines. In addition, GLR203101 exhibited favorable PK properties with high exposure and moderate oral bioavailability in mice and SD rats. After 24 hours of oral administration of GLR203101, a robust degradation of SMARCA2 while sparing SMARCA4 was observed in transplanted tumors in the xenograft model. GLR203101 is being evaluated as a preclinical candidate. Citation Format: Xiaoguang Li, Siyu Gu, Yongzheng Ding, Jing Cheng, Kanghua Wang, Weiwei Yu, Wenmin Chen, Fuming Xu. Discovery of GLR203101, a selective and orally bioavailable PROTAC of SMARCA2 for the treatment of SMARCA4 mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 405.
Novel Trispecific Neutralizing Antibodies With Enhanced Potency and Breadth Against Pan‐Sarbecoviruses
Authors: Rui Qiao, Yuanchen Liu, Qiyu Mao, Jiayan Li, Yinying Lu, Jialu Shi, Chen Li, Jizhen Yu, Jiami Gong, Xun Wang, Yuchen Shao, Lei Sun, Wenhong Zhang, Hongjie Yu, Hin Chu, Pengfei Wang, Xiaoyu Zhao
Journal: MedComm (2025)

ABSTRACT The ongoing emergence of new variants of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) underscores the urgent need for developing antivirals targeting both SARS‐CoV‐2 variants and related sarbecoviruses. To this end, we designed novel trispecific antibodies, Tri‐1 and Tri‐2, engineered by fusing the single‐chain variable fragments (scFvs) of a potent antibody (PW5‐570) to the Fc region of “Knob‐into‐Hole” bispecific antibodies (bsAbs) composed of two distinct broad antibodies (PW5‐5 and PW5‐535). Compared with the parental antibodies, Tri‐1 and Tri‐2 displayed enhanced binding affinities to the receptor‐binding domains of SARS‐CoV, SARS‐CoV‐2 wild type, and Omicron XBB.1.16, with each arm contributed to the overall enhancement. Furthermore, pseudovirus neutralization assays revealed that Tri‐1 and Tri‐2 effectively neutralized all tested SARS‐CoV, SARS‐CoV‐2 variants, and related sarbecoviruses (Pangolin‐GD, RaTG13, WIV1, and SHC014), demonstrating potency and breadth superior to any single parental antibody. Consistently, Tri‐1 and Tri‐2 were found to effectively neutralize authentic SARS‐CoV and SARS‐CoV‐2 variants with IC 50 values comparable to or better than those of parental antibodies. Taken together, this study highlights the potential effectiveness of Tri‐1 and Tri‐2 as novel formats for harnessing cross‐neutralizing antibodies in the development of multivalent agents to combat both current and future SARS‐like coronaviruses.
Alopecia Areata: Pathogenesis, Diagnosis, and Therapies
Authors: Tianyou Ma, Tingrui Zhang, Fengze Miao, Jun Liu, Quangang Zhu, Zhongjian Chen, Zongguang Tai, Zhigao He
Journal: MedComm (2025)

ABSTRACT Alopecia areata (AA) is a complex, chronic inflammatory skin disorder characterized by unpredictable, nonscarring hair loss, affecting millions worldwide. Its pathogenesis remains poorly understood, driven by intricate interactions among immune dysregulation, genetic predisposition, and environmental triggers. Despite significant advances in identifying these contributing factors, substantial gaps persist in our understanding of the full spectrum of AA's molecular mechanisms and in the development of effective therapeutic approaches. This review aims to comprehensively explore the immunological, genetic, epigenetic, and environmental factors underlying AA, with a focus on immune‐mediated mechanisms. We also evaluate diagnostic approaches and recent advancements in assessing disease severity. Furthermore, the review discusses evolving therapeutic options, including traditional therapies, biologics, small‐molecule agents, and emerging treatments. The academic value of this work lies in its synthesis of current knowledge on the multifaceted nature of AA, providing insights for future research and clinical practice. By elucidating the interconnected factors underlying AA, this review seeks to advance both understanding and management of this prevalent, clinically challenging disorder.
Supportive periodontal care during active orthodontic therapy in patients with history of stage <scp>IV</scp> periodontitis: A narrative review
Authors: Alexandra Stähli, Anastasiya Orishko, Jean‐Claude Imber, Andrea Roccuzzo, Anton Sculean, Dimitrios Kloukos, Giovanni E. Salvi
Journal: Periodontology 2000 (2025)

Abstract The present narrative review aims to summarize the existing literature on recommendations for supportive periodontal care (SPC) in patients undergoing combined periodontal–orthodontic treatment. It outlines a comprehensive step‐4 treatment sequence in patients diagnosed with stage IV periodontitis and concurrent orthodontic problems. The delivery of SPC characterizes step 4 of the comprehensive treatment sequence, focusing on the prevention of bacterial re‐infection and the recurrence of the disease. Step 4 includes repeated assessments of residual probing pocket depths (PPD) greater than 5 mm, bleeding on probing (BoP) and/or suppuration around teeth and implants, as well as evaluation of furcation involvement. Extensive evidence indicates the efficacy of rigorous self‐performed plaque control and adherence to regular SPC following active periodontal therapy as vital for managing caries and periodontitis, thereby reducing possible tooth loss. Current evidence indicates that patients with stage IV periodontal disease can safely proceed with orthodontic treatment following active periodontal therapy. Nonetheless, it is the authors' recommendation for patients undergoing periodontal‐orthodontic treatment to participate in an SPC program scheduled every 3–4 months.