tbuckley/cabot-search huggingface dataset:
Abstract 5717: Nesuparib, a dual inhibitor of PARP and tankyrase, is efficacious in preclinical gastric cancer models by regulation of HIPPO and Wnt pathway
Authors: Banyoon Cheon, Jung Young Shin, PARK Dae-In, Jun Kim, John Kim, Hyunju Cha
Journal: Cancer Research (2025)

Gastric cancer is the fifth most common cancer and it still needs to identify novel actionable targets to bring clinical benefits. Here we explored the efficacy of nesuparib, a dual inhibitor for poly-ADP-ribosyl transferase 1/2 (PARP 1/2) and tankyrase 1/2 (TNKS 1/2) in vitro and in vivo models using BRCA wild type gastric cell lines. In addition to PARP 1/2 inhibition, nesuparib selectively inhibits TNKS 1 and 2 enzymatic activities; TNKS is a member of PARP family, and poly-ribosylates target proteins that are involved in Wnt/β-catenin and Hippo signaling pathways. The poly-ribosylated proteins are subsequently ubiquitinated by E3 ligases and undergo proteasomal degradation. The inhibition of TNKS is known to attenuate cancer promoting signaling like Wnt and Hippo signaling. To evaluate the impact of nesuparib on cell growth, half maximal inhibitory concentration (IC50) of nesuparib, Olaparib, and XAV939 in clonogenicity was compared in BRCA wild type gastric cancer cells. Nesuparib is at least 28-fold more potent than Olaparib and 13-fold more potent than XAV939 among cell lines. To examine how nesuparib modulates Wnt/β-catenin and Hippo signaling through TNKS inhibition, we assessed changes in canonical Wnt/β-catenin and Hippo signaling-related molecules at protein levels. Nesuparib stabilized AXIN, reducing nonphospho β-catenin, c-myc, and cyclin D1. In addition, nesuparib stabilized AMOT proteins and increased phospho-YAP reflecting inhibition of the oncogenic YAP pathway. Given the findings that nesuparib treatment regulates Wnt and Hippo signaling in KATO III and NCI-N87 cells (BRCA wild type), we tested its efficacy as a single or with a combination of irinotecan in these cell line xenograft mouse models. Nesuparib showed superior potency than Olaparib alone in both xenograft models. The combination of nesuparib with irinotecan enhanced the anti-tumor activity compared with nesuparib single treatment. In addition, the combination of nesuparib with irinotecan showed stronger tumor growth suppression than the combination of Olaparib with irinotecan.In summary, these results suggest that nesuparib may exert anti-tumor efficacy in specific types of cancers with pro-cancerous signaling of the Wnt or Hippo pathway by the regulation of TNKS. This warrants a proof-of-concept of anti-tumor effect of nesuparib in gastric cancers and its potentials for clinical benefits. Citation Format: Banyoon Cheon, Jung Young Shin, Dae-In PARK, Jun Kim, John Kim, Hyunju Cha. Nesuparib, a dual inhibitor of PARP and tankyrase, is efficacious in preclinical gastric cancer models by regulation of HIPPO and Wnt pathway [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 5717.
Abstract 1: Androgens in glioblastoma: effect of testosterone on the maintenance of glioma stem-like cells
Authors: Juan Carlos Quintero-Gallegos, Karina Hernández-Ortega, Martha Robles-Flores, Néstor Fabián Díaz, Ignacio Camacho-Arroyo
Journal: Cancer Research (2025)

Abstract Glioblastoma is the most common and lethal primary malignant tumor of the central nervous system, with a prevalence 1.6 times more frequent in men than in women, suggesting that sex hormones such as androgens play an important role in tumor progression. Poor prognosis has been associated with the presence of cancer stem cells that in glioblastoma are known as glioma stem cells. There is evidence that patients with glioblastoma have a higher serum concentration of testosterone, as well as a higher expression of the androgen receptor. In addition, the use of androgen receptor antagonists reduces the percentage of cancer stem cells. However, the role of testosterone in regulating stemness is unknown. In this study we analyzed the role of testosterone (100 nM) in processes associated with stem cell maintenance in the human glioblastoma cell lines U251 and T98G. Analyzing the presence of the androgen receptor, a higher expression was found in stem cell-enriched suspension cultures compared to monolayer cultures. The sequences of the stemness-associated genes PROM1, SOX2 and NES presented androgen response elements in their promoter regions. Consistently, testosterone increased the expression of these genes in stem cell-enriched cultures. Additionally, the self-renewal was evaluated by neurosphere generation assays, finding that testosterone favored the generation of primary and secondary neurospheres. Taken together, these results suggest that testosterone regulates the growth of cancer stem cells present in human glioblastoma by promoting the expression of stemness-associated genes as well as their self-renewal. Citation Format: Juan Carlos Quintero-Gallegos, Karina Hernández-Ortega, Martha Robles-Flores, Néstor Fabián Díaz, Ignacio Camacho-Arroyo. Androgens in glioblastoma: effect of testosterone on the maintenance of glioma stem-like 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 1.
Abstract 5705: CHI3L1 overexpression predicts poor prognosis and drives aggressiveness in papillary thyroid cancer
Authors: Pratheesh Kumar Poyil, Abdul K. Siraj, Sandeep Kumar Parvathareddy, Khadija Alobaisi, Rafia Begum, Fouad Al-Dayel, Khawla S. Al-Kuraya
Journal: Cancer Research (2025)

Abstract Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein that is pivotal in regulating inflammation, macrophage polarization, apoptosis, and the process of carcinogenesis. While its expression is markedly increased in various cancer types, its specific role in papillary thyroid cancer (PTC) has not been fully elucidated. In our study, we assessed the expression of CHI3L1 protein in a large cohort of PTC patient samples and investigated its functional significance and underlying mechanisms in PTC cell lines. CHI3L1 over-expression was noted in 38.9% (638/1613) of PTC cases and was significantly associated with aggressive clinicopathological characteristics such as extrathyroidal extension (p &amp;lt; 0.0001), advanced T stage (p &amp;lt; 0.0001), lymph node metastasis (p &amp;lt; 0.0001), distant metastasis (p = 0.0003), stage IV tumors (p = 0.0007) and tumor recurrence (p &amp;lt; 0.0001). Interestingly, a significant association was also noted between CHI3L1 over-expression and phosphor-AKT (P = 0.0007) as well as PD-L1 (P &amp;lt; 0.0001). In addition, CHI3L1 was associated with shorter recurrence-free survival (p = 0.0004). Our in vitro studies revealed that inhibition of CHI3L1 reduced cell proliferation and triggered apoptosis in PTC cell lines. Notably, the downregulation of PLK1 impaired the self-renewal capacity of spheroids derived from PTC cells, indicating its role in maintaining cancer stem-like properties. Furthermore, CHI3L1 knockdown resulted in decreased expression of phosphorylated AKT and PD-L1, while its overexpression led to an upregulation of both. These findings underscore the role of CHI3L1 in PTC prognosis and promoting its progression. This study also identifies CHI3L1 as a promising therapeutic target, offering a novel strategy for managing aggressive and treatment-resistant forms of PTC. Citation Format: Pratheesh Kumar Poyil, Abdul K. Siraj, Sandeep Kumar Parvathareddy, Khadija Alobaisi, Rafia Begum, Fouad Al-Dayel, Khawla S. Al-Kuraya. CHI3L1 overexpression predicts poor prognosis and drives aggressiveness in papillary thyroid cancer [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 5705.
Abstract 5692: Distinct effectors of FSTL1 promote melanoma growth and angiogenesis and FSTL1 blockade mitigates resistance to BRAF and MEK inhibitors
Authors: Umar Patel, Jiaying Ng, Chiu Wang Chau, Alex To, Ryohichi Sugimura, Martin Cheung
Journal: Cancer Research (2025)

Melanoma is a highly lethal form of skin cancer due to its propensity for metastasis through angiogenesis, which confers melanoma initiating cells with resistance to BRAF and MEK inhibitors. However, current drugs for targeting angiogenesis have shown limited efficacy, highlighting the need to develop new anti-angiogenic therapies to effectively combat this devasting malignancy. Here, we found that Follistatin-like 1 (FSTL1) expression is significantly increased in metastatic melanoma, and correlates with higher microvessel density, and poor prognosis. FSTL1 is both required and sufficient for the growth, metastasis, and angiogenesis of melanoma. FSTL1 functions downstream of SOX10-DLC1-FOXK1 to mediate its oncogenic activity, which can be inhibited by FSTL1 neutralizing antibody (FSTL1 nAb). Mechanistically, intracellular FSTL1 promotes G1/S transition in proliferative melanoma cells by activating an AKT/Lamin B2 axis. Secreted FSTL1 activates endothelial expression of TMSB4X to induce nuclear NF-kB-dependent regulation of angiogenesis. Furthermore, FSTL1 expression is selectively upregulated in melanoma-initiating cells that are resistant to BRAF and MEK inhibitors, driving stemness through interactions with the tumor microvasculature. Treatment with FSTL1 nAb depletes melanoma-initiating cells and slows down drug resistance development, suggesting that FSTL1 nAb may be a promising adjunct therapy to BRAF and MEK inhibitors for melanoma treatment. Citation Format: Umar Patel, Jiaying Ng, Chiu Wang Chau, Alex To, Ryohichi Sugimura, Martin Cheung. Distinct effectors of FSTL1 promote melanoma growth and angiogenesis and FSTL1 blockade mitigates resistance to BRAF and MEK inhibitors [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 5692.
Abstract 6019: AI-guided development of CAR-T drugs
Authors: Chao Cheng, Yanjun Ge, Ermin Xie, Huajing Wang, Xiaowen He, Haiyan Zhu
Journal: Cancer Research (2025)

Abstract Background: Chimeric Antigen Receptor T-Cell (CAR-T) therapy is an innovative cancer treatment that involves genetically engineering a patient’s T-cells to recognize and attack cancer cells.Artificial Intelligence (AI) is playing an increasingly important role in drug development, accelerating drug discovery, optimizing treatment protocols, and enhancing efficacy.Building on the in-depth research of Nobel laureates Demis Hassabis and John Jumper in structural prediction, AI technology has been combined with antibody library techniques. Under the guidance of AI, antibodies targeting the second epitope of FOLR1 were successfully identified from hundreds of candidates. Methods: In this study, we performed phage display panning for FOLR1, a tumor target, followed by monoclonal identification and sequencing. This resulted in a large number of antibodies targeting the same epitope. Due to the structural characteristics of FOLR1, most antibodies bind to its folate binding site. To obtain antibodies targeting different epitopes and enhance therapeutic efficacy, we combined AI-guided selection with antibody library screening. We conducted NGS sequencing of the antibody library and utilized AI for extensive modeling analysis. Results: Through next-generation sequencing (NGS) of the antibody library, we obtained a large number of sequences distinct from those obtained through monoclonal sequencing. We modeled and docked these antibodies to predict their targeted epitopes. After analyzing over 300 antibodies with the highest binding potential, we identified one antibody that targets a different epitope. This antibody demonstrated significant binding efficacy and does not compete with our previously identified candidate antibodies. Conclusions: By integrating AI technology with our antibody library, we successfully identified a second epitope-targeting antibody against FOLR1. This antibody exhibits properties comparable to those obtained through wet lab experiments. As AI technology continues to advance, its role in antibody development will become increasingly significant, transitioning from AI-assisted drug development to AI-guided drug development. Finally, we extend our heartfelt gratitude to Demis Hassabis and John Jumper for their contributions to AI research. Without their foundational work, it would have been very difficult for us to achieve these results. Citation Format: Chao Cheng, Yanjun Ge, Ermin Xie, Huajing Wang, Xiaowen He, Haiyan Zhu. AI-guided development of CAR-T drugs [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 6019.
Abstract 5720: Novel selective FEN1 nuclease inhibitor shows synergy with PARP-targeting drugs
Authors: Jason Munguia, Sanjay Agarwalla, Dave Martin, Junhua Fan, Dave Lonergan, Celeste Giansanti, David Cortez, David Puerta, Zachary Zimmerman, Konstantin Taganov
Journal: Cancer Research (2025)

Abstract Tumors with homologous recombination defects (HRD) due to mutations in BRCA1/2 genes or other genes associated with HR repair are typically sensitive to poly(ADP-ribose) Polymerase 1/2 inhibitors (PARPi), platinum-based drugs or other agents that target DNA repair pathways. Despite initial responsiveness to PARPi, many patients eventually experience disease progression. To that end, novel drug combination strategies involving PARPi plus other DNA replication and repair inhibitors have the potential to achieve more durable responses. Flap endonuclease 1 (FEN1) is a structure-specific metallonuclease that has been shown to be overexpressed in a variety of tumor types and has been reported to have many synthetic lethality partners, including PARP and BRCA2, making it an attractive target for the development of novel anticancer therapeutics. Utilizing an innovative library of metal-binding pharmacophores (MBPs) and a fragment-based drug discovery approach we identified a novel FEN1-selective chemical scaffold represented by BSM-1516 (IC50 of 7 nM and 460 nM in biochemical assays for FEN1 and EXO1, respectively; FEN1 cellular thermal shift target engagement assay EC50 of 24 nM). Examination of proteins on replication forks by iPOND-SILAC-MS in the presence of BSM-1516 revealed rapid enrichment of Okazaki fragment maturation (OFM) proteins FEN1/PCNA/LIG1, PARP1/2 enzymes, poly(ADP-ribose) binders (e.g. CHD1L) and alternative OFM pathway repair proteins XRCC1 and LIG3. Combination of BSM-1516 with inhibitors of PARP1/2 was strongly synergistic in vitro, enhanced their antiproliferative effect up to 100-fold (an effect not observed in normal fibroblasts) and led to robust activation of ssDNA break repair markers: phospho-Chk1(Ser345), phospho-RPA2(Ser33) and chromatin-bound RPA2. In vivo PK studies showed that BSM-1516 had oral bioavailability of 40% and T1/2 of 2.9 hours in mice. Safety of BSM-1516 was assessed in vitro in lineage-specific differentiation of human hematopoietic CD34+ progenitor cells and in vivo in mice at a daily dose of 120 mg/kg PO and 90 mg/kg IP for 7 days and revealed no signs of hematological toxicity. These collective data support further in vivo testing in PD and efficacy studies either as a single agent or in combination with PARPi. Citation Format: Jason Munguia, Sanjay Agarwalla, Dave Martin, Junhua Fan, Dave Lonergan, Celeste Giansanti, David Cortez, David Puerta, Zachary Zimmerman, Konstantin Taganov. Novel selective FEN1 nuclease inhibitor shows synergy with PARP-targeting drugs [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 5720.
Abstract 6241: Predicting treatment outcomes from adaptive therapy: a new mathematical biomarker
Authors: Kit Gallagher, Maximilian A. Strobl, Philip K. Maini, Alexander R. Anderson
Journal: Cancer Research (2025)

Abstract Standard-of-care cancer therapy regimens are characterized by continual treatment at the maximum tolerated dose, however, this approach often fails on metastatic cancers due to the emergence of drug resistance. An evolution-based treatment paradigm known as 'Adaptive Therapy' has been proposed to counter this, dynamically adjusting treatment to control, rather than minimize, the tumor burden, thus suppressing the growth of treatment-resistant cell populations and hence delaying patient relapse. Promising clinical results in prostate cancer indicate the potential of adaptive treatment protocols, but demonstrate broad heterogeneity in patient response. This naturally leads to the question: why does this heterogeneity occur, and is a 'one-size-fits-all' protocol best for patients across this spectrum of responses? Using a Lotka-Volterra representation of drug-sensitive and -resistant tumor populations' dynamics, we obtain a predictive expression for the expected benefit from Adaptive Therapy and show that this is effective at identifying the best responders in a clinical dataset. Incorporating techniques from Optimal Control theory, we further derive an analytic expression for the optimal treatment strategy, based on individual patient tumor dynamics. In contrast to prior approaches, this strategy also accounts for clinical limitations such as fixed time intervals between clinical appointments, to produce clinically realistic treatment strategies. We show that this strategy varies significantly between patients, and present a framework to generate individual treatment schedules from a patient's initial treatment data. Finally, we develop metrics to predict which patients have the greatest sensitivity to unplanned schedule changes, such as delayed appointments, allowing clinicians to identify high-risk patients that need to be monitored more closely and potentially more frequently. Overall, the proposed strategies offer personalized treatment schedules that consistently outperform clinical standard-of-care protocols. Citation Format: Kit Gallagher, Maximilian A. Strobl, Philip K. Maini, Alexander R. Anderson. Predicting treatment outcomes from adaptive therapy: a new mathematical biomarker [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 6241.
Abstract 6020: Quantitative measurement of Fc-mediated ADCC &amp; ADCP activity of therapeutic antibodies using a robust, universal cell-based assay platform
Authors: Alpana Prasad, Surekha Bonasu, Gaurav Agrawal, Jane E. Lamerdin
Journal: Cancer Research (2025)

Abstract The clinical success of a broad range of biologics has driven the development of diverse immunomodulatory agents with unique mechanisms of action (MOA) targeting novel antigens. Regulatory guidelines now require evaluation of antibody effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), particularly for lot-release assays that measure immune cell-mediated killing directly rather than surrogate endpoints. Additionally, antibody-dependent cellular phagocytosis (ADCP) has become a key MOA, especially for IND-enabling studies involving antibodies with modified Fc regions. To address these needs, Eurofins DiscoverX® developed the KILR® cytotoxicity assay platform that accurately measures the killing of antigen-expressing target cells in co-culture with immune effector cells. This dye-free, radioactivity-free platform leverages the validated Enzyme Fragment Complementation (EFC) technology and supports various immune-mediated killing mechanisms, including ADCC, CDC, ADCP, and T-cell redirection. Here, we showcase the KILR platform’s versatility across multiple antigens (e.g., HER2, CD20, CD19) and effector cell types. Combined with engineered KILR CD16 Effector Cells, the KILR platform provides robust, reproducible assay performance necessary for testing in the quality-controlled environment for commercial lot release. This platform also quantifies ADCP cost-effectively, simplifying traditional FACS or imaging-based workflows. To ensure assay reproducibility, many KILR target cell models are now available in an assay-ready format, with phase-appropriate qualification data supporting their suitability for potency and screening applications. Citation Format: Alpana Prasad, Surekha Bonasu, Gaurav Agrawal, Jane E. Lamerdin. Quantitative measurement of Fc-mediated ADCC &amp; ADCP activity of therapeutic antibodies using a robust, universal cell-based assay platform [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 6020.
Abstract 5702: Knockdown of COP1 disrupts lipid metabolism and reduces migration ability in hepatocellular carcinoma cells
Authors: Hun-Mo Ryoo, Eun-Hye Jeon, Keon Uk Park, Ilseon Hwang, Yun-Han Lee
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC) is one of the cancers with the highest mortality rates worldwide, being the sixth most commonly diagnosed cancer globally and the third leading cause of cancer-related deaths. COP1 gene, an E3-ubiquitin ligase, is generally overexpressed in human HCC and that plays an important role in the degradation of p53 tumor suppressor via ubiquitination. We have previously defined the COP1 gene as a therapeutic target in HCC. A recent study demonstrated that COP1 induces nonalcoholic fatty liver disease (NAFLD) in normal hepatocytes and that reducing COP1 expression in the liver significantly improves high-fat diet-induced hepatic steatosis. Thus in this study, we investigated if the function of COP1 was associated with HCC metabolism as well. siRNA-mediated inhibition of COP1 expression suppressed long-term colony formation in both Huh7 and HepG2 HCC cell lines. RNA sequencing of COP1-silenced HCC cells revealed the same directional regulation of 24 (10 down- and 14 up-regulated) genes. Notably, AKR1D1 gene, which negatively regulates bile acid biosynthesis and lipid metabolism, was up-regulated and that TMEM65 gene, which promotes migration and invasion of cancer cells, was down-regulated. Correlation analysis using publicly available databases further supported an inverse relationship between COP1 and AKR1D1 expression in HCC. Subsequent studies showed that COP1 knockdown inhibits synthesis of cellular lipids through the downregulation of GLUT4, DGAT2, FASN, and ChREBPα genes that are functionally involved in glucose transport or fatty acid synthesis. Furthermore, silencing of COP1 significantly reduced the abilities of migration and sphere formation in HCC parental cell population. Collectively, our findings indicate that the function of COP1 is associated with HCC lipid metabolism and migration. Citation Format: Hun-Mo Ryoo, Eun-Hye Jeon, Keon Uk Park, Ilseon Hwang, Yun-Han Lee. Knockdown of COP1 disrupts lipid metabolism and reduces migration ability in hepatocellular carcinoma 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 5702.