tbuckley/cabot-search huggingface dataset:
Abstract 6843: MegaScreen, a useful platform for ADC drug evaluation
Authors: Guoqian Wang, Yao Tang, Jingxiao Xu, Tingduo Lv, Jinying Ning, Feng Hao
Journal: Cancer Research (2025)

Abstract Since the approval of the first antibody-drug conjugate (ADC) , Mylotarg, in 2000, there are now 15 approved ADCs on the market, with over 210 in clinical trials. The development of ADC drugs has entered a flourishing stage, particularly showing significant efficacy and good safety in targets such as HER2, EGFR, Trop2, CLDN18.2, and Nectin-4. The application prospects of ADC therapy in cancer treatment are very broad. ADCs are drugs composed of three parts: a monoclonal antibody, a linker, and a toxin. Among these, the ADC toxin, also known as the ADC payload, is a crucial component of ADC drugs. The toxin is the key to determining the potency of the ADC drug. The payloads of approved ADC drugs are highly toxic, primarily including MMAE/MMAF, calicheamicin, DM1/DM4, SN38/Dxd, etc. These payloads are 1-2 orders of magnitude more toxic than chemotherapy drugs, with some even reaching pM levels. The mechanisms of action of the payloads currently under development mainly include DNA alkylating agents, DNA topoisomerase inhibitors, microtubule disruptors, and RNApolII inhibitors. We have established a substantial cell bank, containing over 800 human tumor cell lines and 100 animal tumor cell lines, covering all types of cancers. Based on this rich cell bank, we are building an Megascreen platform. Through extensive testing, we obtain efficacy data for different ADC payloads across various cell lines, guiding us in selecting suitable cell lines for in vitro evaluation of ADCs. To date, we have tested more than 200 commonly used cell lines particularly breast cancer cell lines. with several ADC palyloads, such as MMAE, SN38, Dxd, exatecan. Our plan is to complete testing of all cells within a year. This Megascreen platform is a large-scale project that will significantly contribute to the screening and evaluation of ADCs. Citation Format: Guoqian Wang, Yao Tang, Jingxiao Xu, Tingduo Lv, Jinying Ning, Feng Hao. MegaScreen, a useful platform for ADC drug evaluation [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 6843.
Abstract 4772: AI-guided engineering and preclinical development of biparatopic anti-DLL3 antibody-drug conjugates (ADCs)
Authors: Chuan Chen, Yue Wu, Liang Tian, Chenpeng Su, Zhaohui Chen, Jiyuan Tian, Dandan Liu, Yang He, None Xiaoqian chen, Yongxin Shang, Jian Peng, Zhenping Zhu
Journal: Cancer Research (2025)

Abstract Delta-like ligand 3 (DLL3) is often overexpressed in small cell lung cancer (SCLC) and several other neuroendocrine tumors, with no or very low expression in normal issues. An anti-DLL3 x CD3 bispecific T-cell engager, tarlatamab, has demonstrated significant clinical benefits and was recently approved by the US FDA for the treatment of DLL3-expressing SCLC. On the other hand, Rova-T, the first antibody-drug conjugate (ADC) targeting DLL3 entered advanced clinical development, failed in phase III studies due to insufficient efficacy and an unfavorable safety profile. In this study, via AI-guided engineering and optimization, we produced a novel biparatopic anti-DLL3 antibody and generated a number of ADCs utilizing various linkers and cytotoxic payloads. The ADCs demonstrated efficient DLL3-mediated cell binding and rapid internalization at a much higher efficiency than the mono-epitope targeting ADCs. The ADCs showed selective cytotoxicity towards multiple tumor cell lines with varying levels of DLL3 expression in vitro, and potently inhibited the growth of several DLL3-expressing tumor xenografts in animal models. Taken together, our findings underscore the significance of AI-guided antibody engineering and optimization, and provide support for the further development of the biparatopic anti-DLL3 ADCs in patients with DLL3-expressing tumors such as SCLC and other neuroendocrine tumors. Citation Format: Chuan Chen, Yue Wu, Liang Tian, Chenpeng Su, Zhaohui Chen, Jiyuan Tian, Dandan Liu, Yang He, Xiaoqian chen, Yongxin Shang, Jian Peng, Zhenping Zhu. AI-guided engineering and preclinical development of biparatopic anti-DLL3 antibody-drug conjugates (ADCs) [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 4772.
Abstract 4520: Assessing treatment strategies in high-risk metastatic nephroblastoma: A trinetx-based comparison of chemotherapy with surgery vs. primary nephrectomy
Authors: Zayan Musa, Javier Prieto, Fatemeh Adabifirouzjaei
Journal: Cancer Research (2025)

Abstract Introduction: Wilms Tumor, or nephroblastoma, is the most prevalent kidney cancer in pediatric populations. With a survival probability nearing 90%, the disease carries a 15% risk of recurrence. Wilms Tumor has a developmental origin, frequently involving mutations in genes such as WT1, WTX, CTNNB1, and TP53, which correlate with a poorer prognosis. The tumor can present unilaterally or bilaterally, often due to excess metanephric tissue cultures. Despite favorable survival rates, the potential for recurrence and malignancy calls for continuous evaluation of treatment strategies. Methods: A retrospective analysis was conducted on patients aged 0-18 diagnosed with Wilms Tumor and treated either by chemotherapy followed by surgery (Cohort 1) or surgery alone (Cohort 2). Cohort 1 included 289 patients who underwent chemotherapy prior to nephrectomy, while Cohort 2 consisted of 84 patients who received only a partial or full nephrectomy. Outcomes were compared over a 10-year follow-up period, focusing on secondary malignancies and survival rates. Results: Over the 10-year follow-up, Cohort 2 (surgery-only) demonstrated a significantly higher survival probability compared to Cohort 1 (chemotherapy plus surgery). The risk of a secondary malignancy was 97.23% in Cohort 1, compared to 73.8% in Cohort 2, indicating a 12.4% increase in malignancy risk with the addition of chemotherapy (p &amp;lt; 0.0001). This data suggests that chemotherapy prior to surgery may not be the safest option in terms of long-term outcomes for nephroblastoma patients. Conclusion: Current nephroblastoma treatment involves chemotherapy followed by surgical resection. Our study suggests that surgery alone may provide better outcomes, reducing the risk of secondary malignancies by 12.4% and significantly improving long-term survival. While surgical excision alone may not be feasible in all cases, it warrants consideration as an individualized treatment option. Further research should investigate nephrectomy-only treatment as a potentially safer and more effective alternative for pediatric Wilms Tumor patients. Citation Format: Zayan Musa, Javier Prieto, Fatemeh Adabifirouzjaei. Assessing treatment strategies in high-risk metastatic nephroblastoma: A trinetx-based comparison of chemotherapy with surgery vs. primary nephrectomy [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 4520.
Abstract 6841: Improved Ba/F3 kinase engineered cell lines: an innovative in vivo screening platform
Authors: Hao Huang, Yunpeng Zhai, Xuyang Duan, Na Li, Siyu Li, Guoqian Wang, Jinying Ning, Feng Hao
Journal: Cancer Research (2025)

Abstract Background: Ba/F3 engineered cells commonly cause tumor metastasis when implanted into immune-deficient mice, resulting in reduced survival time and narrower dosing windows. To overcome this limitation, we have developed a novel approach that modifies these cells without compromising target pathway activation while significantly reducing their metastatic potential. This modification extends both the survival duration and the therapeutic window available for treatment interventions. Methods: We utilized two distinct cell lines, KC-2400 Ba/F3-TPR-Met-D1228A and KC-4183-Ba/F3-plus-TPR-MET-D1228A respectively. Both cell types were implanted subcutaneously (SC) into NOD SCID female mice. Key parameters such as time to staging at 100 mm^3, time to reach 1000 mm^3, time to first death, dosing window duration, and average tumor volume (ATV) at the point of first death were meticulously recorded and compared between the two groups. Results: The modified cell line demonstrated a slower progression rate, taking 28 days to reach 1000 mm^3 compared to 18 days for the unmodified group. Survival time increased by 11 days, from 24 days to 35 days, while the therapeutic dosing window expanded from 14 days to 25 days. Futhermore, the ATV at the time of first death was reduced from approximately 1700 mm^3 to around 1300 mm^3, reflecting better tumor growth control. Conclusion: Engineering Ba/F3 cells to diminish their metastatic capability effectively prolongs survival and broadens the therapeutic window in immune-deficient mouse models. This strategy offers a promising enhancement for preclinical research and holds potential for improving therapeutic outcomes in related clinical applications. Citation Format: Hao Huang, Yunpeng Zhai, Xuyang Duan, Na Li, Siyu Li, Guoqian Wang, Jinying Ning, Feng Hao. Improved Ba/F3 kinase engineered cell lines: an innovative in vivo screening 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 6841.
Abstract 5902: Quantification of the effect of early-stage cancer on cell-free DNA levels in plasma
Authors: Konstantinos Mamis, Ivana Bozic
Journal: Cancer Research (2025)

Abstract Elevated cell-free DNA (cfDNA) levels are often observed in cancer patients. However, the exact effect of cancer on cfDNA concentration is not fully understood. In order to obtain insight into cfDNA dynamics in the presence of early-stage cancer, we analyze a rich, previously published dataset of cfDNA in healthy individuals and patients with stage I-III lung, breast, colorectal, pancreatic, ovarian, esophageal, stomach and liver cancer. We find that, despite the high variance of cfDNA levels among both healthy individuals and cancer patients, early-stage cancer exhibits a systemic effect resulting in a multiplicative, cancer-type specific increase in cfDNA concentration originating from healthy tissue. For each cancer type, we also observe similar multiplicative increases in the concentration of mutant DNA fragments detected in plasma that do not originate from tumor, providing additional validation that increased cfDNA levels in early-stage cancer originate from healthy tissue and not from the tumor. The magnitude of the multiplicative increase in cfDNA differs greatly between the cancer types considered, ranging from a ∼1.3-fold increase in lung cancer, to a ∼12-fold increase in patients with liver cancer. To determine the mechanism responsible for the increase in cfDNA levels, we employ an additional dataset that reports the cfDNA composition regarding its tissue of origin, in healthy individuals and patients with pancreatic and ovarian cancer. We find that elevated cfDNA levels in cancer patients do not originate from a proportional increase in cfDNA shedding, but from impaired clearance of cfDNA. The impaired cfDNA clearance could stem either from a direct decrease in cfDNA clearance rate in the presence of cancer, or can be due to a saturation effect in the cfDNA clearance mechanism, triggered by smaller increases in cfDNA shedding due to cancer. Our results contribute to the development of quantitative understanding of cfDNA dynamics in the presence of cancer. Citation Format: Konstantinos Mamis, Ivana Bozic. Quantification of the effect of early-stage cancer on cell-free DNA levels in plasma [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 5902.
Abstract 5385: Concurrent inhibition of the serine/threonine protein kinase AURKB and the fatty acid oxidation enzyme CPT1A demonstrates synthetic lethality in preclinical glioblastoma models
Authors: Qiuqiang Gao, Chang Shu, Jeongyeon Mun, Zhe Zhu, Hasan O. Akman, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin
Journal: Cancer Research (2025)

Abstract Glioblastoma IDH-wild type, an aggressive and treatment-resistant brain cancer, urgently requires novel and more effective therapeutic approaches to enhance patient outcomes. Analysis of public genomic databases has revealed that the serine/threonine protein kinase Aurora kinase B may represent a promising therapeutic target for GBM. This study provided compelling evidence that AURKB is significantly upregulated in GBM tumors, and elevated AURKB levels are associated with poorer survival in GBM patients. Remarkably, the selective AURKB inhibitor barasertib was found to potently suppress the growth of established GBM cell lines, patient-derived xenograft models, and neurosphere cultures at low, nanomolar concentrations. Similarly, genetic depletion of AURKB substantially impaired the growth of patient-derived xenograft lines. Notably, in an orthotopic PDX GBM xenograft model, the loss of AURKB function was found to extend animal survival. Mechanistically, the study revealed that AURKB depletion or inhibition significantly impacts mitochondrial energy metabolism in GBM cells. Paradoxically, the loss of AURKB led to increased cellular respiration and oxidative phosphorylation, facilitated by enhanced fatty acid oxidation. Consistently, the absence of AURKB sensitized GBM cells to the cytotoxic effects of CPT1A inhibition, i.e., fatty acid oxidation inhibition. Furthermore, the BH3-mimetic ABT263 was found to reduce the growth of GBM lines in the context of AURKB loss of function, likely due to the heightened dependence on mitochondrial metabolism. These findings uncover a previously unappreciated role for AURKB in regulating GBM metabolism and provide a strong rationale for further developing AURKB-targeted therapies, potentially in combination with metabolic inhibitors and BH3-mimetics, to improve clinical outcomes for patients with GBM. Citation Format: Qiuqiang Gao, Chang Shu, Jeongyeon Mun, Zhe Zhu, Hasan O. Akman, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin. Concurrent inhibition of the serine/threonine protein kinase AURKB and the fatty acid oxidation enzyme CPT1A demonstrates synthetic lethality in preclinical glioblastoma models [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 5385.
Abstract 5959: Outcomes of small HER2+ breast cancers including those with micro-metastatic lymph node involvement (SOLEMN HER2)
Authors: Uttamjot Kaur, Jacob M. Liberman, Ajay Dhakal
Journal: Cancer Research (2025)

Abstract Background: HER2-positive breast cancer (HER2+BC) accounts for 15-20% of early-stage breast cancers and is treated based on tumor size and Stage. For locally advanced HER2+BC [Stage (AJCC 8th ed, Anatomic) II, III], patients typically receive 2-3 chemotherapy drugs plus two HER2-targeted monoclonal antibodies (HER2-MABs): trastuzumab (T) and pertuzumab (P) before surgery. Stage I cancers are treated differently. Stage IA tumors( ≤2 cm, no lymph node involvement) usually receive one chemotherapy [paclitaxel (Tax)] plus T after surgery. However, it's unclear if chemotherapy is needed for a subset with very small tumors [T1a (≤5 mm), T1b (&amp;gt;5 - ≤10 mm)]. Stage IB cancers (≤2 cm tumor with micrometastases in axillary lymph node) may require more aggressive treatment. This study aims to describe various demographic, clinical, pathological characteristics, perioperative treatments, outcomes, including overall survival (OS) and invasive disease-free survival (IDFS) for patients with Stage IB (Cohort A) and very small (T1a/b) Stage IA (Cohort B) HER2+BC. Methods: This is a single institution retrospective study conducted at URMC with IRB approval. It uses electronic medical records for data collection. Patients diagnosed with Stage IB or very small (T1a/b) Stage IA HER2+BC between January 2010 - June 2024 were included in the study. Patients who had received systemic therapy before surgery were excluded. Results: Results from Cohort A are submitted in this abstract. Among seven patients included in the study, 43% had a pathological stage pT1a, 14% were pT1b and 43% were pT1c. Four patients received Tax+ T, one patient received Tax+T+P, one received two chemotherapies+T, and one received two chemotherapies+ T+P. There were no recurrence or death after a median follow-up of four years. Investigation into Stage IA cases (n= 91) is ongoing. Conclusions: This small retrospective study suggests an excellent clinical outcome for Stage IB HER2+ breast cancer patients. A larger study is needed to validate this finding. Citation Format: Uttamjot Kaur, Jacob M. Liberman, Ajay Dhakal. Outcomes of small HER2+ breast cancers including those with micro-metastatic lymph node involvement (SOLEMN HER2) [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 5959.
Glucose and insulin actions after glucose loading on myocardial glucose metabolism in pulmonary hypertension
Authors: Yuki Koga, Nobuhiro Tahara, Yoichi Sugiyama, Shoko Maeda-Ogata, Atsuko Tahara, Munehisa Bekki, Akihiro Honda, Sachiyo Igata, Shuichi Tanoue, Yoshihiro Fukumoto
Journal:  (2025)
Abstract 2755: The m6A epitranscriptomic landscape of bladder cancer is characterized by sequential 3'UTR hypermethylation and global methylation dilution
Authors: Jonas Koch, Felix Bormann, Vitor Coutinho Carneiro, Manuel Neuberger, Katja Nitschke, Malin Nientiedt, Philipp Erben, Maurice S. Michel, Frank Lyko
Journal: Cancer Research (2025)

Abstract N6-Methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNAs and affects the regulation of its target transcripts in all aspects of the mRNA life cycle. Cancer-associated changes in the m6A epitranscriptomic landscape as well as the deregulation of m6A regulators have been linked to cancer development. However, most studies have focused on in vitro or in vivo models and antibody-dependent mapping techniques, which have limited resolution and lack quantitative methylation information. Here, we provide the first transcriptome-wide, base-resolution map of m6A in cancer and determine methylation levels with absolute stoichiometric information by comparative sequencing of nine urothelial carcinoma of the bladder (UCB) and nine non-malignant uroepithelial control samples. Our results define key signatures of the cancer-associated m6A epitranscriptomic landscape of UCB, which was characterized by differential methylation of cancer-related mRNAs. m6A hypermethylation primarily occurred near stop codons and was associated with upregulation of the VIRMA subunit of the m6A methyltransferase complex, and alternative polyadenylation. Furthermore, the integration of methylation data and expression data revealed a global dilution of methylation marks in UCB, which was caused by the decreased expression of highly methylated transcripts, combined with the increased expression of unmethylated transcripts. Notably, both changes appeared sequentially during the progression to muscle-invasive bladder cancer. Our study thus characterizes the systematic differences in the m6A methylome of UCB and establishes the potential of m6A profiling for cancer biomarker development. Citation Format: Jonas Koch, Felix Bormann, Vitor Coutinho Carneiro, Manuel Neuberger, Katja Nitschke, Malin Nientiedt, Philipp Erben, Maurice S. Michel, Frank Lyko. The m6A epitranscriptomic landscape of bladder cancer is characterized by sequential 3'UTR hypermethylation and global methylation dilution [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 2755.
Abstract 4159: Investigating the role of Akt isoforms in hepatocellular carcinoma and liver fibrosis
Authors: Manahil Ghazi, Ahmed Abd El Razek, Nissim Hay
Journal: Cancer Research (2025)

Abstract Liver fibrosis and hepatocellular carcinoma (HCC) are major global health issues, with HCC being the most common primary liver cancer and a leading cause of cancer-related death. Metabolic dysfunction-associated steatohepatitis (MASH) is an emerging risk factor for HCC. Theserine/threonine protein kinase Akt plays a central role in cell survival, growth, and metabolism, and its hyperactivation via the PI3K/Akt pathway is implicated in many cancers. Mammalian cells express three Akt isoforms, but the effects of isoform-specific Akt inhibition remain poorly understood. We previously showed that global deletion of Akt2 along with hepatic deletion of Akt1 surprisingly leads to early onset of spontaneous HCC. The current study investigates the mechanisms underlying spontaneous HCC in these mouse models and examines the roles of Akt1 and Akt2 in MASH-induced liver fibrosis and HCC. Two mouse strains were generated: Akt2-/-; Akt1hep-/- and Akt1-/-; Akt2hep-/-. Akt2-/- mice survived hepatic Akt1 deletion, but all developed early onset HCC with elevated insulin and glucose levels, increased lipid droplet accumulation, and CD36 expression. In contrast, Akt1-/- mice survived hepatic Akt2 deletion without tumor development and had normal glucose levels. These findings suggest that HCC development in Akt2-/-; Akt1hep-/- mice occurs despite the loss of Akt activity, likely due to compensatory mechanisms or alternative pathways in hepatocarcinogenesis. Given the high insulin and glucose levels in Akt2-/-; Akt1hep-/- mice, we hypothesize that reducing insulin levels may prevent HCC. Additionally, we are examining whether CD36 is essential for HCC development in these mice. The second part of this study explores the impact of Akt isoforms on MASH-induced liver fibrosis and HCC. We have generated five mouse groups (Akt1-/-, Akt2-/-, Akt1hep-/-, Akt2hep-/-, andAkt1hep-/-; Akt2hep-/-), and these are fed with Western diet and subject to weekly CCl4 injections for MASH induced HCC. This model will help to understand the role of Akt1 or Akt2 upon hepatic versus systemic deletion and its effect on liver fibrosis and HCC progression in the MASH-induced model. Together, these studies will provide insights into the isoform-specific roles of Akt in liver carcinogenesis and fibrosis, with implications for targeted therapies in HCC. Citation Format: Manahil Ghazi, Ahmed Abd El Razek, Nissim Hay. Investigating the role of Akt isoforms in hepatocellular carcinoma and liver fibrosis [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 4159.