tbuckley/cabot-search huggingface dataset:
Abstract 6743: Patient-derived organoids: an <i>in vitro</i> platform for evaluating ADC efficacy, potency, and specificity
Authors: Daniele Mori, Claudia Beaurivage, Eider Valle Encinas, Yara Hendriksen, Anna Schepers, Foteini Gkogkou, Joris Maas, Ka Wai Lai, Mariana Silva, Sumeyra Mucuk, Vineeta Adegbenro, Ricardo Korporaal, Merel Derksen, Sylvia F. Boj
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) are pharmaceutical drugs that selectively deliver cytotoxic agents to cells expressing a specific target antigen (TA). Structurally, ADC consists of a highly specific monoclonal antibody linked to a cytotoxic payload. HUB patient-derived organoids (PDOs) are a unique in vitro 3D adult stem cell-based model. They closely resemble the architecture and physiology of the tissue of origin, maintaining the patient-specific genetic and phenotypic characteristics, including surface marker expression. This unique feature makes them a patient-relevant in vitro model for ADC screenings. The work presented here demonstrates the potential of the HUB PDO platform in an in vitro basket trial. Organoids derived from 7 different tissue origins were used for ADC screening, showcasing the platform's reliability and ability to assess ADC specificity, potency, and efficacy. ADCs directed to different TAs, such as Tissue Factor (F3) or trophoblast antigen 2 (TROP2), were tested, and organoid viability was assessed with CellTiter Glo® 3D after 7 days of treatment. Further parameters, such as TA expression and the percentage of the cell population expressing TA in each organoid, were evaluated by flow cytometry. The analysis of ADCs targeting F3 revealed an ADC-dependent organoid-killing correlation with F3 expression for a subset of PDOs across all different tumor tissue types. However, as observed in clinical trials, the impact of ADC on the viability of some PDOs was unrelated to F3 expression. The lack of correlation between ADC efficacy and target antigen expression was more evident for the TROP2 ADC. These findings underscore the importance of the study in understanding the differential activity between ADCs. Altogether, these results highlight the value of the PDO platform in assessing ADC target specificity and as a patient-relevant model to study the mechanism behind differential activity between ADCs such as antibody internalization dynamics or bystander effects. Citation Format: Daniele Mori, Claudia Beaurivage, Eider Valle Encinas, Yara Hendriksen, Anna Schepers, Foteini Gkogkou, Joris Maas, Ka Wai Lai, Mariana Silva, Sumeyra Mucuk, Vineeta Adegbenro, Ricardo Korporaal, Merel Derksen, Sylvia F. Boj. Patient-derived organoids: an in vitro platform for evaluating ADC efficacy, potency, and specificity [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 6743.
Abstract 1903: Actionable mutational landscape in solid tumors: a case study of ovarian and colon cancer
Authors: Amit Kumar, Samir Agarwal, Pankaj Khanna, Shobit Gupta, Rama Chandran, Ananth S. Bommakanti
Journal: Cancer Research (2025)

Abstract Background: Solid tumors are abnormal tissue masses that can be benign or malignant. They are named after the type of cells that form them, and can be categorized by where they originate such as breast, colon, bladder, ovary, and lung. Methods: Genomic profiling was done with sequencing of FFPE tumor samples 40 using Genes2Me PanCancer assay with 681 genes and the target size of 1.7 Mb on Illumina platform. Bioinformatics analysis was performed using standard GATK.v4.1.2 somatic variant calling pipeline. Mutational plots were generated using MAFtools and inhouse python script for post data analysis. Results: The number of mutant allele frequency (MAF) of the most frequently mutated genes varied significantly across tumor types, with the highest MAF observed in this cancer type. Significantly mutated cancer-related genes in solid tumors found the most frequently altered genes to be TP53(45%), KRAS(18%), TERT(14%), CDKN2A(12%), PIK3CA(11%), APC(36%), EGFR(10%), ESR1(20%), KIT(9%), AR(64%), MYC(44%), FGFR1(21%), BRCA1(22%), BRCA2(63%), CCND1(46%) in colon and ovarian carcinoma. Tumormutational burden (TMB) varied significantly across tumor types, and patients with high MAF had a significantly higher TMB score with one of the investigated platforms. Conclusion: These findings describe the similarities and differences between mutational signature of different solid tumors from cancer patients, providing valuable information for personalized medicine and also an important implication for the selection of patients for clinical trials with molecularly targeted therapies. Citation Format: Amit Kumar, Samir Agarwal, Pankaj Khanna, Shobit Gupta, Rama Chandran, Ananth S. Bommakanti. Actionable mutational landscape in solid tumors: a case study of ovarian and colon 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 1903.
Abstract 3521: A novel T cell engager targeting HLA-A02:01 TP53-R175H for cancer immunotherapy
Authors: Mark Ng, Emily Zygiel, Alexander McQuown, Jinsheng Liang, Luhua Shen, Joshua Francis, Xingyue He, Hubert Lam, Gary Shapiro, Loic Vincent
Journal: Cancer Research (2025)

Background: The tumor suppressor protein p53 (TP53) plays a pivotal role in preventing tumor formation by inducing cell cycle arrest and apoptosis in response to DNA damage. However, TP53 mutations are prevalent across various cancer types, and these mutations not only result in loss of tumor suppressive functions but also confer gain-of-function properties that drive oncogenesis. Among these mutations, HLA-A0201 TP53-R175H represents the largest TP53 population with &amp;gt;34,000 cases per year in the US and EU across all solid tumor indications, with no therapies explicitly targeting this mutation in the clinic. Leveraging Affini-T’s TETHER™ platform, we present the development of a novel TCR-based T cell engager designed to redirect the cytotoxic potential of T cells against mutant TP53-expressing cancer cells. Methods: A bispecific T cell engager was engineered to simultaneously engage T cells via CD3 and target TP53-R175H-expressing cancer cells by an affinity-matured specific TCR. Affinity maturation of the TCR was performed to increase its specificity and binding affinity towards the mutant peptide. Tumor co-culture assays were conducted to evaluate T cell-mediated cytotoxicity. T cell activation was assessed by measuring cytokine production. The tolerability profile of the engagers was established by X-scan, evaluating T cell activation by normal tissue. Results: The data demonstrate successful affinity maturation of the TCR, resulting in enhanced recognition of the HLA-A0201 TP53-R175H peptide with high specificity. Tumor co-culture assays revealed potent T cell-mediated killing of mutant TP53-R175H-expressing cancer cells by the engager, accompanied by robust T cell activation characterized by cytokine production. Importantly, the engager exhibited favorable tolerability profiles, demonstrated by minimal off-target activation via X-scan and with minimal T cell activation towards normal tissue. Conclusions: These findings highlight the promising activity and tolerability profile of a novel T cell engager targeting HLA-A02 TP53-R175H for cancer immunotherapy. Harnessing the cytotoxic potential of T cells against mutant TP53-expressing tumors presents a promising approach for the development of innovative cancer treatments. Citation Format: Mark Ng, Emily Zygiel, Alexander McQuown, Jinsheng Liang, Luhua Shen, Joshua Francis, Xingyue He, Hubert Lam, Gary Shapiro, Loic Vincent. A novel T cell engager targeting HLA-A02:01 TP53-R175H for cancer immunotherapy [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 2521.
Abstract 2155: Phage display discovery of Trop-2 peptide for targeted liposomal chemo-immunotherapy in lung cancer
Authors: Bahaa S. Mustafa, Bolni M Nagalo, Mulu Tesfay, Usran Khandoker Ferdous, Aleksandra Cios
Journal: Cancer Research (2025)

Abstract Background: Lung cancer remains a leading cause of cancer-related mortality worldwide. Targeted therapies offer a promising approach to improve treatment efficacy and reduce systemic toxicity. Trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein that is overexpressed in multiple cancers including lung cancer. Trop-2 is an ideal candidate for targeted therapy of NSCLC as it is highly expressed in NSCLC in comparison to normal cells and it is a transmembrane protein with an extracellular domain that can be targeted by therapies. Recently various Trop-2-targeted therapies have been investigated in clinical trials, including anti-Trop-2 antibodies and Trop-2-targeted antibody-drug conjugates (ADC). This study aims to discover a Trop-2 specific peptide using phage display biopanning and develop a liposomal formulation surface-modified with the identified peptide for targeted chemo-immunotherapy. Methods: A peptide phage display library was screened to identify peptides with high affinity for Trop-2 protein. The selected Trop-2 peptide was conjugated to the surface of liposomes encapsulating cisplatin and anti-PDL1 single-chain variable fragment (scFv). The targeting efficiency, cytotoxicity, and immunomodulatory effects of the Trop-2 peptide-modified liposomes were evaluated in vitro using A549 lung cancer cell lines and in vivo in Calu-3 NSCLC xenograft model. Results: The phage display biopanning successfully identified a high-affinity Trop-2 peptide. Liposomes modified with this peptide demonstrated enhanced binding and uptake by A549 lung cancer cells compared to non-targeted liposomes. In vivo, the targeted liposomal formulation exhibited superior tumor growth inhibition and prolonged survival in the Calu-3 NSCLC xenograft model. Conclusion: The discovery of a Trop-2 specific peptide via phage display and its application in targeted liposomal delivery of cisplatin and anti-PDL1 scFv represents a novel and effective strategy for lung cancer chemo-immunotherapy. This approach holds potential for improving therapeutic outcomes and minimizing adverse effects in lung cancer patients. Citation Format: Bahaa S. Mustafa, Bolni M Nagalo, Mulu Tesfay, Usran Khandoker Ferdous, Aleksandra Cios. Phage display discovery of Trop-2 peptide for targeted liposomal chemo-immunotherapy in lung 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 2155.
Abstract 6486: Prognostic impact of the immune environment in non-small cell lung cancer
Authors: Lisa Hornsteiner, Natalia Gorbokon, Jonas B Raedler, Claudia Hube-Magg, Monika Kaszubowski, Nina Schraps, Katharina Möller, Florian Viehweger, Florian Lutz, Till S Clauditz, Christoph Fraune, Eike Burandt, Ronald Simon, Guido Sauter, Martin Reck, Klaus Raabe, Maximilian Lennartz, Stefan Steurer, Elena Bady
Journal: Cancer Research (2025)

Abstract Lung cancer is the most frequent tumor related reason for death worldwide. It is hoped that a better understanding of the immune environment can foster the development of new immune checkpoint therapies to improve patient management and survival. To study the composition and prognostic impact of the immune infiltrate in non-small cell lung cancer, a tissue microarray containing 798 lung cancer patients, including 441 lung adenocarcinomas, 219 squamous cell carcinomas, was analyzed by multiplex fluorescence immunohistochemistry. A set of 14 antibodies was used to detect cytotoxic-, T-helper- and regulatory T-cells, B-cells, M2 macrophages, and dendritic cells (CD3, CD4, CD8, FOXP3, CD20, CD11c, CD163) expression of immune checkpoint molecules (TIGIT, PD-1, CTLA-4, TIM-3, PD-L1), and immune cell proliferation (Ki67) as well as panCK as an epithelial cell marker for tumor detection. Comparison with clinical data revealed significant associations between a high fraction of intratumoral CD3+ T-cells (p=0.0182), cytotoxic T-cells (p=0.0192) and dendritic cells (p=0.0080) and favorable prognosis, and between a low fraction of intratumoral CD3+T-cells (p=0.0007) and advanced tumor stage. A high Ki-67 labelling index was linked to poor prognosis (p=0.0002) and nodal positivity in all 798 lung cancer patients (p&amp;lt;0.0001), as well as in the subsets of 441 lung adenocarcinomas (p=0.0002) and 219 lung squamous cell carcinomas (p=0.0015). No prognostic relevance was found for the expression of the immune checkpoint molecules TIGIT, PD-L1, TIM-3, CTLA-4 and PD-1 on the immune cells in our series of cancers. In conclusion, a high T-cell infiltrate is linked to beneficial tumor characteristics in non-small cell lung cancers. Citation Format: Lisa Hornsteiner, Natalia Gorbokon, Jonas B Raedler, Claudia Hube-Magg, Monika Kaszubowski, Nina Schraps, Katharina Möller, Florian Viehweger, Florian Lutz, Till S Clauditz, Christoph Fraune, Eike Burandt, Ronald Simon, Guido Sauter, Martin Reck, Klaus Raabe, Maximilian Lennartz, Stefan Steurer, Elena Bady. Prognostic impact of the immune environment in non-small cell lung 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 6486.
Abstract 6747: A next generation ADC: AR153, pH-dependent anti-B7H3 MMAE
Authors: wonhwa kang
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) demonstrate significant anti-cancer efficacy, but their therapeutic index (TI) can be restricted due to toxicity in normal tissues. To address this limitation, pH-dependent antibodies have emerged as a promising solution. These antibodies exhibit weak binding to their target under physiologically neutral pH conditions but show strong binding in the acidic environment of the tumor microenvironment (TME), improving tumor selectivity and reducing off-target toxicity, thereby increasing the TI of ADCs. B7-H3, a member of the B7 family, is overexpressed in various solid tumors, making it a promising therapeutic target for ADC development. We screened a recombinant human antibody library (Ymax-ABL) and identified pH-dependent antibodies against B7-H3. We developed a pH-dependent anti-B7-H3 antibody (pH-B7-H3 Ab) that shows strong binding under acidic conditions such as TME, and reduced binding under neutral pH, as seen in healthy tissues. We generated ADCs by conjugating a pH-independent anti-B7-H3 antibody (Non-pH-B7-H3 Ab) and the pH-B7-H3 Ab with GGFG-Dxd and vc-PAB-MMAE, achieving drug-to-antibody ratios (DAR) of 3.8, 3.8, 3.5 and 3.9, respectively. Comparative studies revealed that pH-B7-H3-MMAE exhibited lower cytotoxicity than Non-pH-B7-H3-MMAE under neutral pH conditions typical of normal tissues. However, under acidic conditions (pH 6.0), both ADCs displayed comparable cytotoxicity. Additionally, in a B7-H3-expressing CDX model, ADCs demonstrated similar anti-cancer efficacy. Notably, pH-B7-H3 Ab exhibited superior penetration into tumor tissues compared to Non-pH-B7-H3 Ab, highlighting its potential to improve therapeutic outcomes by selectively targeting tumor cells while minimizing harm to normal tissues. Citation Format: wonhwa kang. A next generation ADC: AR153, pH-dependent anti-B7H3 MMAE [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 6747.
Abstract 6759: <i>In vivo</i> tumor growth control by general control nonderepressible 2 targeting agents results from kinase activation
Authors: Feven Tameire, Paulina Wojnarowicz, Crissy Dudgeon, Sho Fujisawa, Savi Ramurthy, Owen Reilly, Christopher G. Thomson, Bradley Sherborne, Simon Taylor, Fang He, Pengwei Pan, Baozhong Li, Earl May, Alan C. Rigby, Mark J. Mulvihill, Nandita Bose, David Surguladze, Eric Scott Lightcap
Journal: Cancer Research (2025)

Abstract General Control Nonderepressible 2 (GCN2; EIF2AK4) is a serine-threonine kinase in the integrated stress response (ISR) signaling pathway that initiates adaptive responses during nutrient stress conditions. While pharmacological inhibition of GCN2 under nutrient stress conditions induces apoptosis and inhibits tumor growth, GCN2 inhibition without nutrient stress has been reported to have no effect on tumor growth. By exploring an array of GCN2 inhibitors, we demonstrate that multiple agents in fact activate GCN2 in biochemical and cell-based assays at low concentrations and inhibit GCN2 at higher concentrations. Unexpectedly, it is this activation, and not inhibition, of the GCN2 pathway that is associated with decreased viability in vitro and tumor growth inhibition in vivo across multiple models. Knockdown and knockout experiments show that activation of the ISR by GCN2-targeting agents is dependent on GCN2. We also uncover that Type 1 GCN2-targeting agents do not activate GCN2 whereas non-Type 1 agents activate GCN2 in the absence of stress. We demonstrate that a Type 1 GCN2-targeting agent does not have the same viability effects as the non-Type 1 GCN2-targeting agents. These results provide a clearer understanding of the challenges and opportunities for the clinical development of compounds targeting GCN2. Citation Format: Feven Tameire, Paulina Wojnarowicz, Crissy Dudgeon, Sho Fujisawa, Savi Ramurthy, Owen Reilly, Christopher G. Thomson, Bradley Sherborne, Simon Taylor, Fang He, Pengwei Pan, Baozhong Li, Earl May, Alan C. Rigby, Mark J. Mulvihill, Nandita Bose, David Surguladze, Eric Scott Lightcap. In vivo tumor growth control by general control nonderepressible 2 targeting agents results from kinase activation [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 6759.
Abstract 6764: Lipophagy-dependent fatty acid oxidation is a metabolic vulnerability for KRAS signaling inhibition in pancreatic cancer
Authors: Junzhang Zhao, Ravi Thakur, Dezhen Wang, Tuo Hu, Chunbo He, Surendra K. Shukla, Kirsten L. Bryant, Kamiya Mehla, Channing J. Der, Pankaj K. Singh
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is frequently driven by activating mutations in KRAS, which promote tumor progression through sustained activation of the MAPK (RAS/RAF/MEK/ERK) signaling pathway. This study investigates the metabolic vulnerabilities associated with PDAC by examining the metabolic reprogramming that occurs upon KRAS signaling inhibition via targeting MEK/ERK/KRASG12D, and utilizing metabolomic, lipidomic, and isotope-tracing approaches. Our findings reveal that MEK/ERK/KRASG12D inhibition results in enhanced lipid turnover and fatty acid oxidation while suppressing glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Notably, we observed that the increased lipid turnover and fatty acid oxidation are mediated by lipophagy, rather than cytosolic lipolysis. Furthermore, these processes are driven by enhanced nuclear translocation and transcriptional activity of TFEB, a key regulator of lysosomal biogenesis and autophagy. Pharmacological inhibition of fatty acid oxidation, when combined with MEK/ERK/KRASG12D inhibitors, exhibited synergistic anti-tumor effects, significantly reducing the growth of PDAC cell lines and organoids. This combination therapy also decreased tumor burden and improved overall survival in orthotopic cell line-derived and patient-derived xenograft (PDX) mouse models. These results provide novel mechanistic insights into the metabolic adaptations underlying resistance to KRAS signaling inhibition. These studies highlight fatty acid oxidation as a critical metabolic vulnerability in PDAC, offering a promising therapeutic target to enhance the efficacy of KRAS pathway inhibitors. Citation Format: Junzhang Zhao, Ravi Thakur, Dezhen Wang, Tuo Hu, Chunbo He, Surendra K. Shukla, Kirsten L. Bryant, Kamiya Mehla, Channing J. Der, Pankaj K. Singh. Lipophagy-dependent fatty acid oxidation is a metabolic vulnerability for KRAS signaling inhibition in pancreatic 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 6764.
Abstract 1875: PBK expression promotes the aggressive phenotypes of mesothelioma
Authors: Kazumi Hori, Ichidai Tanaka, Tatsuhiro Sato, Mika Sato, Yuta Kodama, Hideyuki Itoigawa, Yuichi Abe, Taketo Kato, Ayumu Taguchi, Mitsuo Sato, Yoshitaka Sekido, Toyofumi Fengshi Yoshikawa, Makoto Ishii
Journal: Cancer Research (2025)

Abstract Mesothelioma is one of the most aggressive neoplasms worldwide that has a particularly poor prognosis. Novel therapeutic strategies to effectively treat patients with mesothelioma are urgently needed. We have previously discovered that oxytocin receptors (OXTR) are highly expressed in mesothelioma and that OXTR knockdown significantly decreases the proliferation of mesothelioma cells with high OXTR expression by disturbing the tumor cell cycle but targeted therapies utilizing the OXTR signaling system have not emerged. In this study, we performed quantitative proteomic profiling of two mesothelioma cell lines with high OXTR expression using mass spectrometry to investigate the downstream signals of OXTR in mesothelioma cells. We found that OXTR knockdown significantly downregulated PDZ-binding kinase (PBK)—a serine/threonine protein kinase belonging to the bispecific MAPKK family which is a crucial factor in cell mitosis, cell proliferation, migration, and anti-apoptosis and support of testicular functions. PBK knockdown significantly suppressed proliferation, migration, and colony formation in mesothelioma cells with high PBK expression, and decreased Akt and MAPK phosphorylation levels. We also found that a PBK inhibitor, OTS-514, suppressed the proliferation of these cell lines at low concentration. Furthermore, immunohistochemical analysis of PBK in surgical specimens obtained from patients with mesothelioma showed that high PBK expression was strongly associated with poor overall survival (log-rank test P=0.0031; hazard ratio 3.339 and 95% confidence interval 1.12-10.00) and recurrence-free survival (log-rank test P=0.0024; hazard ratio 3.355 and 95% confidence interval 1.25-9.04). In addition, the clinical significance of PBK expression was validated in mesotheliomausing datasets from TCGA. Multivariable Cox regression analysis, incorporating stage and OXTR mRNA expression, demonstrated that PBK mRNA expression was the strongest independent predictor of overall survival and the hazard ratio for PBK was higher than that for OXTR. Our findings indicate that PBK plays a crucial role in the aggressiveness of mesothelioma, making it a promising therapeutic target and potential prognostic biomarker for mesothelioma. Citation Format:Kazumi Hori, Ichidai Tanaka, Tatsuhiro Sato, Mika Sato, Yuta Kodama, Hideyuki Itoigawa, Yuichi Abe, Taketo Kato, Ayumu Taguchi, Mitsuo Sato, Yoshitaka Sekido, Toyofumi Fengshi Yoshikawa, Makoto Ishii. PBK expression promotes the aggressive phenotypes of mesothelioma [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 1875.