tbuckley/cabot-search huggingface dataset:
Abstract 7409: Effectiveness of lung cancer screening by sex and tumor histology: Extended, pooled analysis of the ITALUNG and LUSI trials, with comparison to findings in the NLST
Authors: Rudolf Kaaks, Francisco O. Cortès-Ibañez, Stefan Delorme, Erna Motsch, Verena Katzke, Claus-Peter Heussel, Hans-Ulrich Kauczor, Giulia Picozzi, Giuseppe Gorini, Francesca Maria Carozzi, Laura Carrozzi, Eugenio Paci, Donella Puliti, Mario Mascalchi
Journal: Cancer Research (2025)

Abstract Introduction: Low-dose computed tomography (LDCT) screening can reduce lung cancer (LC)-related mortality, but questions remain about the duration of this effect and differences by sex and tumor histology. Methods: Extended follow-up data from the ITALUNG and LUSI trials were pooled to examine screening-related tumor stage-shifts and to estimate relative hazards for LC-related mortality, by sex and histology. Findings were compared to, and additionally combined with, those from the US National Lung Screening Trial (NLST). Results: In ITALUNG-LUSI, screening yielded a 30% reduction of overall LC mortality up to 8 years after final screening (dilution-adjusted HR=0.70[0.51-0.96]). This reduction, however, was more pronounced for women (HR=0.49[0.25-0.96]) than men (HR=0.78[0.54-1.11]), which was confirmed in combined data of ITALUNG-LUSI plus NLST (6 years post-screening, women: HR=0.74[0.61-0.90], men: HR=0.93[0.80-1.06]; pheterogeneity=0.06). Analyses of stage-shifts and relative mortality hazards suggested that screening reduced mortality by non-small cell and non-squamous tumors in both sexes. In women (18-20%), more than among men (5-9%), screening also resulted in frequent detection of adenocarcinomas with lepidic growth. Finally, in both ITALUNG-LUSI and NLST, LDCT screening reduced the incidence and mortality for small-cell lung cancer (SCLC) among women (HR=0.63[0.43-0.94], all trials combined) but not among men (pheterogeneity=0.04). Conclusion: LC-related mortality reduction by LDCT screening may last until 8 or more years after cessation, and appears to be stronger for women than men, due to reduced incidence and mortality of SCLC in women only. The latter might be caused by removal of (likely EGFR-mutated, and slowly growing) adenomatous precursor lesions that over time would transform into SCLC (lineage plasticity). These findings may have major implications for the optimization of screening programs in terms of eligibility criteria and screening intervals Citation Format: Rudolf Kaaks, Francisco O. Cortès-Ibañez, Stefan Delorme, Erna Motsch, Verena Katzke, Claus-Peter Heussel, Hans-Ulrich Kauczor, Giulia Picozzi, Giuseppe Gorini, Francesca Maria Carozzi, Laura Carrozzi, Eugenio Paci, Donella Puliti, Mario Mascalchi. Effectiveness of lung cancer screening by sex and tumor histology: Extended, pooled analysis of the ITALUNG and LUSI trials, with comparison to findings in the NLST [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 7409.
Abstract 5108: Decoding tumor intrinsic and stroma-related drug resistance in EGFR mutant NSCLC
Authors: Radhika Koranne, Aimee Gleason, Emily Hensley, Xiaodong Wang, Alba Font-Tello, Brian Rabe, Fayaz Seifuddin, Eugene Drokhlyansky, Kartik Subramanian, Martino Colombo, Jason Dobson, Mavrakis J. Konstantinos, Leila Dardaei, Aaron Hata
Journal: Cancer Research (2025)

Abstract The presence of oncogenic driver mutations such as EGFR, ALK, or KRAS renders non-small cell lung adenocarcinomas sensitive to molecularly targeted therapies, however the inevitable emergence of acquired drug resistance remains an unsolved clinical problem. Osimertinib, a third-generation EGFR inhibitor that was initially developed to overcome the EGFRT790M resistance mutation, is now the standard first-line therapy. Although various mechanisms of acquired resistance to osimertinib have been identified, the specific drivers of resistance remain unexplained in over half of patients. Recent work from our group and others has suggested that cancer-associated fibroblasts may play a role in drug resistance to tyrosine kinase inhibitors (TKIs). Notably, we have observed that patient-derived cancer-associated fibroblast (PDF) cell lines established from TKI-resistant tumors display heterogeneous phenotypes with ability to rescue cancer cells from TKIs. To enable parallel discovery of both tumor cell-intrinsic and stroma-driven resistance mechanisms to osimertinib, we developed a genome-wide CRISPR sensitizer screening approach that incorporates osimertinib-resistant patient-derived EGFR-mutant NSCLC cell lines and conditioned media from matched immortalized PDFs. These studies aim to uncover intrinsic and extrinsic resistance pathways and nominate targets for next-generation therapies to overcome acquired resistance to osimertinib Citation Format: Radhika Koranne, Aimee Gleason, Emily Hensley, Xiaodong Wang, Alba Font-Tello, Brian Rabe, Fayaz Seifuddin, Eugene Drokhlyansky, Kartik Subramanian, Martino Colombo, Jason Dobson, Mavrakis J. Konstantinos, Leila Dardaei, Aaron Hata. Decoding tumor intrinsic and stroma-related drug resistance in EGFR mutant NSCLC [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 5108.
Abstract 5191: Modeling the metastatic tumor microenvironment: A co-culture platform for cancer and vascular organoids in drug screening
Authors: Mingyun Lee, Yeojoon Yoon, Yong Soo Lee, Jinguen Rheey
Journal: Cancer Research (2025)

Abstract Patient-derived organoids (PDOs) have emerged as a promising tool for drug screening, as they can closely mimic the genetic profile and heterogeneity of real tumor tissues. Despite these advantages, PDOs cultured in isolation fall short in replicating the complex in vivo tumor environment, particularly the critical interactions with the vascular network. Research that neglects these tumor-vascular interactions provides only partial insights into drug responses and the metastatic potential of cancer cells. To address these limitations, we developed a co-culture system of cancer and vascular organoids to better simulate the authentic tumor microenvironment (TME). After four days of vascularized tumor organoid (vTO) culture, RFP-positive lung cancer organoids (LCO) were centrally positioned, encircled by blood vessels, creating an interconnected structure between the LCO and blood vessel organoids (BVO). As the culture period progressed, the LCO began to spread along the vascular network, and by day 10, RFP-positive LCO cells were observed in the peripheral BVO regions. To investigate strategies for limiting metastasis, we targeted the TGF-β pathway, known to play a key role in metastatic progression, within this novel metastatic platform. On day 5, we administered the TGF-β/Smad inhibitor A83-01. Image-based analysis revealed a reduction in LCO dissemination, while quantitative PCR analysis showed a dose-dependent decrease in the expression of genes associated with epithelial-to-mesenchymal transition (EMT) following A83-01 treatment. Additionally, to assess anti-cancer drug responses, we treated the vTO with the AXL inhibitor Bemcentinib. Image analysis indicated that the vTO exhibited higher drug resistance compared to LCO alone, and qPCR analysis confirmed a reduction in metastasis-associated gene expression. Taken together, this innovative co-culture platform, which incorporates metastatic cancer organoids, offers a structurally advanced model that more closely resembles the in vivo TME than previous drug screening methods. Therefore, this platform serves as a powerful new tool for studying metastatic cancer and provides a novel approach to evaluating metastasis-inhibiting drugs, new therapeutics targeting metastatic tumors, and combination therapies. Citation Format: Mingyun Lee, Yeojoon Yoon, Yong Soo Lee, Jinguen Rheey. Modeling the metastatic tumor microenvironment: A co-culture platform for cancer and vascular organoids in drug screening [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 5191.
Abstract 6049: Fibroblast growth factor receptor modulates IFN-γ response in breast cancer
Authors: Marvis Monteiro, Mitchell G. Ayers, Michael K. Wendt
Journal: Cancer Research (2025)

Abstract FGFR is amplified in 20% of metastatic breast cancer cells (MBCs) where it promotes growth, sustains mesenchymal plasticity, and mediates drug resistance. Systemic inhibition of FGFR kinase activity increases the numbers of CD4+ and CD8+ T-cells and decreases abundance of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. These data indicate an immunosuppressive role of FGFR signaling pathway in MBCs. However, a mechanism by which blockade of FGFR kinase activity affects T-cell presence in the tumor is not well understood. T-cells decrease tumor progression by releasing cytokines such as interferon gamma (IFN-γ). IFN-γ binds to its cognate receptor to activate the JAK-STAT1 signaling pathway, promoting immune recognition of cancer cells. Herein, we investigate the signaling cross talk between FGFR-IFN-γ and the resultant pathophysiological effects on cancer cells. We observe that FGFR signaling reduces STAT1 phosphorylation in breast cancer cells. Conversely, inhibiting FGFR kinase activity in murine mammary carcinoma cells leads to increased STAT1 phosphorylation, increased expression of downstream interferon response genes including the T-cell chemoattractants CXCL9 and CXCL10, and increased cell surface expression of major histocompatibility complex I (MHC-I). A key mediator of the FGFR signaling cascade is SH2 containing protein tyrosine phosphatase (SHP-2). Pharmacological inhibition of SHP-2 causes a decrease in in-vivo metastatic burden and an increase in T-cell presence in the tumor. Similar to targeted inhibition of FGFR, blockade of SHP-2 activity also increases STAT1 phosphorylation and expression of IFN-γ response genes. We propose a mechanism in which FGFR mediated activation of SHP-2 dephosphorylates tyrosine 701 of STAT1 thereby tempering anti-tumorigenic effects of IFN-γ. Our findings suggest that increased immunogenicity caused by FGFR pathway inhibition can be leveraged to make tumor cells more susceptible to immune attack and can be used in conjunction with immunotherapy for treatment of MBCs. Citation Format: Marvis Monteiro, Mitchell G. Ayers, Michael K. Wendt. Fibroblast growth factor receptor modulates IFN-γ response in breast 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 6049.
Abstract 5204: Morphology-guided classification of oral cancer using patient-derived organoids and its therapeutic implications
Authors: Mi Rim Lee, None sumin Kang, Jonghyun Lee, Sun-Young Kong, Yu-Sun Lee, Hye Won Shon, Gyeongmin Kang, Jiyoung Lee, Suk Min Youn, Da Woon Kwack, Joo Yong Park, Soung Min Kim, Wonyoung Choi, Jong-Ho Lee, Dongkwan Shin, Ik-Jae Kwon, Sung-Woen Choi, Yun-Hee Kim
Journal: Cancer Research (2025)

Abstract Oral cancer is an aggressive malignancy with a survival rate below 50% and a high rate of locoregional recurrence in advanced stages. The treatment method for patients with oral cancer is highly dependent on surgery and radiation, because there is still no therapeutic target due to the low mutation rate and the absence of molecular subtypes due to high tumor heterogeneity. Patient-derived organoid (PDO) is a good model that can overcome the limitations in translational study of oral cancer, as they reflect the characteristics of patient tissues at a high level and serve as a valuable preclinical model.In this study, we classified oral cancer into three subtypes based on patient-derived organoid (PDO) morphology and proposed new treatment strategies based on subtype-specific mutations and -transcriptional characteristics. First, we classified OSCC organoids into three distinct morphologies from successfully established 77 cancer and 81 normal oral cancer PDO libraries: normal-like, dense, and graph-like. Morphological subtypes were consistent with genomic mutations and transcriptome characteristics. Morphological subtypes were correlated not only with genomic mutations and transcriptomic characteristics, but especially with clinical recurrence prognosis. Patients with normal-like had a low mutation burden and a good prognosis, whereas patients with dense or grape-like had many mutations and a poor prognosis for recurrence. As a result of evaluating 14 drugs by organoid subtype in a high-throughput drug evaluation system using a 384-well plate, normal-like or grape-like organoids showed a good response to single drug treatment. We observed that dense organoids, which exhibited resistant responses to single drugs, showed an increased synergistic effect when co-treated with the first-line standard chemotherapy drug, cisplatin, and the ATR inhibitor (bay1895344), compared to other subtypes. Citation Format: Mi Rim Lee, sumin Kang, Jonghyun Lee, Sun-Young Kong, Yu-Sun Lee, Hye Won Shon, Gyeongmin Kang, Jiyoung Lee, Suk Min Youn, Da Woon Kwack, Joo Yong Park, Soung Min Kim, Wonyoung Choi, Jong-Ho Lee, Dongkwan Shin, Ik-Jae Kwon, Sung-Woen Choi, Yun-Hee Kim. Morphology-guided classification of oral cancer using patient-derived organoids and its therapeutic implications [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 5204.
Abstract 4476: Curcumin gold nanoparticles significantly boost the effectiveness of docetaxel-induced apoptosis in breast cancer
Authors: Santosh K. Singh, Rajesh Singh
Journal: Cancer Research (2025)

Abstract Breast cancer (BrCa) is the most diagnosed cancer in women; it develops locally and then metastasizes to other organs. Due to tumor heterogeneity, the prevalence of drug resistance, and disease recurrence, current therapy options are proving less effective for specific BrCa subtypes, such as triple-negative breast cancer (TNBC). Therefore, BrCa treatment has shifted from a one-size-fits-all strategy to a more focused approach. In this study, we demonstrated folate receptor-based targeted delivery of either curcumin (Cur), a natural compound isolated from Curcuma longa, or docetaxel (DTX), a chemotherapeutic drug, or a combination of the two, using gold nanoparticles (AuNPs) for successful BrCa therapy. We synthesized AuNPs coated with folic acid (FA)-conjugated with poly (ethylene glycol) copolymer, encapsulated with DTX and Cur, and then characterized these NPs for size, charge, shape, conjugation, and distribution using various techniques, including a Zetasizer, scanning electron microscope (SEM), transmission electron microscope (TEM), nuclear magnetic resonance (NMR), and nanoparticle tracking analysis (NTA). The results confirmed the successful conjugation of both drugs. To evaluate whether Cur enhanced the efficacy of DTX-AuNPs on BrCa cell lines (MCF-7 and MDA-MB-231), we treated the cells with Cur- or DTX- alone or in combination -AuNP followed by cell viability assessment using MTT assay and apoptosis assays. The live/dead cells immunofluorescence test confirms the effectiveness of combined drugs, showing an increase in dead nuclei in MCF-7 and MDAMB 231 cells treated with the combination (FA-Cur+ DTX-AuNP) for 48 hours. The combination was most effective in inducing apoptosis, inhibiting EMT (epithelial-mesenchymal transition), and BrCa cell proliferation. It showed the downregulation of the anti-apoptotic Bcl-xL and the upregulation of pro-apoptotic markers Bak and Bid. The EMT markers, E-cadherin, were upregulated, and the N-cadherin and Snail markers were downregulated in western blots and RT-PCR. Further, the combination of NPs increases the expression of p27KIP1, inhibiting the CDK4, Cyclin D1 complex and the transition of cells into G0/G1 to the S phase in both cell lines. The NPs internalization, colony formation, and migration assays further confirm the synergistic effect of both NPs. These findings indicate that Cur may serve as a therapeutic contender for enhancing the effectiveness of DTX, representing a promising advancement in breast cancer treatment. Citation Format: Santosh K. Singh, Rajesh Singh. Curcumin gold nanoparticles significantly boost the effectiveness of docetaxel-induced apoptosis in breast 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 4476.
Abstract 4292: Targeting YB-1 as a treatment strategy for high-grade serous ovarian carcinoma
Authors: Dhanir Tailor, Fernando Jose Garcia-Marques, Abel Bermudez, Wenqi Li, Arpit Dheeraj, Annah Rolig, Chia-Feng Tsai, Tao Liu, Tanja Pejovic, Sharon J. Pitteri, Sanjay V. Malhotra
Journal: Cancer Research (2025)

Background: High-grade serous ovarian carcinoma (HGSC) is an aggressive type of ovarian cancer, accounting for 75% of ovarian epithelial cancers. It is often diagnosed at advanced stages and frequently develops treatment resistance, resulting in poor survival rates. A key protein associated with this resistance is Y-box binding protein 1 (YB-1), which binds to both RNA and DNA. We hypothesize that pharmacological inhibition of YB-1 may enhance HGSC treatment effectiveness and reduce the development of treatment resistance. Method: We collected tumor tissue and adjacent normal tissue samples from HGSC patients whose disease relapsed after receiving four to six different therapies. These tissues were used for proteomics, multiplex immunohistochemistry (mIHC), and to create patient-derived xenograft (PDX) models. In mice, the PDX tumors were subjected to treatment with a combination therapy of YB-1 inhibition and chemotherapy agents. Additional proteome analysis was conducted on mouse HGSC cells. Results: Proteome profiling of patient HGSC samples revealed that malignant tissues significantly overexpress YB-1 and related mRNA processing pathways in comparison to adjacent normal tissues. mIHC analysis of patient HGSC tissue indicated high YB-1 expression correlated with low infiltration of CD45-positive immune cells. In vivo mouse studies using the PDX models derived from HGSC samples indicated that treatment with a YB-1 inhibitor (monotherapy with SU056) slowed tumor progression and enhanced sensitivity to cisplatin and paclitaxel. Consistent with the analysis of patient tissues and PDX models, both in vitro and in vivo studies of mouse cell lines indicated that treatment with SU056 hindered tumor growth and the development of treatment resistance. Furthermore, proteome profiling of mouse HGSC cells treated with SU056 corroborated the patient tissue observations, demonstrating that YB-1 inhibition resulted in the downregulation of mRNA processing-associated pathways. Conclusions: Combination therapy using a YB-1 inhibitor with chemotherapy enhances chemotherapeutic responses in HGSC PDX models. Citation Format: Dhanir Tailor, Fernando Jose Garcia-Marques, Abel Bermudez, Wenqi Li, Arpit Dheeraj, Annah Rolig, Chia-Feng Tsai, Tao Liu, Tanja Pejovic, Sharon J. Pitteri, Sanjay V. Malhotra. Targeting YB-1 as a treatment strategy for high-grade serous ovarian carcinoma [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 4292.
Abstract 5114: Investigating the novel role of the protease A Disintegrin And Metalloprotease (ADAM)-17 in small cell lung cancer
Authors: Mohamed I. Saad, Karen Hon, Jelena Solujic, Teresa Weng, Arash Badiei, Clifford Young, Stefan Düsterhöft, Daniel Gough, Stefan Rose-John, Peter Hoffmann, Phan Nguyen, Brendan Jenkins
Journal: Cancer Research (2025)

Abstract Lung cancer is the most lethal and common cancer worldwide, which comprises two main subtypes, non-small cell lung cancer and small cell lung cancer (SCLC), accounting for ∼85% and ∼15%, respectively, of all diagnoses. SCLC is a highly aggressive neuroendocrine malignancy which is detected in two thirds of SCLC patients at a late stage with a dismal 5-year survival rate of less than 5%. This poor outcome is largely due to the stagnated clinical management of SCLC over the last 3 decades, comprising first-line platinum-based chemotherapy with etoposide, which, despite initial high response rates, is associated with rapid disease relapse due to acquired chemoresistance. Therefore, there is a pressing clinical need to identity new molecular drivers of SCLC which can serve as therapeutic targets. In this regard, A Disintegrin And Metalloprotease 17 (ADAM17) is the major “sheddase” for &amp;gt;80 membrane-tethered pro-tumourigenic substrates, including epidermal growth factor receptor ligands, notch receptor and tumour necrosis factor-α, which control many cellular processes (e.g. inflammation, proliferation) in immune and non-immune cells. Therefore, ADAM17 modulates key physiological and pathophysiological cellular processes. Despite the large body of data implicating ADAM17 in lung cancer, the pathological role of ADAM17 in SCLC is unknown. Using our unique highly relevant and well-established clinical and preclinical models, including SCLC patient biopsies, the Rb1fl/fl;Trp53fl/fl (RP) and Rb1fl/flTrp53fl/flMycLSL/LSL (RPM) genetic mouse models, patient-derived xenografts and human SCLC cell lines, as well as proteomics pipeline and a suite of biochemical and molecular biology techniques, we aim to define the role of ADAM17 in SCLC. ADAM17 expression, interactome and substrate repertoire was investigated while the anticancer activity of ADAM17 inhibitors in SCLC was assessed. This research therefore could pave the way for the development of novel therapeutic and biomarker avenues for SCLC. Citation Format: Mohamed I. Saad, Karen Hon, Jelena Solujic, Teresa Weng, Arash Badiei, Clifford Young, Stefan Düsterhöft, Daniel Gough, Stefan Rose-John, Peter Hoffmann, Phan Nguyen, Brendan Jenkins. Investigating the novel role of the protease A Disintegrin And Metalloprotease (ADAM)-17 in 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 5114.