tbuckley/cabot-search huggingface dataset:
Abstract 4623: The relationship of KRAS mutation and clinical outcomes in patients treated with consolidation durvalumab for locally advanced non-small cell lung cancer
Authors: William J. Phillips, Michelle Pradier, David J. Stewart, Sara Moore
Journal: Cancer Research (2025)

Introduction: KRAS G12C is associated with a favorable response to immunotherapy in patients with advanced non-small cell lung cancer (NSCLC), while other KRAS variants show mixed effects. In addition, there is little known on how KRAS mutations affect immunotherapy responsiveness in the curative setting. This study aims to evaluate the impact of KRAS mutations on clinical outcomes of patients treated with consolidation durvalumab for unresected locally advanced NSCLC. Methods: Clinical data were gathered from the medical records of patients seen at The Ottawa Hospital Cancer Centre from June 1, 2019 to Mar 1, 2024. Adult patients with non-squamous NSCLC who completed chemoradiation therapy and received at least 1 dose of consolidation durvalumab were included. Patients were grouped by KRAS mutation as follows, (1) G12C, (2) non-G12C, or (3) wild type/unknown. Real world progression free survival (PFS) was the primary outcome. Univariable analysis was performed using the Cox Proportional Hazards Model. Results: 78 patients were included. The median age was 68 years old and 64% of patients were female. PDL1 expression was &amp;lt;1% in 14 (18%) patients, ≥1% in 51 (65%), and missing in 13 (17%). 50 cases were tested for KRAS and 31 (62%) harbored a KRAS mutation. Of those, 16 (32%) were G12C and 15 (30%) were non-G12C. Non-G12C point mutations included G12V (n=6), G12A (n=3), G12D (n=3), G13D (n=2), and G13V (n=1). The median PFS of the entire cohort was 40.6 months (95% CI: 23.1-58.2), G12C mutated was 32.1 months (95% CI: 26.0-38.1), and non-G12C was 20.5 months (95% CI: 12.7-28.3). Compared to KRAS wild type/unknown, there was a trend to improved PFS in patients with G12C mutations (hazards ratio (HR) 0.48, p=0.17), and shortened PFS in patients with non-G12C (HR 1.47, p=0.35). Furthermore, PDL1≥1% was associated with improved PFS (HR 0.21, p&amp;lt;0.01). Conclusions: This study demonstrates the potential prognostic value of both KRAS G12C and non-G12C mutations in locally advanced unresectable NSCLC treated with consolidation durvalumab. It also supports PDL1 expression as an established biomarker of immunotherapy sensitivity in the real world. Further studies to prospectively validate KRAS as a predictive marker are warranted. Citation Format: William J. Phillips, Michelle Pradier, David J. Stewart, Sara Moore. The relationship of KRAS mutation and clinical outcomes in patients treated with consolidation durvalumab for locally advanced 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 4623.
Abstract 3903: Multi-omics and histological assessment to identify patient derived xenograft models of invasive lobular carcinoma
Authors: Jagmohan Hooda, Jennifer M. Atkinson, Osama Shah, Megan Yates, Daniel D. Brown, Morgan DeBerry, Rohit Bhargava, Paolo Schiavini, Stefano Cairo, Mara Gilardi, Marianna Zipeto, Steffi Oesterreich, Adrian V. Lee
Journal: Cancer Research (2025)

Abstract Breast cancer is a heterogeneous disease with various histological subtypes. Invasive Lobular Cancer (ILC) is the most common special subtype, accounting for 10-15% of all breast cancers. The pathognomonic feature of ILC is the loss of E-cadherin (CDH1), which leads to a unique single-file growth pattern of discohesive ILC cells. Although ILCs show better prognostic factors than No Special Type (NST), patients with ILC have worse long-term outcomes, which is not well understood. ILC has historically been understudied, in part due to the lack of appropriate research models. Since ILC affects "only" 10-15% of all breast cancers, most models have been generated from the more frequent subtype, NST. In this study, we characterized Patient-Derived Xenograft (PDX) models for Invasive Lobular Cancer (ILC) research. We collaborated with Champions Oncology and utilized the genomic data from their LUMIN portal to perform genomic characterization of PDX models. We identified potential ILC PDX models based on CDH1 mutation, low E-cadherin mRNA expression, or clinical annotation of ILC. We analyzed whole-exome sequencing (WES) and RNAseq data on the LUMIN portal to characterize these models. We also performed Immunohistochemistry (IHC) analysis for E-Cadherin, p120, ER, PR, and Her2 to further assess the PDX models. Our study characterized a total of 10 PDX models and identified 7 ILC models and 3 NST models. We showed that the identified ILC PDX models exhibited lower levels of CDH1 mRNA expression compared to NST, which is consistent with the characteristics of ILC. We also found that the top gene alterations in ILC PDX models included P53, CDH1, PIK3CA, FOXA1, and PTEN. The frequency and type of alterations varied between ILC and NST PDXs. Our study provides valuable tools for studying ILC biology and testing targeted therapies. The identification of potential ILC PDX models could provide insights into the molecular characteristics of ILC and provide tools for research for the development of new treatment strategies. Citation Format: Jagmohan Hooda, Jennifer M. Atkinson, Osama Shah, Megan Yates, Daniel D. Brown, Morgan DeBerry, Rohit Bhargava, Paolo Schiavini, Stefano Cairo, Mara Gilardi, Marianna Zipeto, Steffi Oesterreich, Adrian V. Lee. Multi-omics and histological assessment to identify patient derived xenograft models of invasive lobular 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 3903.
Abstract 4271: Discovery of NNC 05-2090, a small molecule antagonist of the neuromedin U receptor 2 for glioma treatment
Authors: Yuna Roh, Taesang Son, Jang-Seong Kim, Tae-Su Han, Hyun Seung Ban, Seon-Kyu Kim
Journal: Cancer Research (2025)

Abstract Gliomas account for approximately 30% of all brain and central nervous system tumors, and 80% of all malignant brain tumors. Despite their high frequency, the causes of gliomas remain largely unknown. Temozolomide is the standard treatment for glioma, but its efficacy is limited due to the high rate of recurrence and the development of drug resistance in glioma patients. Therefore, discovering novel therapeutic targets and drugs is crucial to improving survival rate for glioma patients. This study aims to investigate the functions of neuromedin U receptor 2 (NMUR2) as a novel target for glioma and to identify NMUR2-specific regulatory drugs. NMUR2 is highly expressed in glioma tissue, and its overexpression promotes cell proliferation and migration, while its knockdown suppresses these effects. RNA sequencing analysis revealed that NMUR2 knockdown downregulates cell cycle-related genes. STAT5, a transcription factor, mediates the link between NMUR2 and cell cycle regulation. To discover an NMUR2-specific antagonist, we performed cell-based drug screening with 6, 331 repurposing drugs and finally identified NNC 05-2090. The NNC 05-2090 treatment in glioma cells reduced cell cycle progression through its downstream signaling pathway. Additionally, we observed a synergistic effect between NNC 05-2090 and temozolomide in both in vitro and in vivo. In conclusion, this study suggests that NMUR2 is a promising novel target, and its antagonist, NNC 05-2090, combined with temozolomide, might offer a promising strategy to improve glioma treatment. Citation Format: Yuna Roh, Taesang Son, Jang-Seong Kim, Tae-Su Han, Hyun Seung Ban, Seon-Kyu Kim. Discovery of NNC 05-2090, a small molecule antagonist of the neuromedin U receptor 2 for glioma treatment [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 4271.
Impact of myelodysplasia-related gene mutations and residual mutations at remission in venetoclax/azacitidine for AML
Authors: Yoshikazu Ikoma, Nobuhiko Nakamura, Yuto Kaneda, Hiroyuki Takamori, Tomokazu Seki, Nobuhiro Hiramoto, Junichi Kitagawa, Junya Kanda, Kei Fujita, Tetsuji Morishita, Yotaro Ochi, Shigeru Chiba, Nana Sasaki, Michiko Ichii, Kazunori Imada, Mizuki Watanabe, Masakatsu Hishizawa, Yasuko Miyahara, Yoshitomo Maesako, Yasuhiro Tanaka, Satoko Oka, Masaaki Tsuji, Satoshi Yoshihara, Kinuko Mitani, Yasunori Ueda, Toshiyuki Kitano, Mitsumasa Watanabe, Nobuo Sezaki, Tadakazu Kondo, Senji Kasahara, Akifumi Takaori-Kondo, Nobuhiro Kanemura, Seishi Ogawa, Yasuhito Nannya
Journal: Leukemia (2025)

Abstract Venetoclax plus azacitidine (VEN + AZA) is widely used in acute myeloid leukemia (AML). This study explored the role of static and dynamic profiles of mutational clonal burden to predict outcomes by analyzing marrow samples from 228 VEN + AZA treated AML cases at “Pre-treatment” ( n = 228), “Best-response” ( n = 105), and “Relapse” ( n = 27) phases using targeted-capture sequencing. In a multivariate model, older age, prior AZA, TP53 mutation with variant allele frequency ≥0.10, and RAS-pathway mutations predicted shorter overall survival (OS), while BCORL1 mutation predicted longer OS. Notably, myelodysplasia-related gene mutations, which constitute adverse factors in ELN 2022, predicted favorable survival. Achieving composite complete remission (CRc) significantly predicted longer OS ( P &lt; 0.001) but showed residual mutations in 76.2% of the cases. Among CRc cases, relapse-free survival was stratified by molecular clearance of mutations other than DNMT3A , ASXL1 , and TET2 ( P = 0.04). In addition, 37% of relapsed cases showed a change of major clones, with 40% having potential targets of molecular-targeting treatment. This study revealed the novel prognostic role of myelodysplasia-related gene mutations and established the importance of molecular response assessment in CRc phase.
Abstract 4166: The RNA demethylase FTO promotes glutamine metabolism in clear cell renal cell carcinoma through the regulation of SLC1A5
Authors: Man Zhao, Dalin Zhang, Haowen Jiang, Nishanth Kuganesan, Suchitra Natarajan, Leighton Pu, Kaushik N. Thakkar, Hongjuan Zhao, James D. Brooks, Donna M. Peehl, Jiangbin Ye, Erinn B. Rankin
Journal: Cancer Research (2025)

Abstract Glutamine reprogramming is a hallmark feature of clear cell renal cell carcinoma (ccRCC). However, the regulation of glutamine reprogramming in ccRCC is incompletely understood. Here we demonstrate that the RNA demethylase enzyme, FTO, promotes glutamine reprogramming in ccRCC cells to support growth and survival. Genetic and pharmacologic inhibition of FTO reduced glutamine-derived reductive carboxylation, de novo pyrimidine synthesis and glutathione biosynthesis. FTO inhibition resulted in increased DNA damage and reduced growth and survival that were rescued by the administration of pyrimidines and the antioxidant N-acetylcysteine. Mechanistically, FTO demethylates the glutamine transporter SLC1A5 mRNA transcript to promote SLC1A5 expression and glutamine reprogramming in ccRCC cells. In FTO knockdown cells, restoration of SLC1A5 expression was sufficient to rescue glutamine-derived reductive carboxylation, glutathione levels, DNA damage as well as growth and survival. Further, we observed that the FTO inhibitor FB23-2 enhanced the efficacy of the PARP inhibitor talazoparib in vitro and in vivo. Our study reveals a novel role for FTO in glutamine reprogramming of ccRCC, highlighting the therapeutic potential of targeting the epitranscriptomic regulation of metabolic reprogramming in ccRCC. Citation Format: Man Zhao, Dalin Zhang, Haowen Jiang, Nishanth Kuganesan, Suchitra Natarajan, Leighton Pu, Kaushik N. Thakkar, Hongjuan Zhao, James D. Brooks, Donna M. Peehl, Jiangbin Ye, Erinn B. Rankin. The RNA demethylase FTO promotes glutamine metabolism in clear cell renal cell carcinoma through the regulation of SLC1A5 [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 4166.
Abstract 3866: A new approach to suppress triple-negative breast cancer metastasis by blocking apurinic/apyrimidinic endonuclease 1 interaction with G-quadruplex
Authors: Yingling Chen, Suravi Pramanik, Mason Tarpley, Achyuth Kalluchi, Sutapa Ray, Bhopal Mohapatra, Kyle Hewitt, Jordan Rowley, Vimla Band, Kishor K. Bhakat
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer (TNBC) has a relatively high metastasis rate as compared to other breast cancer subtypes. Metastasis and tumor recurrence remain major challenges for TNBC patients, resulting in poor prognosis. Therefore, it is imperative to identify and elucidate the molecular mechanisms that drive metastasis to allow the development of new therapeutic agents to inhibit TNBC metastasis and improve patients’ outcomes. Herein, we uncovered a new mechanistic connection between a multifunctional DNA repair protein APE1 and G-quadruplex (G4), a secondary DNA structure present in many metastasis-related signature genes promoters in TNBC. We found that APE1 is highly enriched at the G4 regions on the promoters of metastasis related genes and APE1 knockout or knockdown impairs the tumorigenic and pro-metastatic traits of TNBC cell lines in vitro. Intriguingly, we found that G4 is required for APE1’s enrichment at these promoters and APE1 promotes transcription factors (TFs) binding to these promoters, thereby promoting the expression of these metastasis-related genes. Deletion of APE1 impeded TFs’ binding to promoters and downregulated expression of these genes. In addition, we found that G4 deletion in some target gene promoters exerted similar inhibitory effects as APE1 knockout on cell migration, cell invasion and tumor sphere formation. We discovered that a small molecule which disrupts APE1: G4 interaction significantly disrupted APE1’s enrichment to G4 on promoters, thereby blocking TFs binding, gene expression, cell migration, invasion and tumor sphere formation in vitro. We generated orthotopic TNBC metastasis mouse model using an aggressive TNBC cell line, MDA-MB-231 and found that disrupting G4-APE1 axis either by APE1 knockout or G4 deletion or small molecules significantly inhibited the primary tumor growth and impeded TNBC distant metastasis to lungs. Overall, our study uncovered a novel functional axis of G4-APE1 in regulating TNBC growth and metastasis and identified that this regulatory axis has the potential to serve as a new therapeutic target to prevent metastasis in TNBC patients. Citation Format: Yingling Chen, Suravi Pramanik, Mason Tarpley, Achyuth Kalluchi, Sutapa Ray, Bhopal Mohapatra, Kyle Hewitt, Jordan Rowley, Vimla Band, Kishor K. Bhakat. A new approach to suppress triple-negative breast cancer metastasis by blocking apurinic/apyrimidinic endonuclease 1 interaction with G-quadruplex [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 3866.
Abstract 4171: ADRM1 inhibitor, Up284 induces replication stress and suppresses cell proliferation in triple-negative breast cancer
Authors: Iffat Jahan, Shacoya Mack, Ravi Anchoori, Balasubramanyam Karanam, Komaraiah Palle
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer stands as the most aggressive and deadliest subtype of breast cancer associated with poor prognosis and limited treatment options due to the lack of important receptors; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) used for targeted therapy. Relying exclusively on chemotherapy enhances the chances of resistance and recurrence and leaves TNBC challenging to treat. Thus, it mandates the need for novel drug compounds and combination therapies. Adhesion-regulating molecule 1 (ADRM1/RPN13), a ubiquitin receptor of 26S proteasome that supports recognition of polyubiquitinated substrates and their subsequent deubiquitination and degradation by unique deubiquitinase UCH37/UCHL5.Its inhibition causes a rapid and toxic accumulation of its substrate polyubiquitinated proteins in very high molecular weight (HMW) aggregate; disrupting the protein homeostasis. In response to that, the cancer cells halt the cell cycle and induce replication stress. Consequently, cells signal the survival mechanism by signaling the DNA damage repair (DDR) pathway activation. Using the Cancer Gene Genome Atlas and GEO datasets, our primary analysis demonstrated that ADRM1 is overexpressed in all types of breast cancer including TNBC. Higher expression in tumor cells compared to normal cells strengthens the stands for ADRM1 as a potent target for therapy. In vitro analysis has been performed in TNBC cell lines MDAMB 453 and MDAMB 231. The dose dependency assay demonstrated that the UP284 compound showed activation of CHK1 (Checkpoint kinase1) mediated DNA damage response and γH2AX foci formation confirms the double-stranded DNA breakage. Clonogenic assay confirms the suppression of cell proliferation and colony formation in a concentration-dependent manner in both BRCA positive and BRCA mutant cell lines. Up284 treated cells also showed cell cycle arrest at the G2/M phase. Together, our results indicate that ADRM1 is a promising target for TNBC therapy and suggest that this ADRM1 inhibitor, Up284, has the potential for clinical application in the treatment of TNBC. Our analysis will unravel the novel mechanistic insight into the therapeutic potential of this compound and provide preclinical evidence to develop further combination therapy. Citation Format: Iffat Jahan, Shacoya Mack, Ravi Anchoori, Balasubramanyam Karanam, Komaraiah Palle. ADRM1 inhibitor, Up284 induces replication stress and suppresses cell proliferation in triple-negative 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 4171.
Abstract 3446: Acinar to ductal metaplasia is an evolutionary dead end and does not actively contribute to pancreas regeneration after damage
Authors: Rutvi Shah, I-Lin Ho, Er-Yen Yen, Charles Dyke, Hyuk Jean Kwon, Matthew Wong, Francesca Citron, Zhaoliang Liu, Sergio Attanasio, Ruparoshni Jayabalan, Ricardo Gonzalez Delgado, Luca Cecchetto, Elisabetta Granato, Ashish Damania, Shan Jiang, Haoqiang Ying, Giulio Draetta, Mauro Di Pilato, Nadim Ajami, Andrea Viale
Journal: Cancer Research (2025)

Abstract One of the major risk factors strongly associated with PDAC is pancreatitis and meta-analysis studies have revealed that inflammation of the pancreas increases the relative risk of developing pancreatic cancer by up to 13-fold. During pancreatitis, acinar cells transiently undergo metaplasia known as acinar to ductal metaplasia (ADM). It is well known that in the presence of activated oncogenes, for example mutated Kras, this metaplastic state can progress into PDAC with ADM being the first step towards tumorigenesis. To understand the pathophysiological role of ADM during pancreatitis and tumorigenesis, we utilized different mouse models to study the function and fate of ADM cells. We found that although ADM can effectively mitigate pancreatitis-induced tissue damage, it is not a regenerative process. Instead, cells that underwent ADM were eventually exhausted. We confirmed these findings by performing lineage tracing experiments to understand the fate of the cells and found that they were indeed not responsible for regenerating the pancreas. To better capture the dynamic process distinct sub-populations of epithelial cells undergo, during ADM induction and resolution, we are leveraging spatial transcriptomics of the entire pancreatic tissue at different timepoints after damage induction. We are also actively studying how oncogenic Kras activation reverts this process and contributes to tumorigenesis. This study will shed light on initiation of pancreatic cancer and how it can be prevented in the context of evolution from pancreatitis. Citation Format: Rutvi Shah, I-Lin Ho, Er-Yen Yen, Charles Dyke, Hyuk Jean Kwon, Matthew Wong, Francesca Citron, Zhaoliang Liu, Sergio Attanasio, Ruparoshni Jayabalan, Ricardo Gonzalez Delgado, Luca Cecchetto, Elisabetta Granato, Ashish Damania, Shan Jiang, Haoqiang Ying, Giulio Draetta, Mauro Di Pilato, Nadim Ajami, Andrea Viale. Acinar to ductal metaplasia is an evolutionary dead end and does not actively contribute to pancreas regeneration after damage [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 3446.