tbuckley/cabot-search huggingface dataset:
Abstract 1933: Dissecting acquired resistance to KRASG12D inhibition in a mouse model of pancreatic ductal adenocarcinoma
Authors: Julien Dilly, Laleh Abbassi, Connor J. Hennessey, Giselle A. Uribe, Brendan Parent, Annan Yang, Kevin S. Kapner, Ziyue Li, Kyle E. Evans, Shatavisha Dasgupta, Megan T. Hoffman, Li Qiang, Felix P. Hambitzer, Seema Chugh, Alex K. Shalek, Stephanie K. Dougan, Brian M. Wolpin, Jonathan A. Nowak, Srivatsan Raghavan, Peter S. Winter, Andrew J. Aguirre
Journal: Cancer Research (2024)

Abstract KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC) and is mutationally activated in approximately 90% of cases, with the glycine-to-aspartic acid substitution at position 12 (p.G12D) being the most prevalent alteration. Mutations in this oncogene have been associated with more aggressive disease and poorer outcomes and have remained “undruggable” for more than three decades. However, the recent development of mutant-specific small molecule inhibitors of KRAS has given hope for the treatment of this highly lethal and treatment-refractory malignancy. Here we evaluated the genomic and transcriptional mechanisms of resistance to MRTX1133, a first-in-class inhibitor of KRASG12D, in an autochthonous mouse model of PDAC. We leveraged single-nucleus RNA sequencing and whole-exome sequencing on 17 tumors from KPC mouse specimens (LSL-KrasG12D/+; LSL-Trp53R172H/+; p48-Cre) that were treated with either MRTX1133 or the vehicle, including 6 samples from mice that developed acquired resistance to KRASG12D inhibition. Our analysis has uncovered that resistance is multifaceted and characterized by both emergent genomic and transcriptional features. Genetically, resistant tumors harbored clonal and subclonal amplifications in the HIPPO pathway, cell cycle regulators, and ABC transporters. Transcriptionally, we employed non-negative matrix factorization and identified recurrent gene expression programs in resistant and vehicle samples. Using this approach, we uncovered the existence of an intermediate phenotype between classical and mesenchymal cell states that is enriched in tumors with evolved resistance to MRTX1133. In summary, our study provides a high-resolution genomic and transcriptional landscape of resistance to KRAS targeting in a preclinical in vivo model of PDAC, highlighting the complexity of treatment resistance and identifying various pathways and effectors that may serve as potential new targets for combination therapy. Citation Format: Julien Dilly, Laleh Abbassi, Connor J. Hennessey, Giselle A. Uribe, Brendan Parent, Annan Yang, Kevin S. Kapner, Ziyue Li, Kyle E. Evans, Shatavisha Dasgupta, Megan T. Hoffman, Li Qiang, Felix P. Hambitzer, Seema Chugh, Alex K. Shalek, Stephanie K. Dougan, Brian M. Wolpin, Jonathan A. Nowak, Srivatsan Raghavan, Peter S. Winter, Andrew J. Aguirre. Dissecting acquired resistance to KRASG12D inhibition in a mouse model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1933.
Abstract 1762: Characterization of somatic copy number deletion of chromosome 22q in papillary thyroid carcinoma
Authors: Olivia W. Lee, Danielle Karyadi, Stephen Hartley, Weyin Zhou, Mitchell Machiela, Mykola Tronko, Tetiana Bogdanova, Liudmyla Zurnadzhy, Lindsay Morton, Stephen Chanock
Journal: Cancer Research (2024)

Abstract Deletion in the long arm of chromosome 22 (22qDEL) is the most prevalent somatic copy number alteration (SCNA) observed in papillary thyroid carcinoma (PTC). Despite its recurrence, the specific characteristics and role of 22qDEL in PTC have not been fully studied. We conducted a pooled analysis of 22qDEL by integrating patient and clinical information and molecular profiles from 1,094 primary PTC tumors across four major published PTC genomic studies: The Cancer Genome Atlas (TCGA) PTC profile study, the National Cancer Institute (NCI) post-Chornobyl PTC study, the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSKCC-IMPACT) PTC cases, and the Seoul National University (SNU) thyroid cancer profile study. The majority of PTC with 22qDEL demonstrated arm-level loss of heterozygosity (86%). Even in PTC cases with partial 22qDEL, we observed a loss across 70% of chromosome 22, encompassing regions 22q12 and 22q13, which harbors known cancer genes (NF2 and CHEK2). More than 90% of 22qDEL co-occurred with established oncogenic drivers of PTC, though a full assessment of PTC drivers was not available for all cases. 22qDEL occurred more frequently with RAS point mutations (50.4%) than other drivers (9.3%). A higher fraction of 22qDEL was clonal in RAS-driven PTCs (78.3%), suggesting 22qDEL occurs early in RAS-driven tumor development. We did not observe any association between 22qDEL and established PTC risk factors such as age, sex, and radiation, nor with clinical features including tumor size, multifocality, and metastasis (p-values&amp;gt;0.22). RNA sequencing gene expression analysis based on 22qDEL status revealed downregulation of most genes residing on chromosome 22q and significant differential expression activity of immune-related genes, further implicating a role of immune dysregulation in PTC. Our study suggests that 22qDEL may not act as a primary driver of PTC but plays an important role as a co-factor of RAS point mutations, which could further drive PTC development. Citation Format: Olivia W. Lee, Danielle Karyadi, Stephen Hartley, Weyin Zhou, Mitchell Machiela, Mykola Tronko, Tetiana Bogdanova, Liudmyla Zurnadzhy, Lindsay Morton, Stephen Chanock. Characterization of somatic copy number deletion of chromosome 22q in papillary thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1762.
Abstract 194: Single-cell mechanical analysis reveals that astrocytes and glioblastoma cells have similar viscoelastic properties
Authors: Julian Najera, Killian Onwudiwe, Luke Holen, Alice A. Burchett, Dorielis Rodriguez, Maksym Zarodniuk, Saeed Siri, Meenal Datta
Journal: Cancer Research (2024)

Abstract Despite recent advances in treatment, the survival rate of glioblastoma (GBM) patients remains low due to the cancer’s resistance to current treatment modalities. Solid tumors like GBM are known to harbor physical abnormalities at the tissue and cell level. An understanding of GBM cell mechanics may therefore lead to the identification of novel disease mechanisms, biomarkers, and therapeutic strategies to improve treatment outcomes. In this study, we aimed to compare the mechanics of human GBM cells and their normal counterpart, immortalized human astrocytes (IHAs). To accomplish this, we used a parallel-plate flow system to expose single cells to physiological fluid shear stress and recorded the resulting deformation using a camera-coupled microscope. We then utilized digital image correlation analysis to create strain-time profiles of individual cells and fit the profiles with a three-parameter generalized Maxwell model to characterize their nuclear and cytoplasmic viscoelastic properties. We also used fluorescence microscopy and atomic force microscopy to quantify actin density and alignment and adhesion energy in both cell types, respectively. Our results showed that, contrary to extracranial cancer cells, the viscoelastic properties of GBM cells are similar to their normal counterpart. This may explain why metastasis in GBM patients is rare and conventional treatment options are unsuccessful. We also found that actin organization and localization and adhesion energy is different between GBM cells and IHAs. Thus, future research which links the genetic and microenvironmental factors that modulate these unique mechanical features may lead to the development of rational and novel clinical strategies against GBM. Citation Format: Julian Najera, Killian Onwudiwe, Luke Holen, Alice A. Burchett, Dorielis Rodriguez, Maksym Zarodniuk, Saeed Siri, Meenal Datta. Single-cell mechanical analysis reveals that astrocytes and glioblastoma cells have similar viscoelastic properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 194.
Abstract 2640: HBI-2375, a first-in-class IND ready selective MLL1-WDR5 inhibitor, retains desirable preclinical characteristics in solid tumors and in leukemias to be pursued in clinical studies
Authors: Farbod Shojaei, Che Fang, Jill M. Ricono, Mireille Gillings
Journal: Cancer Research (2024)

Abstract MLL1 (mixed lineage leukemia1) interaction with WDR5 (WD repeat domain 5) is critical for its histone methyl transferase (HMT) activity leading to transcriptional regulation of gene expression. MLL1 dysregulation such as its translocation at chromosome 11q23 results in generation of MLL1 fusion genes and leukemia development. Additionally, recent studies indicated a role for MLL1-WDR5 interaction in solid tumors progression via directly affecting cancer cells or by suppression of tumor immunity. Therefore, MLL1-WDR5 interaction is an important target in the discovery of anti-cancer drugs for both leukemia and solid tumors. We recently identified HBI-2375 as a selective inhibitor of MLL1-WDR5 interaction. HBI-2375 showed potent inhibition of WDR5 (IC50: 4.48nM) in biochemical assay and inhibited MV4-11 cellular proliferation (average IC50: 3.17µM) in CTG assays. In addition, HBI-2375 was stable in liver S9 and whole blood, with moderate to high plasma protein binding rates in multiple species, and acceptable hERG (IC50: 17µM). Furthermore, HBI-2375 displayed reasonable oral PK properties (Cmax, T1/2, AUC, and F%) in mouse, rat and dog and showed good safety profile in GLP tox studies. In pharmacology studies HBI-2375 showed significant dose dependent anti-tumor activity in MV4-11 AML model along with reduction in methylation of H3K4 in the tumors harvested from the treated animals demonstrating the targeted disruption of HMT activity in cancer cells by HBI-2375. Furthermore HBI-2375 in combination with PD-1 mAb significantly inhibited tumor growth in MC38, colorectal tumor model, and in 3LL lung carcinoma syngeneic tumor models. Flow cytometry and IHC showed significant increase in the infiltration of CD8+ CTLs in the combination group further providing immune-driven mechanisms for greater efficacy of combination therapy. Gene expression analysis also identified genes that are involved in promoting immune system activity in the combination group. Tissue distribution studies also showed greater accumulation of HBI-2375 in brain tissue indicative of a potential to target glioma and glioblastoma in clinical studies. Therefore, HBI-2375 represents a first-in-class MLL1-WDR5 inhibitor with promising characteristics for future testing in the clinic. Citation Format: Farbod Shojaei, Che Fang, Jill M. Ricono, Mireille Gillings. HBI-2375, a first-in-class IND ready selective MLL1-WDR5 inhibitor, retains desirable preclinical characteristics in solid tumors and in leukemias to be pursued in clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2640.
Abstract 5869: Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in melanoma
Authors: Armond J. Isaak, GeGe R. Clements, Lei Huang, Yifei Qin, Qiang Zho, Glenn Merlino, Yanlin Yu
Journal: Cancer Research (2024)

Abstract More than 50% of melanomas harbor activating BRAF kinase mutations, with BRAFV600E representing more than 90% of BRAF mutations. Inhibition of mutant BRAF by BRAF inhibitors (BRAFi) in patients with advanced melanoma yields a remarkable initial clinical response. Limited duration response and disease recurrence of inhibitors occurs due to acquired drug resistance. Recently identified mechanisms of MAPK hyperactivation in acquired resistance to BRAFi have encouraged clinicians to employ a combination of BRAF and MAPK inhibitors to block the MAPK signaling pathway more effectively. However, most patients treated with this combination therapy still relapse due to de novo drug resistance. Therefore, innovative strategies are still necessary to improve the precision and durability of anti-melanoma therapies. To investigate the mechanism of both BRAFi and MEKi resistance (double resistance, DR) in mutant BRAF melanomas, we have developed models from four human melanoma cell lines to explore the hypothesis that molecular alterations are related to double resistance to BRAFi and MEKi in melanoma. We have found that BRAFi-MEKi double-resistant models exhibit distinct differences in morphology and growth kinetics. Specifically, BRAFi-MEKi double-resistant human melanomas express a higher level of FGFb and PAI-1 expression. We confirmed that overexpression of FGFb and PAI-1 in parental cells could increase the ability to resist BRAF and MEK inhibition. Additionally, we discovered that decreased expression of FGFb and PAI-1, via knock-down, inhibition, or CRISPR in double resistant cells, can restore cell sensitivity to treatments of BRAFi and MEKi. To further elucidate the role of FGFb and PAI-1 on resistant melanoma, we have extended our scope to in vivo mouse xenograft models. Our findings uncovered the mechanism of how melanoma cells can escape BRAFi and MEKi attacks and offer a rational strategy to guide future clinical treatments. Citation Format: Armond J. Isaak, GeGe R. Clements, Lei Huang, Yifei Qin, Qiang Zho, Glenn Merlino, Yanlin Yu. Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5869.
Abstract 3624: A low-cost kit for gentle, effective and timely extracellular vesicle (GET EVs) isolation: Accelerating development of RNA-based liquid biopsies for neuroendocrine neoplasms
Authors: Boyang Su, Morteza Jeyhani, Xiaojing Yang, Jina Nanayakkara, Reese Wunsche, Neil Renwich, Scott Tsai, Hon Leong
Journal: Cancer Research (2024)

Abstract Extracellular vesicles (EVs) are cell fragments released by all cells, making them promising platforms for cancer biomarker development. Effective isolation of ultra-pure EVs for downstream analyses is key for EV-based liquid biopsy development. However, current EV isolation methods such as ultracentrifugation (UC) and other commercialized EV isolation kits are lackluster because of damage to EVs, length of time required, and low EV recovery rates. In response, we developed an “GET EV” kit which is based on the principles of lipid energy states, also known as the aqueous two-phase system (ATPS) to isolate EVs from any media. Nanoscale flow cytometry (nFC) analysis revealed that ATPS has greater EV enrichment capability (21.4 × vs. 10.9 × times fold enrichment) and higher EV recovery efficiency (97.6% vs. 69.3% recovery) than UC. Other EV isolation kits were tested and were inferior to ATPS in terms of EV recovery and EV-RNA recovery. EV subpopulations as determined by EV biomarkers (CD9, CD63, CD81, etc.) were confirmed by nFC. “Omics” studies (small RNA sequencing and proteomics) also confirmed the presence of expected EV markers. We developed an RNA-based liquid biopsy for Neuroendocrine Neoplasms (NENs) by quantitating the presence of EVs containing miR-375, an established biomarker for NENs. Using the GET EVs kit, we isolated EVs from healthy volunteer and patient plasma samples of NEN patients. RT-qPCR demonstrated enriched expression of miR-375 in EVs isolated from Lung and GI NEN patient plasma samples. Our study establishes the use of GET EV kits to efficiently, rapidly, and gently isolate EVs from small plasma samples (250 uL). This is a low-cost innovation that will finally enable the development of other RNA-based Liquid Biopsies for other disease sites with significant diagnostic and prognostic implications. Citation Format: Boyang Su, Morteza Jeyhani, Xiaojing Yang, Jina Nanayakkara, Reese Wunsche, Neil Renwich, Scott Tsai, Hon Leong. A low-cost kit for gentle, effective and timely extracellular vesicle (GET EVs) isolation: Accelerating development of RNA-based liquid biopsies for neuroendocrine neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3624.
Abstract 7319: Glycemic traits and colorectal cancer survival in a cohort of South Korean patients: A Mendelian randomization analysis
Authors: So Yon Jun, Sooyoung Cho, Min Jung Kim, Ji Won Park, Seung Yong Jeong, Aesun Shin
Journal: Cancer Research (2024)

Abstract Background: Clinical diabetic traits have been reported to be associated with increased colorectal cancer risk (CRC) in observational studies. Using the Mendelian randomization (MR) analysis method, we examined the causal association between glycemic traits, such as fasting glucose (FG), fasting insulin (FI), and glycosylated hemoglobin A1c (HbA1c), and survival in a cohort of CRC patients. Methods: We conducted a two-sample MR analysis among a cohort of patients with locally advanced CRC at Seoul National University Hospital. Single-nucleotide polymorphisms robustly associated (P&amp;lt;5 × 10−8) with the three glycemic traits were obtained from the Meta-Analyses of Glucose and Insulin-related traits Consortium, Asian Genetic Epidemiology Network, and Korea Biobank Array. Three-year and five-year overall survival (OS) and progression-free survival (PFS) were used as outcomes. Survival analysis was conducted using subgroup analysis by cancer stage and subsite in a multivariate Cox proportional hazards model adjusted for age and sex to examine whether glycemic traits affected survival. Results: A total of 509 patients were included in our final analysis. MR analysis showed that HbA1c levels were associated with poor three-year OS (β=4.20, P=0.02). Sensitivity analyses did not show evidence of any violations of the MR assumptions. In the cancer subgroup analysis of the Cox proportional hazards model, pooled hazard ratios for FG were significantly associated with poor three-year OS and PFS regardless of cancer stage. FI was not significantly associated with any three-year survival endpoints. Among stage III patients, three glycemic traits were significantly associated with both five-year OS and PFS. Location-specific subgroup analysis showed a significant association between three glycemic traits and five-year PFS in patients with left-sided colon cancer. FG was associated with poor three-year survival for colon cancer but not rectal cancer. Conclusions: Our results suggest that FG and HbA1c could be used to predict prognosis in CRC patients. Lifestyle and/or pharmacological interventions targeting glycemic traits could help improve survival for CRC patients. Citation Format: So Yon Jun, Sooyoung Cho, Min Jung Kim, Ji Won Park, Seung Yong Jeong, Aesun Shin. Glycemic traits and colorectal cancer survival in a cohort of South Korean patients: A Mendelian randomization analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7319.
Abstract 2297: Longitudinal monitoring of HPV circulating tumor DNA in cervical cancer
Authors: Preetiparna Parida, Krishna Sharan, Shirley Lewis, Rama Rao Damerla
Journal: Cancer Research (2024)

Abstract Introduction Detecting circulating tumor DNA (ctDNA) in the blood using minimally invasive techniques known as a "liquid biopsy", is gaining tremendous popularity in oncology research. Integration of human papillomavirus (HPV) DNA and the overexpression of the E6 and E7 oncogenes are crucial steps in the development of cervical cancer. We investigated the potential utility of HPV ctDNA as a biomarker for monitoring treatment outcomes in patients with cervical cancer. Material and Methods We use droplet digital PCR (ddPCR) to measure the amount of HPV16/18 ctDNA in plasma of cervical cancer patients. The HPV standard GP5+/6+ primers were used to determine HPV positivity in our patients. Specific primers were designed to amplify specifically the E6 oncogene of HPV16 and HPV18. Plasmid constructs were made using the PCR-purified products of HeLa and SiHa cell lines which would act as a positive control for the assay. HPV16 and 18 plasmids were serially diluted and then tested in qPCR as a template using different primer sets. Standard curves were made from the recombinant plasmids. This will serve as a positive control and will also provide a correlation between the sensitivity and specificity of qPCR vs ddPCR. Results and Discussions We hypothesize that our dPCR test will be able to detect minute quantities of HPV ctDNA in plasma of cervical cancer patients as ctDNA levels are expected to be decrease as treatment progresses. The assay sensitivity and specificity will be obtained by comparing results to QPCR. The study samples involve a tumor biopsy and a blood sample at the baseline prior to the therapy and serial blood sampling in different stages of treatment and follow-ups. These samples will also serve for treatment monitoring of these patients through ddPCR. Tumor samples are used to confirm the HPV status of patients using HPV-specific GP5+/GP6+ qPCR. We have recruited 75 cervical cancer patients with majority of them being squamous cell carcinoma and stage IIB disease. The qPCR results from tumor biopsy revealed HPV 16 was most prevalent (32/43), followed by HPV18 (6/43) and HPV 33(2/43). Conclusion we will now use Qiagen digital PCR system to understand HPV ctDNA levels in our patient cohort. we believe that our comprehensive sample collection after every treatment milestone and thorough follow-up for upto 2 years after diagnosis will allow us to study the utility of this sensitive test in monitoring disease and relapse. Citation Format: Preetiparna Parida, Krishna Sharan, Shirley Lewis, Rama Rao Damerla. Longitudinal monitoring of HPV circulating tumor DNA in cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2297.