tbuckley/cabot-search huggingface dataset:
Abstract 1696: ACTL6A deficiency drives cell death through KLF4-involved chromatin accessibility changes in colorectal cancer
Authors: Hye-Ju Yang, Eun-Ju Kim, Sang-Hyun Song, Tae-You Kim
Journal: Cancer Research (2024)

Abstract ACTL6A is a subunit of the SWI/SNF and INO80 chromatin remodeling complexes and plays roles in neural development and cancer cell proliferation. Additionally, it is known to be upregulated in various types of cancer and is associated with a decrease in patient survival rates. However, the mechanism of how chromatin remodelers including ACTL6A cause cell death has yet to be defined. Therefore, we would like to investigate how the depletion of ACTL6A promotes cell growth reduction by mediating changes in the epigenetic landscape in colorectal cancer cells. We engineered ACTL6A knockout by CRISPR-Cas9. We performed Assay for transposase-accessible chromatin using sequencing (ATAC-seq), RNA sequencing (RNA-seq), and Chromatin Immunoprecipitation sequencing (ChIP-seq) for SMARCB1 and INO80, as representative members of their respective families, and KLF4. Moreover, HCT116 cells stably transduced with doxycycline-inducible shGFP or shACTL6A were implanted into the flank of nude mice. One week after tumor implantation, mice were randomly allocated to 4 groups (n=13-15 per group) and doxycycline treated group was administered with doxycycline (1mg/ml) and 5% sucrose in the drinking water. Tumor volume was measured with calipers. Upon depletion of ACTL6A, the regions of increased chromatin accessibility were correlated with the upregulated genes. After the loss of ACTL6A, there was a significant increase in KLF4 expression and genomic binding largely increased, coinciding with an increase in newly accessible regions containing KLF4 motifs. Interestingly, there is a strong positive correlation between changes in chromatin accessibility and overall changes in the binding of KLF4, SWI/SNF, and INO80 complexes. We find that changes in chromatin accessibility are co-regulated by KLF4, the SWI/SNF and the INO80 complex, while SWI/SNF and INO80 complex have a low correlation in binding between the SWI/SNF and INO80 complexes at newly accessible regions, indicating no physical interactions between these two chromatin complexes. Overall, we demonstrated that the redistribution of ACTL6A-deficient two chromatin remodeling complexes and KLF4 is associated with changes in chromatin accessibility, which are also linked to upregulated genes that promote the p53 pathway. These findings revealed the role of KLF4 along with the SWI/SNF and INO80 complexes, in regulating the chromatin landscape and gene expression in ACTL6A-depleted colorectal cancer cells. Citation Format: Hye-Ju Yang, Eun-Ju Kim, Sang-Hyun Song, Tae-You Kim. ACTL6A deficiency drives cell death through KLF4-involved chromatin accessibility changes in colorectal 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 1696.
Abstract 1945: Mechanisms of acquired resistance to EGFR tyrosine kinase inhibitor osimertinib and KRAS-G12C inhibitor sotorasib in lung cancer
Authors: Yuri Yagami, Takashi Sato, Hiroki Yamamoto, Masayuki Shirasawa, Yoshiro Nakahara, Watanabe Hideo, Naoki Katsuhiko
Journal: Cancer Research (2024)

Abstract A series of molecular targeted drugs have been developed for the treatment of non-small cell lung cancer (NSCLC) harboring driver gene alterations. Although the use of these drugs has substantially improved the clinical outcomes of patients with the genetically altered NSCLC, these patients ultimately develop resistance to the drugs. Various molecular mechanisms of resistance to the molecular target therapies have been reported, it is still a crucial challenge to overcome the drug resistance. Osimertinib, the most used third-generation EGFR tyrosine kinase inhibitor to target both common EGFR mutations and secondary T790M mutation, and sotorasib, a recently developed KRAS inhibitor to target KRAS G12C mutation, are no exception. In this study, we aimed to investigate the mechanisms of acquired resistance to osimertinib and sotorasib in NSCLC by profiling drug-resistant lung cancer cell lines, which were established from EGFR-mutant HCC827(del E756_A750) and KRAS G12C-mutant H23 through exposure to each of the molecular targeted drugs. Phospho-RTK array and western blot analyses revealed MET overexpression and phosphorylation in the osimertinib-resistant HCC827 (HCC827OR) as previous studies reported. Notably in our study, HCC827OR cells were incompletely sensitive to a selective MET inhibitor savolitinib without osimertinib, suggesting that HCC827OR partially lost its dependency on mutant EGFR and got addiction to MET signaling. When sotolasib was administered to the sotolasib-resistant H23 (H23SR) cells, KRAS-GTP, and the downstream ERK and AKT phosphorylation were suppressed. To identify novel mechanisms of the resistance, we performed epigenomic profiling of active enhancer in those cells and found a candidate transcription factor, at whose gene locus H3K27 acetylation signal was increased in H23SR cells compared to parent H23 cells. Immunoblotting showed that protein expression of the gene was indeed higher in H23SR cells than the parent cells. To confirm the involvement of this gene to the resistance, further investigation is warranted. Citation Format: Yuri Yagami, Takashi Sato, Hiroki Yamamoto, Masayuki Shirasawa, Yoshiro Nakahara, Watanabe Hideo, Naoki Katsuhiko. Mechanisms of acquired resistance to EGFR tyrosine kinase inhibitor osimertinib and KRAS-G12C inhibitor sotorasib in lung 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 1945.
Abstract 4968: Discovery of cancer-associated factors in 293.5 million diagnosis records using statistical machine learning analysis
Authors: Md Ashad Alam, Nick Duesbery, Daniel Daniel Fort
Journal: Cancer Research (2024)

Abstract Cancer, a leading global public health issue, ranks as the second leading cause of death in the United States, with projections indicating 1,958,310 new cases and 609,820 deaths in 2023. Accurately quantifying specific pre-disease diagnosis factors associated with cancer, as well as predicting cancer through disease trajectories and imaging modalities, presents a complex and formidable challenge. A comprehensive temporal trajectory analysis of cancer diseases, using disease trajectories as an insight within large cohorts in the USA, has not yet been developed. Our analysis used a comprehensive EHR dataset stretching back to 1999, encompassing 293,501,891 records and involving 3,019,978 patients within Ochsner Health, a large integrated health system across the State of Louisiana. According to our investigation, those diagnosed at the ICD chapter level with diseases of the genitourinary system (genitourinary diseases, ICD-10 Chapter 14, relative risk (RR=1.65)) or endocrine nutritional and metabolic diseases (obesity, ICD-10 Chapter 4, RR=1.35) have an elevated risk of being diagnosed with cancer in the subsequent five years. The top four individual diagnosis ICD-10 codes associated with increased risk are N60 (Benign Mammary dysplasia, RR=7.80), M34 (Systemic sclerosis, RR=7.72), R43 (Disturbances of smell and taste, RR=6.93), and R92 (Abnormal and inconclusive findings on diagnostic imaging of the breast, RR=6.59). Furthermore, in our investigation of specific types of cancer risk across 17 cancer types (Breast, Skin, Prostate, Lung, Pancreatic, etc.), we observed that the most common diseases associated with breast and skin cancer involved immune mechanisms (RR=8.35 and 8.68), genitourinary issues (RR=4.13 and 2.48), obesity (RR=3.42 , 3.35), and cardiovascular conditions (ICD-10 Chapter 9, RR=1.73 and 2.19). For prostate cancer, associations were found with obesity (RR=3.50), human immunodeficiency virus (HIV, ICD-10 Chapter 1, RR=2.39). Across lung cancer, involvement with chronic viral hepatitis (ICD-10 Chapter 1, RR=4.00), cardiovascular issues (RR=3.52), genitourinary problems (RR=4.13), and obesity (RR=3.42) were indicated. Our comprehensive analysis has the potential to contribute to the early detection, diagnosis trajectories, and improved understanding of the pathological processes underlying cancer in patients worldwide. Citation Format: Md Ashad Alam, Nick Duesbery, Daniel Daniel Fort. Discovery of cancer-associated factors in 293.5 million diagnosis records using statistical machine learning 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 4968.
Abstract 2945: Using pooled minimal genome-wide sgRNA libraries to drive oncology drug discovery
Authors: Sebastian Lukasiak, Alex Kalinka, Nikhil Gupta, Khalid Saeed, Angelos Papadopoulos, Ultan McDermott, Gregory J. Hannon, Douglas Ross-Thriepland, David Walter
Journal: Cancer Research (2024)

Abstract The emergence of CRISPR technologies has enabled rapid and precise gene editing opportunities. The Functional Genomics Centre (FGC) - a joint venture between Cancer Research UK’s (CRUK) drug discovery engine, Cancer Research Horizons, and AstraZeneca has been launched to better utilize and improve the CRISPR technology within cancer research. The FGC leverages the strengths of both CRUK’s and AstraZeneca’s world-class oncology research and drug discovery experience, with the potential to drive scientific innovation in how new drug targets are identified and validated, and uniquely democratize access to the latest cutting-edge research tools and expertise for many thousands of scientists and clinicians funded by CRUK. Here, we will showcase how the FGC is leading the development and refinement of functional genomics technologies. Through independent evaluation of publicly available CRISPR tools and leveraging this data we have designed optimized, minimal genome-wide CRISPR libraries. These libraries permit a reduction of the experimental scale of CRISPR screens by 50% and enable our Target Discovery platform to impact more projects, faster, at a lower cost and importantly - more sustainably. Citation Format: Sebastian Lukasiak, Alex Kalinka, Nikhil Gupta, Khalid Saeed, Angelos Papadopoulos, Ultan McDermott, Gregory J. Hannon, Douglas Ross-Thriepland, David Walter. Using pooled minimal genome-wide sgRNA libraries to drive oncology drug discovery [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 2945.
Abstract 7486: Development and analytic validation of an ARv7/PSMA dual biomarker circulating tumor cell assay
Authors: Jon Ladd, Erin Bayer, Brock Bartels, Eric Kaldjian, Arturo Ramirez
Journal: Cancer Research (2024)

Abstract Background Prostate cancer drug targets and biomarkers may be investigated non-invasively on circulating tumor cells (CTCs) obtained via liquid biopsies. PSMA is an important drug target in prostate cancer, and ARv7 is a splice variant that confers resistance to second-generation androgen receptor inhibitors. In this study, we describe the development and analytic validation of a novel assay to quantify ARv7 and PSMA protein expression on CTCs. The assay was validated with blood samples from patients with Stage IV prostate cancer to demonstrate clinical feasibility. To our knowledge, a PSMA/ARv7 dual protein assay for CTCs has not previously been reported. Methods LNCaP (PSMA positive), PC3 (PSMA negative), 22Rv1 (ARv7 positive), and BT474 (ARv7 negative) cells were spiked into healthy donor blood to generate model CTCs. Nucleated cells were collected from these spike-in samples using the AccuCyte® sample preparation kit and spread onto microscope slides. Slides were fixed and stained with antibodies to cytokeratin, EpCAM, and CD45 to detect CTCs and exclude white blood cells (WBCs), and with PSMA and ARv7 to evaluate protein expression on identified CTCs. The slides were imaged with the CyteFinder® automated immunofluorescence scanning microscope that identifies CTCs for confirmation by trained reviewers based on machine learning algorithms and quantitatively measures biomarker signal mean fluorescence intensity (MFI). Results For ARv7/PSMA expression classification of the model CTCs, the dual biomarker assay showed analytic sensitivity of 83%/97% and specificity 98%/99%, yielding accuracy of 90.2%/97.9%, respectively. The dynamic range of MFI for both biomarkers was approximately three orders of magnitude. Inter-run reproducibility CV was 13.6% (ARv7) and 6.9% (PSMA). Slide repeatability mean CV was 11.1% (ARv7) and 12.0% (PSMA). Clinical feasibility of the assay was investigated in 9 progressing Stage IV prostate cancer patient blood samples. CTCs were identified in all clinical samples (median 4, range 1 - 384). Thresholds for biomarker positivity were established based on MFI measurements of positive and negative control cell lines. ARv7 positivity in clinical samples ranged from 33% to 100%, and PSMA positivity ranged from 0% to 75%. Conclusions We have developed a dual ARv7/PSMA assay that simultaneously measures protein expression of both biomarkers on individual CTCs. The assay is accurate and reproducible for the assessment of ARv7 and PSMA expression by liquid biopsy in clinical studies. Citation Format: Jon Ladd, Erin Bayer, Brock Bartels, Eric Kaldjian, Arturo Ramirez. Development and analytic validation of an ARv7/PSMA dual biomarker circulating tumor cell assay [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 7486.
Abstract 767: The role of abdominal obesity in the association between obesity and prostate cancer: A U.S. population-based cross-sectional study NHANES 2001-2020
Authors: Anwar E. Ahmed, Callista B. Martin, Bassam Dahman, Sean Q. Kern, Gregory T. Chesnut
Journal: Cancer Research (2024)

Abstract Background: Research suggests inconsistent evidence regarding the association between general obesity and prostate cancer among men in the United States. This study aimed to examine whether the association between general obesity and prostate cancer is influenced by abdominal obesity. Methods: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), 2001-2020, a nationally representative survey. The analysis was restricted to 16,703 non-Hispanic men (10,683 White and 6,020 Black). General obesity was defined by a body mass index of 30 kg/m2 or greater and abdominal obesity was defined by a waist circumference of 102 cm or greater. Respondents were classified into four mutually exclusive groups according to the body fat indicators: 1) presence of both general and abdominal obesity, 2) abdominal obesity without general obesity, 3) general obesity without abdominal obesity, and 4) none of the two (the reference group). Results: The overall prevalence of prostate cancer was 2.25% (95% CI: 2.0-2.5%). Men with abdominal obesity without general obesity have significantly higher prevalence of prostate cancer (4.28%) compared to men with both abdominal obesity and general obesity (2.23%), men with neither abdominal obesity or general obesity (1.70%), and men with general obesity without abdominal obesity (0.18%), P &amp;lt;.0001. Black men with abdominal obesity without general obesity have the highest prevalence of prostate cancer (7.21%), followed by White men with abdominal obesity without general obesity (4.10%). With and without adjusting for age and education, men with abdominal obesity without general obesity had significantly higher odds of prostate cancer, regardless of ethnicity. Black men with both abdominal obesity and general obesity had significantly higher odds of prostate cancer. General obesity without abdominal obesity was inversely associated with prostate cancer in White men but not in Black men. Conclusions: This study illustrates that waist circumference is a potential classifier of prostate cancer as it shows variation in prevalence of prostate cancer by general obesity within the same and different racial and ethnic groups. Citation Format: Anwar E. Ahmed, Callista B. Martin, Bassam Dahman, Sean Q. Kern, Gregory T. Chesnut. The role of abdominal obesity in the association between obesity and prostate cancer: A U.S. population-based cross-sectional study NHANES 2001-2020 [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 767.
Abstract 5048: NF2 mutations are enriched in FH deficient renal cell cancer
Authors: Khaled Bin Satter, Liqian Xi, Christopher Rickets, William M. Linehan, Maria J. Merino
Journal: Cancer Research (2024)

Abstract Introduction: NF2 is a tumor suppressor gene in charge of producing a protein called Merlin that controls cell growth and division. Mutations in the NF2 gene affect predominantly the nervous system causing the development of benign tumors. NF2 mutations have been reported in Renal cancers with morphologically specific tumor types and in aggressive tumors. We studied a cohort of 16 cases of RCC in which the NF2 mutation was identified and describe other molecular changes as well as morphology and clinic-pathological correlation. Materials and Methods: Sixteen patients had been consented and treated for renal masses in protocols of the UOB division of the NCI. Next generation sequencing was performed with tumor DNA from FFPE tissue using the Illumina TruSight Oncology 500 Kit (TSO500) NextSeq 550DX. TSO500 assay was designed to detect single nucleotide variations, small insertions/deletions, copy number variations from 92 genes, TMB and MSI. Morphology and IHC stains were performed. Results: Nine patients were female and 7 males, ranging in age from 21 to 87 years. Fourteen patients underwent partial or total nephrectomies, one case had a biopsy and in 1 case a metastatic tumor to a lymph node was studied. Morphologically, nine cases were diagnosed as HLRCC, three clear cells, two cases with clear and papillary cell, one medullary and one oncocytoma. Genetic findings revealed mutations in NF2, FH,VHL, SMARCB1, HOBB13, ARID1B, B2M, EP300, BCORL1 and MGA. Concurrent coexistence of NF2 and FH mutations was present in 9 cases. Three patients with concurrent FH and NF2 mutations died of the disease. Conclusions: NF2 mutations have been identified in a variety of morphologic types of Renal cell cancer. However, we were surprised by the number of cases with NF2 mutation in tumors that also harbor the FH (HLRCC) mutation. NF2 tumors have been reported to have an aggressive behavior, and FH cancers are also known to have poor survival. Genomic studies of renal cancers is recommended since some genetic alterations are targetable and may provide adequate therapies that will lead to longer survivals. Citation Format: Khaled Bin Satter, Liqian Xi, Christopher Rickets, William M. Linehan, Maria J. Merino. NF2 mutations are enriched in FH deficient renal cell 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 5048.
Abstract 4669: Differential preclinical activity of Bruton tyrosine kinase inhibitors (BTKis) against <i>BTK</i> resistance-associated mutations
Authors: Matthew S. Davids, Inhye E. Ahn, Jacob J. Riehm, Melih Acar, Vincent Girardi, Sima Patel, Tarikere Gururaja, Jennifer Woyach, Lloyd T. Lam, Edith Szafer-Glusman
Journal: Cancer Research (2024)

Abstract Background: Differences in profiles of acquired mutations of resistance to BTKis might have implications for treatment sequencing. We evaluated preclinical activity of BTKis (ibrutinib [Ibr], acalabrutinib [Acala], zanubrutinib [Zanu], and pirtobrutinib [Pirto]) against multiple clinically relevant BTK mutations and report on the clinical impact of BTK C481S in patients (pts) treated with Ibr. Methods: Inhibition of kinase activity by BTKis was evaluated in a cell-free kinase activity assay (Nanosyn). Cell-killing activity on CRISPR-generated BTK mutant knock-in TMD8 cells was assessed after 3 days of BTKi treatment. Time from first detection of C481S mutation to progressive disease (PD) was evaluated in pts treated with Ibr with previously untreated (n=247) or relapsed/refractory (R/R; n=172) CLL using pooled data from 5 clinical trials. Results: In vitro kinase activity was highest for Ibr compared with Acala or Zanu against C481S (Ibr IC50: 26.3 nM; Zanu: 84.8 nM; Acala: 338 nM) and T474I (Ibr: 1.2 nM; Zanu: 4.4 nM; Acala: 43.6 nM). Ibr maintained cell-killing activity against all tested BTK mutants, whereas limited activity was seen with Acala against C481S and A428D; with Zanu against C481S, L528W, and A428D; and with Pirto against T474I, L528W, V416L, and A428D (Table). In pts treated with Ibr, C481S was detected prior to clinical PD in 3 previously untreated pts and in 26 pts with R/R CLL; median (range) time from first detection of C481S to PD in these pts was 17.0 mo (11.2-34.3) and 10.0 mo (2.6-35.7), respectively. Conclusion: This study demonstrates activity of Ibr against all evaluated BTK variants, which are associated with resistance to covalent and noncovalent BTKis. Clinical data shows that pts who develop C481S mutations continue to derive benefit from Ibr for several months before PD. Together, these data suggest a role for Ibr in the treatment of pts with a broad spectrum of BTK variants. Table. Cell-killing activity of BTKis against wild type and mutant BTK EC50 (nM) BTK Wild type C481S T474I L528W V416L A428D Ibr 0.6 414.0 1.9 181.4 0.5 205.3 Acala 3.9 2973.8 43.3 3.5 106.3 3000.0 Zanu 0.7 2322.0 11.7 3000.0 0.6 1726.0 Pirto 8.2 12.6 2727.5 3000.0 1898.0 3000.0 Citation Format: Matthew S. Davids, Inhye E. Ahn, Jacob J. Riehm, Melih Acar, Vincent Girardi, Sima Patel, Tarikere Gururaja, Jennifer Woyach, Lloyd T. Lam, Edith Szafer-Glusman. Differential preclinical activity of Bruton tyrosine kinase inhibitors (BTKis) against BTK resistance-associated mutations [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 4669.