tbuckley/cabot-search huggingface dataset:
Abstract 1082: Arid1a deletion results in enhanced osteosarcomagenesis and altered chromosome structure
Authors: Kaniz Fatema, Shawn Plyler, Adriene Pavek, Chris Nartker, Yanliang Wang, Kevin Jones, Jared Barrott
Journal: Cancer Research (2020)

Abstract Osteosarcoma (OS) is a primary malignant bone tumor mainly affecting children and young adults. Early metastasis, chemoresistance and stagnation in the treatment options for the last 4 decades result in a less than 20% chance of long-term survival in metastatic OS. Investigating the molecular mechanisms underlying a more aggressive phenotype in osteosarcoma will certainly help develop novel treatment alternatives. Through a transposon-mediated forward genetic screen, we were able to increase osteosarcomagenesis by random mutagenesis. Among the possible candidate genes on our list, we discovered a loss-of-function mutation in ARID1A. ARID1A is a member of the SWI/SNF chromatin-remodeling protein complex and has been implicated as a tumor suppressor in other cancers. We hypothesized that loss of ARID1A in osteosarcoma would increase the rate of tumor progression and metastasis by impacting the epigenetic configuration of the chromatin. In-vitro (CRISPR/Cas9) deletion in human OS cell lines and cell behavioral studies validated that ARID1A loss contributes to faster tumorigenesis. To understand its effect in-vivo, we have developed mice cohorts with or without ARID1A with a Cre-mediated, Osteoblast specific (Osx) conditional knockout system. We observed that Arid1a-mutant mice develop tumors and die on an average 13 weeks earlier than that of the wildtype cohort. By 3D micro CT scanning, we further confirmed a relatively higher number of primary and metastatic tumors in the Arid1a mutant mice, albeit the histology and morphology of the tumors did not change. The analysis of genome-wide chromatin accessibility by ATAC-seq confirmed an open chromatin organization in Arid1a mutant mouse samples. We conclude that, acting as an epigenetic regulator, ARID1A plays a significant role in osteosarcoma progression and metastasis. Further investigation to strengthen this link would present the opportunity for alternatively targeting genetically unstable cancers with epigenetic drugs. Citation Format: Kaniz Fatema, Shawn Plyler, Adriene Pavek, Chris Nartker, Yanliang Wang, Kevin Jones, Jared Barrott. Arid1a deletion results in enhanced osteosarcomagenesis and altered chromosome structure [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1082.
Targeting Isocitrate Dehydrogenase Mutations in Cancer: Emerging Evidence and Diverging Strategies
Authors: Matthew S. Waitkus, Hai Yan
Journal: Clinical Cancer Research (2020)

Abstract Isocitrate dehydrogenase (IDH) active-site mutations cause a neomorphic enzyme activity that results in the formation of supraphysiologic concentrations of D-2-hydroxyglutarate (D-2HG). D-2HG is thought to be an oncometabolite that drives the formation of cancers in a variety of tissue types by altering the epigenetic state of progenitor cells by inhibiting enzymes involved in histone and DNA demethylation. This model has led to the development of pharmacologic inhibitors of mutant IDH activity for anticancer therapy, which are now being tested in several clinical trials. Emerging evidence in preclinical glioma models suggests that the epigenetic changes induced by D-2HG may persist even after mutant IDH activity is inhibited and D-2HG has returned to basal levels. Therefore, these results have raised questions as to whether the exploitation of downstream synthetic lethal vulnerabilities, rather than direct inhibition of mutant IDH1, will prove to be a superior therapeutic strategy. In this review, we summarize the preclinical evidence in gliomas and other models on the induction and persistence of D-2HG–induced hypermethylation of DNA and histones, and we examine emerging lines of evidence related to altered DNA repair mechanisms in mutant IDH tumors and their potential for therapeutic exploitation.
Abstract 4569: DNA vaccine targeting BARF1 induces potent antitumor immunity against Epstein-Barr virus-associated carcinomas
Authors: Xizhou Zhu
Journal: Cancer Research (2020)

Abstract Epstein-Barr Virus (EBV) is an oncogenic pathogen, with which more than 90% of world population has been infected. It is associated with several types of cancer, and no EBV-specific therapies are available for these diseases. Recent studies targeting EBV latent proteins have shown limited efficacy, for their moderate immunogenicity. Therefore, the development of effective anti-EBV immunotherapies is in need. In this study, we screened a group of EBV proteins and selected BARF1 as a vaccine candidate, for its strong immunogenicity and high expression in EBV positive nasopharyngeal and gastric carcinomas. The BARF1 vaccine was developed through a synthetic DNA approach and delivered in vivo by electroporation. The vaccine induced potent BARF1-specific antibody and polyfunctional effector T cell responses in both C57BL/6 and BALB/c mice. We next established two carcinoma models by generating BARF1-expressing CT26 and MC38 cell lines. In the therapeutic model where mice were challenged with cancer cells and then treated, BARF1 vaccine was able to suppress cancer progression alone and showed synergy when combined with anti-PD1 antibody. In the minimal residual disease model where mice were immunized and then challenged with cancer cells, one dose of BARF1 vaccine was able to generate 100% complete response in treated animals. CD8 T cell was shown to be necessary for this protection. Finally, using the in vivo imaging system, we found that the BARF1 vaccine-induced immune responses cleared tumor in 60% of subjects as soon as 48 hours post tumor challenge. Tumors were cleared in all animals by day 10. In summary, BARF1 DNA vaccine provides a novel tool of immunotherapy that is highly specific to EBV positive malignancies and combining it with checkpoint inhibitors might open up new avenues for precision and combination immunotherapy against EBV-associated cancer. In the future, we will also target other viral-specific cancer antigens with our DNA vaccine platform, exploiting its capability to induce potent cytotoxic T lymphocyte response. Citation Format: Xizhou Zhu. DNA vaccine targeting BARF1 induces potent antitumor immunity against Epstein-Barr virus-associated carcinomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4569.
Abstract 94: Pla2g4a: A new cell cycle related gene in patients with non-M3/NPM1 wildtype acute myeloid leukemia
Authors: Hansong Bai, Zeng Ming
Journal: Cancer Research (2020)

Abstract In this study, we aimed to explore and validate the prognostic value of PLA2G4A expression in patients with non-M3/NPM1 wildtype (WT) acute myeloid leukemia (AML) using two independent datasets. Data from the Cancer Genome Atlas-Acute Myeloid Leukemia (TCGA-LAML) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-AML were used to assess the prognostic value PLA2G4A in NPM1-WT AML cases. A single-cell RNA-seq dataset that included 96 AML cells from a recurrent AML case was used to check the correlation between PLA2G4A expression and the functional state of AML cells. Results showed that non-M3 AML cases had significantly increased PLA2G4A expression compared to normal peripheral blood samples. Multivariate analysis showed that high PLA2G4A expression was independently associated with shorter OS in 97 non-M3/NPM1-WT AML cases in TCGA-LAML (HR: 1.932, 95%CI: 1.092-3.419, p=0.024). The prognostic value was validated based on 128 non-M3/NPM1-WT AML cases in TARGET-AML (HR: 1.894, 95%CI: 1.065-3.369, p=0.030). Single-cell RNA-seq data suggested that PLA2G4A expression was positively correlated with cell cycle progression of AML cells. Therefore, PLA2G4A expression might serve as an independent prognostic marker in OS in patients with non-M3/NPM1 WT AML. Its upregulation might confer malignant phenotype of AML cells at least partly by promoting cell cycle progression. Future molecular studies are required to explore other molecular pathways involved. Citation Format: Hansong Bai, Zeng Ming. Pla2g4a: A new cell cycle related gene in patients with non-M3/NPM1 wildtype acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 94.
Abstract 2736: AKT1E17K activates focal adhesion kinase and promotes melanoma brain metastasis
Authors: David A. Kircher, Kirby A. Trombetti, Mark R. Silvis, Gennie L. Parkman, Grant M. Fischer, Stephanie N. Angel, Christopher M. Stehn, Sean C. Strain, Allie H. Grossmann, Keith L. Duffy, Martin McMahon, Michael A. Davies, Michelle C. Mendoza, Matthew W. VanBrocklin, Sheri L. Holmen
Journal: Cancer Research (2020)

Abstract Hyper-activation of the PI3K/AKT signaling pathway occurs in most metastatic melanomas and increased PI3K/AKT pathway activity correlates with disease progression. The serine/threonine kinase, AKT, represents a major signaling hub within the pathway and consists of three highly conserved paralogs that have both distinct and overlapping functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear. Using an established melanoma mouse model, we evaluated the ability of constitutively active E17K, E40K, or Q79K mutants of each AKT paralog to promote tumor progression and metastasis in the context of BRAFV600E expression and loss of Cdkn2a and Pten. Expression of AKT1E17K promoted highly aggressive melanomas that metastasized to the lungs and brain. This metastatic phenotype was not significantly observed in the case of other mutant AKT-positive tumors, suggesting that the AKT paralogs have distinct, non-overlapping roles in the development of melanoma metastases. AKT1E17K-positive tumors showed AKT1E17K-dependent up-regulation of multiple focal adhesion (FA) factors, which are key components of focal adhesions and established stimulators of cell motility, as well as phosphorylation of focal adhesion kinase (FAK). Ectopic expression of AKT1E17K in non-metastatic melanoma cells increased cell invasion, a phenotype abrogated by pharmacological inhibition of AKT or FAK. These findings strongly suggest that one mechanism by which AKT1 promotes melanoma metastasis is through regulation and activation of proteins involved in focal adhesions. This has important implications for the development of therapeutic strategies aimed at preventing or treating disseminated disease. Citation Format: David A. Kircher, Kirby A. Trombetti, Mark R. Silvis, Gennie L. Parkman, Grant M. Fischer, Stephanie N. Angel, Christopher M. Stehn, Sean C. Strain, Allie H. Grossmann, Keith L. Duffy, Martin McMahon, Michael A. Davies, Michelle C. Mendoza, Matthew W. VanBrocklin, Sheri L. Holmen. AKT1E17K activates focal adhesion kinase and promotes melanoma brain metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2736.
Abstract 2774: Longitudinal characterization of patient-derived orthotopic xenograft brain tumor models
Authors: Julia Schueler, Mariette Heins, Artem Shatillo, Kimmo Lehtimäki, Anne-Lise Peille, Taina-Kaisa Stenius, Timo Bragge, Jussi Rytkönen, Diana Miszczuk, Tuulia Huhtala
Journal: Cancer Research (2020)

Abstract Gliomas are the most common primary brain tumors and currently the prognosis is still poor. Due to this, it is one of the main areas in oncological research and drug development programs. Innovative therapies are vital to improve treatment outcomes but must be developed to enable trafficking across the blood brain barrier (BBB). For this advent, animal models provide important information prior to clinical studies. Among the different in vivo models, orthotopic PDX models represent best the tumor microenvironment and natural variability of tumors, hence providing the most reliable results over species. In the brain tumor field, imaging has a central role in clinical diagnosis and as a prognostic factor to monitor therapy response in patients. Magnetic resonance imaging (MRI) is widely used for clinical diagnosis and disease follow up as it offers unprecedented soft tissue contrast and high spatial resolution non-invasive way. In addition to imaging, molecular profiling, e.g. circulating immune biomarkers and local oncometabolites in the tumor environment may facilitate as important translational biomarkers in development of immunotherapy for gliomas in addition to traditional histopathological readouts. The purpose of this work was to analyze possible heterogeneity of tumors in vivo, growth rate and volume in stereotactically implanted orthotopic PDX brain tumor models using MRI/MRS imaging. In addition to imaging, neurological scoring was performed to monitor general animal welfare, cytokine profiles from plasma to observe immunological responses over time and determination of oncometabolites in plasma and brain tissues combined with traditional histopathological changes were performed. The data from orthotopic models was also compared to readouts in subcutaneous models. As a conclusion, translational in vivo imaging techniques were applied to study orthotopic tumor progression combined with circulating immune biomarkers, and general welfare scoring. These readouts provide a powerful and translational research tool together with oncological disease animal models allowing comprehensive evaluation of disease progression and treatment interventions for in vivo studies. Citation Format: Julia Schueler, Mariette Heins, Artem Shatillo, Kimmo Lehtimäki, Anne-Lise Peille, Taina-Kaisa Stenius, Timo Bragge, Jussi Rytkönen, Diana Miszczuk, Tuulia Huhtala. Longitudinal characterization of patient-derived orthotopic xenograft brain tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2774.
Colocality to Cofunctionality: Eukaryotic Gene Neighborhoods as a Resource for Function Discovery
Authors: Fatima Foflonker, Crysten E Blaby-Haas
Journal: Molecular Biology and Evolution (2020)

Diverging from the classic paradigm of random gene order in eukaryotes, gene proximity can be leveraged to systematically identify functionally related gene neighborhoods in eukaryotes, utilizing techniques pioneered in bacteria. Current methods of identifying gene neighborhoods typically rely on sequence similarity to characterized gene products. However, this approach is not robust for nonmodel organisms like algae, which are evolutionarily distant from well-characterized model organisms. Here, we utilize a comparative genomic approach to identify evolutionarily conserved proximal orthologous gene pairs conserved across at least two taxonomic classes of green algae. A total of 317 gene neighborhoods were identified. In some cases, gene proximity appears to have been conserved since before the streptophyte-chlorophyte split, 1,000 Ma. Using functional inferences derived from reconstructed evolutionary relationships, we identified several novel functional clusters. A putative mycosporine-like amino acid, "sunscreen," neighborhood contains genes similar to either vertebrate or cyanobacterial pathways, suggesting a novel mosaic biosynthetic pathway in green algae. One of two putative arsenic-detoxification neighborhoods includes an organoarsenical transporter (ArsJ), a glyceraldehyde 3-phosphate dehydrogenase-like gene, homologs of which are involved in arsenic detoxification in bacteria, and a novel algal-specific phosphoglycerate kinase-like gene. Mutants of the ArsJ-like transporter and phosphoglycerate kinase-like genes in Chlamydomonas reinhardtii were found to be sensitive to arsenate, providing experimental support for the role of these identified neighbors in resistance to arsenate. Potential evolutionary origins of neighborhoods are discussed, and updated annotations for formerly poorly annotated genes are presented, highlighting the potential of this strategy for functional annotation.
Abstract 2379: Elaborating the mechanism of PARP synthetic lethality in ATM loss
Authors: Asli Muvaffak, Kevin G. Coleman
Journal: Cancer Research (2020)

Abstract PARP inhibitors have transformed the treatment for ovarian cancer, which is known to have high incidence of homologous recombination (HR) deficiency through the loss of BRCA1 or BRCA2 genes. 30-35% of ovarian cancer patients have defects in BRCA1/2 genes caused by germline, somatic or epigenetic alterations. PARP inhibitors induce cell death in HR-deficient cells through the mechanism of synthetic lethality where cancer cells cannot tolerate the loss of both SSB and DSB repair machinery. Although genetic or epigenetic alterations in other pathways such as Fanconi anemia, or in non-authentic homologous recombination repair (HRR) genes such as PTEN, IDH, and CDK12 have been reported to contribute to HR deficiency, mechanistic understanding of HR loss remains to be determined. Another DNA damage repair (DDR) protein, ATM, a kinase that phosphorylates and activates major DNA damage checkpoints, i.e. CHK2 &amp; BRCA1, has also being increasingly recognized recently as a synthetic lethal partner with PARP inhibitors in multiple tumor indications such as prostate, lung and colorectal cancers. ATM functions in both cell cycle arrest and DNA repair in response to DSBs, however how cells respond to inhibition of PARP in the absence of ATM is not yet fully understood. In this study, we demonstrated that loss of ATM function, i.e. via generating an ATM KO by CRISPR/Cas9 in two genetic backgrounds, i.e. in DLD-1 and HeLa cell lines, induced HR-deficiency indicated by the impairment of Rad51-foci formation and increased phosphorylation of histone H2AX in ATM KO (-/-) cell lines. Furthermore DLD-1 ATM KO (-/-) cell line demonstrated increased sensitivity to niraparib (i.e. 45-fold difference in sensitivity compared to the DLD-1 parental, HR-proficient cell line) in the 14day colony formation assay. In comparison, BRCA2 (-/-) KO in DLD-1 gave a 125-fold increase compared to parental cell line. In DLD-1 ATM KO (-/-) cell line, we have also detected that loss of ATM was associated with low BRCA1 and BRCA2 protein expression suggestive of downstream effect on impairment of HR-mediated DNA checkpoint signaling in ATM loss. Thus, PARPi synthetic lethality phenotype observed in tumors with ATM loss could be regulated through the combination effect coming from the loss of both of ATM &amp; BRCA1/2 and the subsequent effect on both HR gene functions. Our findings highlight that ATM has a critical role in DNA repair for the synergism with PARP inhibitors. Citation Format: Asli Muvaffak, Kevin G. Coleman. Elaborating the mechanism of PARP synthetic lethality in ATM loss [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2379.
Abstract 3501: Lower perceived colorectal cancer risk is associated with less aerobic physical activity in Latino adults
Authors: Pooja Agrawal, Jocelyn Yanez, Rosenda Murillo
Journal: Cancer Research (2020)

Abstract INTRODUCTION: Engaging in aerobic physical activity (PA) has been linked to reduced risk of adverse health outcomes, such as colorectal cancer (CRC). Despite known benefits of engaging in aerobic PA, Latino adults have a low prevalence of aerobic PA compared to other racial/ethnic groups. Limited research has examined the relationship between perceived risk of CRC and aerobic PA among Latinos. Therefore, the purpose of our study was to examine perceived risk of CRC and aerobic PA among US Latino adults. METHODS: We used cross-sectional 2015 National Health Interview Survey (NHIS) data on Latino participants ≥18 years of age (n=5,457). Perceived CRC risk was assessed based on self-reported measures to which participants responded whether they considered themselves at less than average risk, average risk, or higher than average risk for CRC. Aerobic PA was measured based on self-reported minutes of moderate-to-vigorous aerobic activity per week, which were categorized into none (0 min/week), some aerobic PA (&amp;gt;0 min/week of activity but less than recommendation), and meeting the aerobic activity guideline (≥150 min of moderate-vigorous PA or ≥75 min of vigorous PA or 150 min of moderate PA/week). Multinomial logistic regression models that accounted for complex survey design of NHIS were used to estimate the associations between perceived risk of CRC (ref= less than average risk) with aerobic PA (ref= none). All models were adjusted for age, sex, education, insurance, and nativity. RESULTS: In adjusted models, compared with individuals who perceived themselves at higher than average risk, those who perceived themselves at less than average risk for CRC were significantly less likely to engage in some aerobic activity (Odds Ratio [OR]: 0.63, 95% Confidence Interval [CI]: 0.40-0.99). In addition, those who perceived themselves at average risk for CRC were also significantly less likely to engage in some aerobic activity (OR 0.60, 95% CI: 0.37-0.96). CONCLUSION: These findings suggest that perceived CRC risk is associated with aerobic activity among Latino adults. CRC prevention efforts should consider the role of perception of CRC risk in the promotion of physical activity among Latinos. Citation Format: Pooja Agrawal, Jocelyn Yanez, Rosenda Murillo. Lower perceived colorectal cancer risk is associated with less aerobic physical activity in Latino adults [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3501.