tbuckley/cabot-search huggingface dataset:
Abstract 816: Molecular and genomic characterization of a newly established male breast cancer cell line
Authors: Tereza Vaclova, Sarah Maguire, Matthew Pugh, Peter Barry, Nick Orr
Journal: Cancer Research (2017)

Abstract Although the majority of breast cancers affect women, approximately 1% of cases occur in men. At present comparatively little is known about the molecular mechanisms that influence male breast cancer predisposition and tumorigenicity. This is largely due to the current unavailability of an established cell line model in which to study male breast cancer. Development of in vitro models of the disease is therefore warranted, not least because growing evidence indicates that it is sufficiently different from female breast cancer such that extrapolating knowledge from one to the other may be misleading. Here we report the establishment and characterisation of a male breast cancer cell line derived from a primary tumor arising in a 61-year old male patient. We used 3T3-J2 mouse fibroblast co-culture in the presence of a ROCK inhibitor to conditionally reprogram epithelial cells from freshly resected tumor tissue. Once established, the cell line showed a rapid proliferation rate and growth in full conditioned media without the support of mouse fibroblasts. Immunohistochemical profiling demonstrated expression of epithelium-specific antigens AE1/AE3, breast epithelial marker CK7 and confirmed estrogen receptor positivity in concordance with the primary tumor. Germline sequencing detected no pathogenic germline predisposition mutations in either BRCA1 or BRCA2. There was no evidence of somatic mutation in any of the established female breast cancer driver genes. Somatic whole genome sequencing of early and late passages indicated a paucity of structural aberration and little evidence for obvious accumulation of gross genetic alterations. In conclusion, we have established a novel in vitro model for studying male breast cancer. That the cell line genome displays minimal evidence of significant acquired genetic changes arising due to reprogramming suggests that it will be of value in future studies of the biology of male breast cancer. Citation Format: Tereza Vaclova, Sarah Maguire, Matthew Pugh, Peter Barry, Nick Orr. Molecular and genomic characterization of a newly established male breast cancer cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 816. doi:10.1158/1538-7445.AM2017-816
Abstract 5772: Developing a patient derived 3D co-culture model of prostate organoids to examine biological mechanisms involved in prostate cancer disparities
Authors: Joseph Marsili, Zachary Richards, Jason Garcia, Cindy Voisine, Larisa Nonn
Journal: Cancer Research (2017)

Abstract The prostate is composed of a fibro-muscular stromal and glandular epithelial cells. Cross-talk between these cell populations is essential for normal prostate development and is involved in carcinogenesis. In the past year, an estimated 220,800 new cases of prostate cancer (PCa) were diagnosed and 27,540 died of PCa. PCa in African American men occurs more frequently, develops at a much earlier age, and is more aggressive and lethal compared to men of European descent. Both biological and socioeconomic factors likely contribute to this disparity. There is currently a paucity of relevant preclinical models in which to examine biological mechanisms in African American PCa. Patient-derived organoids are a recently developed in vitro preclinical model which facilitate examination of underlying mechanisms of disease etiology. However, current models of epithelial organoid growth lack the prostate stroma. To address this unmet need, we began development of a 3D organoid model that incorporated both primary human prostatic epithelial (PrE) and stromal (PrS) cells to better mimic the microenvironment of the organ. Prostate organoids were derived from cells collected from radical prostatectomy tissues from patients (UIC IRBs: 2006-0679 (PI Behm), (2013-0341(PI Nonn). Mixtures of single PrE-derived and single PrS-derived cells were seeded in 3D in matrigel. Bright-field microscopy of live organoids and histological examination of fixed organoids showed that the addition of PrS cells to the culture altered the shape of the organoids compared to the spherical phenotype observed in PrE only cultures. Immunofluorescent analysis of the basal cell marker p63 showed increased epithelial differentiation in the co-culture organoids. In summary, these data suggest that inclusion of prostate stroma in co-culture organoid models influences prostatic epithelial organoid development in vitro. Ongoing studies are focused on molecular analysis or organoid phenotypes and comparison of AA and EA-derived organoids. Citation Format: Joseph Marsili, Zachary Richards, Jason Garcia, Cindy Voisine, Larisa Nonn. Developing a patient derived 3D co-culture model of prostate organoids to examine biological mechanisms involved in prostate cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5772. doi:10.1158/1538-7445.AM2017-5772
Abstract 4193: A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor scaffold
Authors: Yihui Shi, Jaehyeon Park, Chandraiah Lagisetti, Wei Zhou, Lidia C. Sambucetti, Thomas R. Webb
Journal: Cancer Research (2017)

Abstract The splicing of pre-mRNA is a critical process in normal cells and is deregulated in cancer. Compounds that modulate this process have recently been shown to target a specific vulnerability in tumors. We have developed a novel cell-based assay that specifically activates luciferase in cells exposed to SF3B1 targeted compounds, such as sudemycin D6. This assay was used to screen a combined collection of approved drugs and bioactive compounds. This screening approach identified several active hits, the most potent of which were CGP-74514A and aminopurvalanol A, both have been reported to be cyclin-dependent kinases (CDKs) inhibitors. We found that these compounds, and their analogs, show significant cdc2-like kinase (CLK) inhibition and clear structure-activity relationships (SAR) at CLKs. We prepared a set of analogs and were able to ‘dial out’ the CDK activity and simultaneously developed CLK inhibitors with low nanomolar activity. Thus, we have demonstrated the utility of our exon-skipping assay and identified new molecules that exhibit potency and selectivity for CLK, as well as some structurally related dual CLK/CDK inhibitors. Citation Format: Yihui Shi, Jaehyeon Park, Chandraiah Lagisetti, Wei Zhou, Lidia C. Sambucetti, Thomas R. Webb. A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor scaffold [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4193. doi:10.1158/1538-7445.AM2017-4193
Abstract 5160: Development of REDX05358, a novel highly selective and potent pan RAF inhibitor and a potential therapeutic for BRAF and RAS mutant tumors
Authors: Helen Mason, Simon Scrace, Richard Testar, Julie Rainard, Fatima Talab, Ryaka Poonawala, Philippa Smith, Harriet Brooke, Sarah Frith, Jonathan Ahmet, Jonathan Hall, David Sorrell, Jon Moore, Caroline Phillips, Dennis France, Matilda Bingham, Richard Armer
Journal: Cancer Research (2017)

Abstract REDX05358 has been identified as a novel, highly selective and potent next generation pan RAF inhibitor with improved therapeutic potential and predicted safety profile. Aberrant signalling via the MAPK pathway is commonly seen in cancer. RAF inhibitors such as Dabrafenib and Vemurafenib have been approved for the treatment of unresectable and metastatic BRAF mutant melanoma, but these agents lack efficacy in BRAF mutant colorectal cancer (CRC), partly because of EGFR-mediated feedback reactivation of the MAPK pathway via CRAF. Furthermore, RAF inhibitor treatment of RAS-mutant, BRAF wildtype melanomas has been associated with other skin cancers, such as cutaneous squamous cell carcinoma due to MAPK pathway paradoxical activation mediated by CRAF. There is therefore a clinical need for novel agents targeting the MAPK pathway that do not have these undesirable properties. Here we present, REDX05358 that demonstrates subnanomolar binding affinity for BRAF and CRAF with high selectivity profile against a panel of 468 kinases that exhibits negligible paradoxical activation due to inhibition of both RAF monomers and dimers. As a result, REDX05358 not only inhibits MAPK signalling in BRAF V600E mutant tumor cells, but also in those harbouring NRAS and KRAS mutations. Furthermore, REDX05358 does not induce feedback reactivation of the pathway through its ability to sustain inhibition of MAPK signalling in CRC cell lines. Correspondingly, profiling of REDX05358 in a panel of CRC, melanoma and NSCLC cell lines shows it has potent anti-proliferative activity in cell lines harbouring BRAF or RAS mutations. REDX05358 is an orally bioavailable, well tolerated small molecule that has demonstrated in vivo efficacy in BRAF V600E CRC xenograft model. In contrast, first generation inhibitors such as Vemarafenib and Dabrafanib have been reported to be ineffective in this genetic background in CRC cell lines and patients. Thus, we have developed a pan RAF inhibitor with unique pharmacological properties enabling it to have utility in treating BRAF and RAS mutant cancers Citation Format: Helen Mason, Simon Scrace, Richard Testar, Julie Rainard, Fatima Talab, Ryaka Poonawala, Philippa Smith, Harriet Brooke, Sarah Frith, Jonathan Ahmet, Jonathan Hall, David Sorrell, Jon Moore, Caroline Phillips, Dennis France, Matilda Bingham, Richard Armer. Development of REDX05358, a novel highly selective and potent pan RAF inhibitor and a potential therapeutic for BRAF and RAS mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5160. doi:10.1158/1538-7445.AM2017-5160
Impact of Birth Place and Geographic Location on Risk Disparities in Cerebrovascular Disease
Authors: Daniel T. Lackland
Journal: JAMA Neurology (2017)

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Abstract 2568: Mutant p53 regulates HSP70 expression and nuclear localization
Authors: Kishore Polireddy, Kanchan Singh, Melissa Pruski, Wasim Dar, John S. Bynon, Jennifer M. Bailey
Journal: Cancer Research (2017)

Abstract Pancreatic cancer is the 3rd leading cause of cancer related deaths in the US with a median survival of less than one year. No effective therapies or early detection tests are available for these patients. Scientists have been studying cellular origins of pancreatic cancer to aid in the development of novel treatments and biomarkers. Several studies have demonstrated that acinar cells have a high propensity to undergo acinar to ductal metaplasia and form precursor lesions of pancreatic ductal adenocarcinoma. We have recently shown that simultaneous expression of Kras and mutant TP53 can generate invasive ductal adenocarcinoma from ductal cells. We hypothesized specific mutations in TP53 have different mechanisms of transforming ductal cells. In order to understand the role of mutant TP53 in transforming pancreatic ductal cells into invasive ductal adenocarcinoma, we used a lentiviral system to express mutant TP53R175H and TP53R273H, two of the most frequently mutated TP53 alleles in pancreatic cancer patients, in immortalized pancreatic ductal epithelial cells carrying a Kras mutation (HPNE-KrasG12D). Trypan blue dye exclusion assay and Spheroid formation assays were used to study cellular proliferation and cancer stem cell (CSC) populations. Mutant TP53 over expression enhanced CSC populations without altering cellular proliferation in HPNE-KrasG12D cells. Reverse phase protein array (RPPA) was carried out to detect gene expression changes in HPNE-KrasG12D cells upon mutant TP53 over expression. RPPA assay results suggested that TP53R175H uniquely induced HSP70 expression in HPNE-KrasG12D cells, as cells expressing either vector control or TP53R273H failed to do so. HSP70 expression was further validated by transiently overexpressing TP53R175H and TP53R273H. Surprisingly, TP53R175H specifically promoted nuclear localization of HSP70 without altering the expression of a recently identified HSP70 nuclear transporter, Hikeshi. Future studies will determine 1) whether HSP70 is required for p53-mediated stemness in HPNE-KrasG12D cells and 2) the function of nuclear HSP70. In summary, over expression of mutant p53 enhanced cancer stem cell properties of HPNE-KrasG12D cells, through upregulation HSP70. The exact mechanism behind HSP70 nuclear localization and increased cancer stem cell properties is being more rigorously explored. Citation Format: Kishore Polireddy, Kanchan Singh, Melissa Pruski, Wasim Dar, John S. Bynon, Jennifer M. Bailey. Mutant p53 regulates HSP70 expression and nuclear localization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2568. doi:10.1158/1538-7445.AM2017-2568
Abstract LB-254: Thymidylate synthase gene polymorphisms is negatively associated with gastric cancer survival
Authors: Jinfei Chen, Maggie Haitian Wang, Benny Chung-Ying Zee
Journal: Cancer Research (2017)

Abstract Background: Gastric cancer (GC) is a major public health problem in China and its carcinogenesis has not been fully understood. It was found that genetic variation played an important role in the etiology. Thymidylate synthase (TYMS) is a critical target for cancer chemo-therapy, which functions in DNA replication, synthesis and repair. However, the results of the relationship between TYMS and cancer is unclear. To find the genomic susceptibility in TYMS, bio-markers are necessary for preventing and understanding the etiology of gastric cancer. Objectives: The research explores the relationship between TYMS and survival time of 876 Chinese gastric cancer patients. Methods: A retrospective cohort of 876 surgically resected gastric cancer patients with clinicopathologic and follow up information were collected. The genotypes of SNPs were examined by SNaPshot method. The median survival time (MST) for each categorical variable and survival curve were estimated by Kaplan-Meier method. The overall survival was analyzed by univariate and multivariate Cox proportional hazard model. Results: TYMS was significantly associated with survival time. The study found eight samples (1.0%) with the novel allele (4R). In univariate analysis, the group of including 4R allele had lowest survival condition (P value = 0.006). The hazard ratio of individual with 4R allele was 2.48 (95% CI: 1.10-5.58) after controlling age, gender, smoking, drinking and TNM stage. Conclusion: Our study found a novel allele (4R) in TYMS in gastric cancer patients. Key words: Gastric cancer; TYMS; overall survival Citation Format: Jinfei Chen, Maggie Haitian Wang, Benny Chung-Ying Zee. Thymidylate synthase gene polymorphisms is negatively associated with gastric cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-254. doi:10.1158/1538-7445.AM2017-LB-254
Impact of atezolizumab (atezo) treatment beyond disease progression (TBP) in advanced NSCLC: Results from the randomized phase III OAK study.
Authors: David R. Gandara, Joachim Von Pawel, Richard N. Sullivan, Aslaug Helland, Ji-Youn Han, Santiago Ponce Aix, Achim Rittmeyer, Fabrice Barlesi, Toshio Kubo, Keunchil Park, Jerome H. Goldschmidt, Mayank Gandhi, Cindy Yun, Wei Yu, Christina Matheny, Pei He, Alan Sandler, Marcus Ballinger, Louis Fehrenbacher
Journal: Journal of Clinical Oncology (2017)

9001 Background: Cancer immunotherapy (CIT) can have a positive impact on OS that exceeds response rate or PFS effects, termed post progression prolongation of survival (PPPS). This effect can also result from unconventional CIT response due to tumor immune infiltration or delayed response, reducing reliability of RECIST v1.1 (RECIST) PD as an indicator of treatment failure. In the primary analysis (N = 850) of OAK, a study of atezo vs docetaxel (doc) in 2L/3L NSCLC, OS favored atezo (HR 0.73; 95% CI: 0.62, 0.87), despite similar PFS between arms (HR 0.95; 95% CI: 0.82, 1.10). Here we evaluate clinical benefit from TBP, defined by post PD tumor regression, OS and safety. Methods: Patients (pts) received atezo 1200 mg IV q3w until PD or loss of clinical benefit per investigator or doc 75 mg/m 2 IV q3w until PD per RECIST. No crossover was allowed. Primary outcome measure: OS. Atezo TBP pts were evaluated for post PD tumor change and for safety pre and post PD. OS from time of PD per RECIST was evaluated in both arms (data cutoff, July 7, 2016; minimum follow-up, 19 mo). Results: Among 332 atezo pts with PD, 51% (n = 168) continued atezo TBP; 7% (12/168) achieved subsequent response in target lesions (≥ 30% reduction from new baseline at PD); 49% (83/168) had stable target lesions (best change between +20% and −30%). mOS was 12.7 mo (95% CI: 9.3, 14.9) post PD for pts on atezo TBP (Table). Atezo TBP was not associated with increased safety risk. Conclusions: This is the first report from a Phase III study of CIT in NSCLC to evaluate post PD OS in pts continuing treatment beyond RECIST PD. Atezo TBP was associated with high frequency of stable or decreased target lesions, mOS &gt; 1 year and a tolerable safety profile, all supporting prolonged treatment benefit consistent with PPPS. NCT02008227 Clinical trial information: NCT02008227. [Table: see text]
Abstract 2016: Novel dual cIAP1/XIAP antagonist ASTX660 activity in preclinical models of human papillomavirus(+) and (-) head and neck squamous cell carcinoma
Authors: Roy Xiao, Yi An, Adeeb Derakhshan, Zhong Chen, Nicole C. Schmitt, Carter Van Waes
Journal: Cancer Research (2017)

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer with a five-year survival of ~50%. HNSCC are linked to human papillomavirus (HPV+) or tobacco carcinogenesis (HPV-). The Cancer Genome Atlas recently analyzed 279 HNSCC, revealing that 30% overexpress FADD (Fas-Associated Death Domain), with or without BIRC2/3 genes encoding cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2), which are critical components of the Tumor Necrosis Factor (TNF) Receptor signaling pathways that determine cell death or survival. The frequency of such mutations provides a window for potential therapeutics, as IAP antagonists have been shown to switch cancer cell TNFα signaling from being pro-survival to pro-apoptotic. We recently showed that birinapant, a second mitochondrial activator of caspases (SMAC) mimetic that promotes IAP degradation, sensitizes HNSCC to cell death by TNFα and eradicates tumors in combination with radiation in HPV- HNSCC models overexpressing FADD+/-BIRC2. ASTX660 (developed by Astex Pharmaceuticals) is a novel dual cIAP1/XIAP antagonist currently in clinical trials for treating advanced solid tumors and lymphomas. The objective of the present study is to determine the therapeutic effects of ASTX660 in HPV+/- HNSCC preclinical models. ASTX660 at nanomolar concentrations was found to potently inhibit cell proliferation (measured using XTT assays) and induce apoptosis (Annexin/7-AAD flow cytometry), and displayed combinatorial activity with TNFα, TRAIL, or cisplatin in multiple human HPV+/- HNSCC cell lines. Western blotting showed near complete degradation of cIAP1 expression at nanomolar concentrations in human HNSCC cell lines. Flow cytometry revealed that ASTX660 in combination with either TNFα or cisplatin reduced MHC-I expression and increased PD-L1 expression, suggesting that potential synergistic efficacy could be observed in combination with immune checkpoint inhibitors. Our results demonstrate that ASTX660 is a potential therapeutic agent for both HPV+/- HNSCC. Experiments evaluating the anti-tumor effects of ASTX660 as a monotherapy and in combination with radiation, cisplatin, and anti-PD-1 therapies are ongoing, using both human HNSCC xenograft and syngeneic mouse oral cancer (MOC) models. Supported by NIDCD intramural projects (ZIA-DC-000016, 73 and 74). Citation Format: Roy Xiao, Yi An, Adeeb Derakhshan, Zhong Chen, Nicole C. Schmitt, Carter Van Waes. Novel dual cIAP1/XIAP antagonist ASTX660 activity in preclinical models of human papillomavirus(+) and (-) head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2016. doi:10.1158/1538-7445.AM2017-2016