tbuckley/cabot-search huggingface dataset:
Abstract 4751: Correlating the genomic and transcriptomic profiles of pre-treatment cervical tumor biopsies with patient recurrence after definitive chemoradiation
Authors: Fiona J. Ruiz, Julie K. Schwarz
Journal: Cancer Research (2017)

Abstract Purpose: The purpose of this study was to identify genomic mutations that correlate with patient recurrence after curative intent chemoradiation therapy in advanced stage cervical cancer patients. Methods: Pre-treatment cervical tumor biopsies and normal blood were prospectively collected from patients treated at Washington University in St. Louis. DNA and RNA was isolated from the fresh frozen tumor biopsies and sent for next-generation sequencing and RNAseq respectively. Targeted exome sequencing was done using a panel of 127 known cancer associated genes, and an additional 8 genes previously reported to be mutated in cervical cancer. Gene tiling was done to probe for 30 different HPV subtypes. Results: The mutational signatures of single nucleotide polymorphisms were an APOBEC cytidine deaminase and CpG site cytidine deamination mutagenesis pattern. The non-silent somatic mutations were analyzed by online prediction algorithms to assess the mutation’s putative effect on protein function. Univariate COX regression was used to correlate patient recurrence with non-silent putatively functional mutations. In our patient cohort 88% of samples were HPV positive, with 74% being the high-risk HPV 16 and 18 subtypes. Patient’s with HPV positive tumors had increased progression-free survival when compared to the HPV negative patient tumors; and the HPV positive patients with HPV 16 had increased progression-free survival over the other HPV subtypes. Complete gene tiling of the HPV 16 and 18 subtypes allowed us to determine whether the HPV DNA was integrated in the host genome or retained episomally. In our patient cohort less than 30% of samples had integrated HPV DNA, and there was no significant difference in progression-free survival between patients with integrated or episomal HPV. Conclusions: The genomic analysis of our advanced staged cervical cancer patient cohort found that epigenetic modifiers were frequently mutated and that cytidine deamination mutagenesis was primarily responsible for the generation of the SNP mutations. Our study identified NSD1 mutations as being correlated with tumor recurrence, indicating that histone modifications and chromatin structure may play an important role in tumor response to ionizing radiation therapy. Gene expression analysis is currently ongoing. Citation Format: Fiona J. Ruiz, Julie K. Schwarz. Correlating the genomic and transcriptomic profiles of pre-treatment cervical tumor biopsies with patient recurrence after definitive chemoradiation [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 4751. doi:10.1158/1538-7445.AM2017-4751
Abstract 3469: Identification of novel human telomerase associated protein by mass spectrometry
Authors: Jing Wang, Xuezhi Bi, Shang Li
Journal: Cancer Research (2017)

Abstract Telomeres are nucleoprotein structures at the ends of eukaryotic chromosomes that prevent them from degradation, recombination, and end-to-end fusion. Telomere consists of DNA repeats, which in human is of the sequence TTAGGG, and it is bound by a group of proteins called shelterin complex. Telomere is synthesized by telomerase. Telomerase is absent in most human somatic cells while it is up-regulated in 90% of cancer cells, in which telomerase plays an essential role in cancer cells’ replicative immortality. However, telomerase is only present at approximately 250 molecules per cancer cell. To exert its function of elongating telomere, telomerase has to find the end of telomeres which needed to be elongated. However, how telomerase is precisely recruited to telomere ends is not clearly understood. To better understand the recruitment process of telomerase, we initially screened and subsequently identified novel binding proteins of hTERT, the catalytic subunit of telomerase, through a pull-down assay using cancer cell lines with endogenously Flag-tagged hTERT. Using mass spectrometry (MS), we were able to identify a promising interesting protein. Further, direct interaction between TERT and this protein was validated. Then, we found that this protein can also interact with the shelterin component, TRF1 (Telomeric repeat-binding factor 1), which binds to double stranded telomeric DNA. Furthermore, from previous published reports, this protein was shown to interact with single-stranded telomeric DNA binding protein POT1 (Protection of Telomeres 1) in the shelterin complex. Functionally, overexpression of this protein in cancer cell lines can result in the elongation of telomeres, while knock-down or knock-out of the protein results in the shortening of telomere. In conclusion, we identified an hTERT-binding protein that affects telomere maintenance which may be involved in telomerase recruitment process. In the long run, it could serve as a potential therapeutic target for cancers. Citation Format: Jing Wang, Xuezhi Bi, Shang Li. Identification of novel human telomerase associated protein by mass spectrometry [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 3469. doi:10.1158/1538-7445.AM2017-3469
Abstract 3728: Imaging biomarkers of aromatase-inhibitor induced joint pain
Authors: Brian A. Goldstein, Mihra Taljanovic, Pavani Chalasani, C. Kent Kwoh, Amanda Hadden, Russell Witte, Jessica Martinez
Journal: Cancer Research (2017)

Abstract Estrogen receptor positive (ER+) breast cancer patients undergoing treatment with aromatase inhibitors (AI) tend to discontinue the supplement when to painful side effects appear. It is believed that women with AI-induced musculoskeletal syndrome (AIMSS) have specific physiological conditions that differentiate them from women with normal aging-related inflammatory processes (e.g., rheumatoid arthritis or RA). Ultrasound shear wave elastography (USWE) provides a real-time, quantitative assessment of the elastic modulus of soft tissue, which is a potential biomarker that is altered in women with AIMSS. Because USWE is a completely noninvasive technique available on state-of-the-art clinical ultrasound scanners, it can be readily applied to study patients who undergo AI treatment and help predict adverse effects during therapy. A Siemens s3000 clinical scanner and 9 MHz linear probe were used for USWE of the hands and wrists in postmenopausal women on AI, postmenopausal women with RA and healthy postmenopausal women. The scans included an evaluation of major wrist tendons, nerve, and joints with shear wave velocities ranging from 0.5 to 15 m/s, which are directly related to the local shear modulus – an absolute measure of tissue stiffness. The ultrasound images and raw shear wave data were then analyzed in MATLAB-TM using a custom graphical user interface (GUI) to calculate the distribution of velocities (or shear moduli) in a user-defined region of interest (ROI). The results were exported to a spreadsheet in Excel for further analysis and comparison among the different groups. Initial results suggest the shear wave velocity and estimated Young’s modulus (λ) were significantly higher in AI patients (14.6 ± 0.2 m/s, λ=642 ± 17 kPa) compared to RA (6.84 ± 1.1 m/s, λ=143 ± 43 kPa) and healthy (7.58 ± 0.9 m/s, λ=174 ± 42 kPa) patients. These values suggest that the mechanical properties of tendons in the wrist may change during treatment with AI and contribute to joint pain in these subjects. It is critical that ER+ patients on AI complete their full treatment. As a potential biomarker of AIMSS and associated pain, USWE may help predict which patients are most susceptible to these side effects, promote early intervention to reduce or eliminate symptoms, and help increase adherence to AI therapy. Citation Format: Brian A. Goldstein, Mihra Taljanovic, Pavani Chalasani, C. Kent Kwoh, Amanda Hadden, Russell Witte, Jessica Martinez. Imaging biomarkers of aromatase-inhibitor induced joint pain [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 3728. doi:10.1158/1538-7445.AM2017-3728
Abstract 2674:Fusobacterium nucleatumsubspeciesanimalisinfluences pro-inflammatory cytokine expression and monocyte activation in human colorectal tumors
Authors: Xiangcang Ye, Rui Wang, Rajat Bhattacharya, Delphine R. Boulbes, Fan Fan, Ling Xia, Adoni Harish, Nadim J. Ajami, Matthew C. Wong, Daniel P. Smith, Joseph F. Petrosino, Susan Venable, Wei Qiao, Veera Baladandayuthapani, Dipen Maru, Lee M. Ellis
Journal: Cancer Research (2017)

Abstract Chronic infection and associated inflammation have long been suspected to promote human carcinogenesis. Recently, certain gut bacteria, including some in the Fusobacterium genus, have been implicated in playing a role in human colorectal cancer (CRC) development. However, the Fusobacterium species and subspecies involved and their oncogenic mechanisms remain to be determined. We sought to identify the specific Fusobacterium spp. and ssp. in clinical CRC specimens by targeted sequencing of Fusobacterium 16S ribosomal RNA gene. Five Fusobacterium spp. were identified in clinical CRC specimens. Additional analyses confirmed that Fusobacterium nucleatum ssp. animalis was the most prevalent F. nucleatum subspecies in human CRCs. We also assessed inflammatory cytokines in CRC specimens using immunoassays and found that expression of the cytokines interleukin-17A and tumor necrosis factor-alpha was markedly increased but interleukin-21 decreased in the colorectal tumors. Furthermore, the chemokine (C-C motif) ligand 20 was differentially expressed in colorectal tumors at all stages. In in vitro co-culture assays, F. nucleatum ssp. animalis induced CCL20 expression in CRC cells and monocytes. It also stimulated the monocyte/macrophage activation and migration. Our observations suggested that infection with F. nucleatum ssp. animalis in colorectal tissue could induce inflammatory response and promote CRC development. Further studies are warranted to determine if F. nucleatum ssp. animalis could be a novel target for CRC prevention and treatment. Citation Format: Xiangcang Ye, Rui Wang, Rajat Bhattacharya, Delphine R. Boulbes, Fan Fan, Ling Xia, Adoni Harish, Nadim J. Ajami, Matthew C. Wong, Daniel P. Smith, Joseph F. Petrosino, Susan Venable, Wei Qiao, Veera Baladandayuthapani, Dipen Maru, Lee M. Ellis. Fusobacterium nucleatum subspecies animalis influences pro-inflammatory cytokine expression and monocyte activation in human colorectal 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 2674. doi:10.1158/1538-7445.AM2017-2674
Abstract 5743: Characterization of mitochondrial DNA mutations and tumor evolution in ulcerative colitis-associated colorectal cancer
Authors: Kathryn Terese Baker, Daniela Nachmanson, Scott R. Kennedy, Teresa A. Brentnall, Rosa Ana Risques
Journal: Cancer Research (2017)

Abstract The role of mitochondrial DNA (mtDNA) mutations in cancer is highly controversial. While specific mtDNA mutations have been associated with certain cancers, it has been recently reported that mtDNA mutations are negatively selected in most tumors. We aimed to clarify the role of mtDNA mutations in cancer progression by: 1) capitalizing on the multi-step sequence of tumorigenesis in ulcerative colitis (UC), a premalignant disease ideal for the study of tumor progression, and 2) employing a highly accurate, ultra-deep sequencing method to fully characterize the mtDNA mutational profile at different stages of tumor evolution. UC is an inflammatory bowel disease characterized by chronic colonic inflammation that increases the risk of colorectal cancer (CRC). UC CRC evolves through a stepwise process that involves the accumulation of molecular alterations in otherwise histologically normal epithelium, low-grade dysplasia (LGD), high-grade dysplasia (HGD), and cancer. Our lab has previously identified mitochondrial alterations as a facet of dysplastic progression in UC. Here we have worked to fully characterize the spectrum and frequency of mtDNA mutations in UC tumorigenesis by applying a novel, highly sensitive NGS technology, Duplex Sequencing (DS), that can accurately detect mutant allele frequencies (MAF) as low as 0.01%. For two patients that developed cancer, we analyzed 15-20 colon biopsies obtained at colectomy, representing all stages of tumorigenesis. The median duplex sequencing depth was 4,000x, which allowed unprecedented resolution to detect subclonal mutations (MAF 1-99%) and rare mutations (MAF&amp;lt;1%). Several subclonal mutations were present in all biopsies, but with variable MAF, thus enabling construction of phylogenetic trees via PHYLIP analysis. Rare mutations were abundant in all biopsies; on average one in every 10,000 nucleotides sequenced was mutated. Most rare mutations were G to A transitions, indicative of replicative errors, but G to T and C to A transversions, the oxidative damage mutational signature, were prevalent in some biopsies. We conclude, therefore, that most mtDNA mutations are caused by proliferation with a contribution by inflammatory processes, and that this may have greater implications for their role in other cancer types. Citation Format: Kathryn Terese Baker, Daniela Nachmanson, Scott R. Kennedy, Teresa A. Brentnall, Rosa Ana Risques. Characterization of mitochondrial DNA mutations and tumor evolution in ulcerative colitis-associated colorectal cancer [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 5743. doi:10.1158/1538-7445.AM2017-5743
Crenolanib besylate, a type I pan-FLT3 inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835 AML.
Authors: Jorge E. Cortes, Hagop M. Kantarjian, Tapan M. Kadia, Gautam Borthakur, Marina Konopleva, Guillermo Garcia-Manero, Naval Guastad Daver, Naveen Pemmaraju, Elias Jabbour, Zeev Estrov, Abhijit Ramachandran, Jamil Paradela, Blake Pond, Farhad Ravandi, Madhuri Vusirikala, Prapti Arvind Patel, Mark J. Levis, Alexander E. Perl, Michael Andreeff, Robert Collins
Journal: Journal of Clinical Oncology (2016)

7008 Background: We investigated the clinical activity, PK, safety and resistance mechanisms to single-agent crenolanib patients (pts) with refractory/relapsed acute myeloid leukemia (R/R AML) with FLT3 ITD. Methods: From Aug 2012 to May 2015, 69 pts (65 evaluable) with R/R FLT3+ AML (29 ITD, 11 D835, 29 ITD+D835) were treated with crenolanib 100 mg TID (42) or 200 mg/m2/d in 3 divided doses (27). Results: Crenolanib therapy resulted in a 39% CRi and 11% PR amongst the 18 pts (6 D835, 9 ITD, 3 ITD+D835) with R/R FLT3 AML who had not received prior FLT3 inhibitors (Cohort A). OS was 234d (238d in pts with ≤ 2 prior therapies and 133d in ≥ 3 prior therapies). Activity was seen in FLT3 ITD (OS 238d), TKD (OS 185d), and TKD+ITD (128d). Pts < 60 had a higher survival (OS 234d) than those ≥ 60 (OS 185d). 36 pts received crenolanib after progressing on prior TKIs (Cohort B), sorafenib (28), quizartinib (11), midostaurin (3), pexidartinib (4), gilteritinib (2) and FLX-925 (1). 10 pts had received ≥ 2 prior TKIs. FLT3-TKD mutations were acquired in 25 pts following TKI exposure: 19/36 had dual mutations with FLT3-ITD and FLT3-D835 (15 ITD, 2 D835). Overall RR was 31% (6 CRi, 5 PRs). OS was 94d in this cohort (158d in ITD, 63d in the dual ITD+D835 mutants). Cohort C consisted of 11 pts who developed FLT3+ AML after prior MDS (8 pts), and 1 pt each after prior myelofibrosis, polycythemia vera and systemic mastocytosis. These pts had only transient benefit from crenolanib, with OS of 55d. Crenolanib had predictable PKs (tmax 2 hrs, T1/2 7.5 hrs), with no accumulation seen with repeated dosing. Median Day 15 trough level was 352 nM documenting therapeutic drug levels. Common AEs included nausea/vomiting, transaminitis and fluid retention (majority Grade 1/2). Only 2 pts discontinued crenolanib due to related AEs. No pt acquired a secondary FLT3 mutation at the time of relapse following crenolanib. Conclusions: Encouraging single-agent activity, safety and PK is observed with crenolanib in multiply relapsed FLT3+ AML (including 40 pts with FLT3 D835 mutations). Crenolanib isnow being assessed in combination with standard chemotherapy in newly diagnosed and R/R AML. Clinical trial information: NCT01657682 and NCT01522469.
Abstract SY06-03: Reprogramming the tumor microenvironment to improve responses to therapy
Authors: David G. Denardo
Journal: Cancer Research (2017)

Abstract Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) significantly limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells, and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists, leading to a near tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and thus renders tumors responsive to immunotherapy. To test this hypothesis in human PDAC patients, we have opened a phase I clinical trial testing the safety and impact on the tumor microenvironment of the FAK inhibitor defactinib, in combination with pembrolizumab and gemcitabine (NCT02546531). These studies are ongoing in patients with advanced cancer, including metastatic PDAC. Early biomarker studies on PDAC tissue collected pre- and post-therapy suggest that this combination impacts the immunosuppressive TME. Citation Format: David G. Denardo. Reprogramming the tumor microenvironment to improve responses to therapy [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 SY06-03. doi:10.1158/1538-7445.AM2017-SY06-03
Abstract 5389: A personalized medicine approach to identifying dysregulated epigenetic enzyme activity in the development of castrate-resistant prostate cancer
Authors: Jin-Hee Lee, Melissa Boersma, Bing Yang, Nathan Damaschke, Eva Corey, John Denu, David F. Jarrard
Journal: Cancer Research (2017)

Abstract Purpose: Recent advances in proteomic and chromatin immunoprecipitation tools have been vital in studying cancer epigenetics, but the ability to measure directly the enzyme activities of dysregulated histone-modifiers understudied. We utilize a novel approach to identify altered histone-modifying enzymes in the progression from hormone sensitive (HS) to castrate-resistant prostate cancer (CRPC) progression. Methods: We developed, validated and utilized a high-throughput peptide microarray assay to identify altered histone lysine (de)acetylation activity in tumor lysates. Functional assays, novel HS and CRPC human tumor arrays and xenografts were utilized to confirm these findings. Results: This microarray-based activity assay revealed up-regulated histone acetyltransferase (HAT) activity against specific histone H3 sites in a castrate-resistant (CR) PCa cell line compared to its hormone-sensitive (HS) isogenic counterpart. NAD+-dependent deacetylation assays revealed down-regulated Sirtuin activity in validated CR lines. Levels of acetyltransferases GCN5, PCAF, CBP and p300 were unchanged between matched HS and CR cell lines. However, auto-acetylation of p300 at K1499, a modification known to enhance HAT activity and a target of deacetylation by SIRT2, was highly elevated in CR cells, while SIRT2 protein level was reduced in CR cells. Interrogation of HS and matched CR xenograft lines reveals that H3K18 hyperacetylation, increased p300 activity, and decreased SIRT2 expression are associated with progression to CR in 8/12 (66%). Tissue microarray analysis revealed that hyperacetylation of H3K18 is a feature of CRPC. Inhibition of p300 results in lower H3K18ac levels and increased expression of androgen receptor. Conclusions: This novel microarray approach provides a method to identify commonly dysregulated chromatin enzymes during progression providing a personalized therapeutic strategy to direct available drugs to target enzymes. Reduced SIRT2 expression and increased p300 activity lead to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18).Support: DOD PCRP (Jarrard) Citation Format: Jin-Hee Lee, Melissa Boersma, Bing Yang, Nathan Damaschke, Eva Corey, John Denu, David F. Jarrard. A personalized medicine approach to identifying dysregulated epigenetic enzyme activity in the development of castrate-resistant prostate cancer [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 5389. doi:10.1158/1538-7445.AM2017-5389