tbuckley/cabot-search huggingface dataset:
Distinct early response dynamics of circulating tumor DNA and circulating tumor cells during therapy of B-cell NHL.
Authors: David Matthew Kurtz, Florian Scherer, Michael Richard Green, Michael Siavash Khodadoust, Daniel M. Klass, Li Zhou, Rashi Krishnan, Cynthia Glover, Chih Long Liu, Katherine A Kong, Malek Faham, Ronald Levy, Maximilian Diehn, Ash A. Alizadeh
Journal: Journal of Clinical Oncology (2015)

8570 Background: Both circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been used for disease monitoring in non-Hodgkin lymphoma (NHL) (Armand BJH 2013; Kurtz ASCO 2014; Roschewski ASH 2014). However, it remains unclear how these compartments compare during induction of active therapy in NHL. Using immunoglobulin high-throughput sequencing (Ig-HTS), we compared the dynamics of ctDNA and CTCs in response to systemic therapy. Methods: We performed 206 Ig-HTS assays from 104 serial blood samples in diverse patients with NHL receiving their first cycle of systemic therapy at Stanford University. Tumor samples were used to define tumor specific DNA sequences by Ig-HTS. Identified sequences were used to track ctDNA and CTCs. Results: A total of 17 patients with NHL were enrolled (DLBCL = 10, FL = 3, transformed FL = 4). All patients received Rituximab-containing regimens. In patients with high-grade disease, CTCs and ctDNA decreased by a mean of 94% (61%-100%) and 95% (68%-100%) after 1 cycle of therapy respectively. CTCs and ctDNA became undetectable in 7/10 and 5/11 patients by cycle 2. However, a dramatic increase or ‘spike’ was seen in ctDNA levels within hours of Rituximab (median increase 8.0x, range 0.3x to 264x). In contrast, a dramatic decrease was seen in CTCs (median decrease 72%, range -23% to 93%), indicating their rapid clearance. This ctDNA spike was observed in 6/6 FL/tFL patients, but only 1/5 DLBCL patients (p = 0.02). The size of the ctDNA spike was significantly associated with the burden of pretreatment CTCs (p < 0.001) and the magnitude of decrease in CTCs (p < 0.001), but was not associated with the pretreatment ctDNA level (p = 0.88). Four of eight patients achieving CR and 2/3 patients not achieving CR had a spike in ctDNA (p = 1.0). Conclusions: While ctDNA and CTCs can be used to monitor NHLs, their dynamics in response to therapy are distinct. Although both clear during therapy, a rapid increase in ctDNA is seen in response to Rituximab, indicating cell death of CTCs. This ctDNA spike is associated with therapeutic effect on CTCs, but not with outcome in this small cohort. Circulating tumor DNA is a potentially useful method to measure cell death in NHL and other malignancies.
Abstract 5844: Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, improved radiosensitivity of human hepatocellular carcinoma
Authors: Fang-Hsin Chen, Ching-Fang Yu, Ji-Hong Hong
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Radiotherapy (RT) is one of modalities for HCC therapy in clinics, but the therapeutic effect is unsatisfied due to high radiosensitivity of normal liver tissues that limits the optimal dose. This study is to develop a new theraprutic approach to enhance the efficiency of RT on HCC tumors. Suberoylanilide hydroxamic acid (SAHA), a FDA approved chemotherapeutic drug, is an inhibitor of histone deacetylase (HDACs) and has been reported to enhance radiosensitivity in many cell lines. This study hypothesized that combination of SAHA and RT could improve tumor control on HCC tumors. HCC-834 cell, a primary culture of human HCC, had a dose-dependent response to RT when analyzed by clonogenic assay. SAHA had mild cytotocixity to HCC-834 cell (IC50=1μM). Combination of SAHA and RT reached a synergestic effect to prevent colony formation. In detailed, SAHA treatment did not induce DNA damage on HCC-834 cells when assayed by the expression of γH2AX. RT of 2Gy induced highest γH2AX expression within 10min and quickly returned to baseline after 24hrs. The expression of γH2AX was sustained at 24hrs when treated by SAHA and RT, and gradually recovered after 48hrs. This data indicated that SAHA inhibited the DNA repair process in HCC-834 cell lines after RT. An orthotopic tumor model was developed for further exploring the role of SAHA on HCC tumor radiotherapy. Mice were orally fed with SAHA (100mg/kg) 3hrs and 24hrs before RT of 25Gy. Mice were sacrificed at day10 after RT and maximum tumor area was examined by H&amp;E staining. Either RT (38.81 ± 15.6mm2) or SAHA alone (45.09 ± 4.493mm2) inhibited tumor growth significantly compared with control tumors (99.1 ± 0.732mm2). Combined SAHA with RT had an additive effect on tumor control (28.03±12.25mm2). These results supported our hypothsis and demonstrated that SAHA combined with local RT was effective on inhibiting DNA repair and anti-tumor growth. This study provided a new strategy on HCC tumor therapy that SAHA could act as a radiosensitizer to improve the therapeutic efficiency of RT on HCC tumors. Citation Format: Fang-Hsin Chen, Ching-Fang Yu, Ji-Hong Hong. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, improved radiosensitivity of human hepatocellular 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 5844. doi:10.1158/1538-7445.AM2017-5844
Parathyroid hormone regulates fates of murine osteoblast precursors in vivo
Authors: Deepak H Balani, Noriaki Ono, Henry M Kronenberg
Journal: Journal of Clinical Investigation (2017)

Teriparatide, a recombinant form of parathyroid hormone (PTH), is the only approved treatment for osteoporosis that increases the rate of bone formation. Teriparatide increases osteoblast numbers by suppressing osteoblast apoptosis and activating bone-lining cells. No direct evidence for teriparatide's actions on early cells of the osteoblast lineage has been demonstrated. Here, we have employed a lineage-tracing strategy that uses a tamoxifen-dependent, promoter-driven cre to mark early cells of the osteoblast lineage in adult mice. We show that teriparatide increases the numbers of osteoblast precursors and drives their differentiation into mature osteoblasts. Unexpectedly, following withdrawal of teriparatide therapy, bone marrow adipocytes increased dramatically in number. Some of these adipocytes derived from cells marked by Sox9-cre expression weeks earlier. Continued therapy with teriparatide prevented the appearance of adipocytes. Selective, inducible deletion of the PTH receptor in Sox9-cre cells demonstrated that PTH receptor expression is required for teriparatide-mediated increases in early osteoblast precursors. The increase in early precursors after teriparatide administration was associated with robust suppression of precursor apoptosis without affecting their rate of proliferation. Thus, teriparatide increases the numbers of early cells of the osteoblast lineage, hastens their differentiation into osteoblasts, and suppresses their differentiation into adipocytes in vivo.
Abstract 2765: Psychosocial predictors of life satisfaction among married women with breast cancer
Authors: Chioma Asuzu, Ngozi Efosa-Urhoghide
Journal: Cancer Research (2017)

Abstract Introduction: Breast cancer presents a challenge to the totality of a woman’s life. Correlates of life satisfaction among married women with breast cancer have not been very well explored. Purpose: This study seeks to determine the relationship that exists between life satisfaction with depression, cognitive emotional regulation, sexuality, self-concept, dejection, interpersonal conflict and social support among married women with breast cancer in Southwest Nigeria. It also seeks to ascertain which of these variables predict life satisfaction among the respondents. Method: The variables in the study were assessed using modified standardized instruments which were revalidated for cultural suitability after ethical approvals were obtained in each of the 5 centres involved in the study. The instruments were given to breast cancer patients after informed consent to participate in the study have been obtained. Result: The larger proportion {148 or 40.5%)} of the participants were in the age range of 46-55 years and 112 (30.7%) had stage III disease. Analysis of data showed that significant linear relationship exists between life satisfaction of married women with breast cancer and depression (r = .200**; p &amp;lt; .001), self-concept (r = .306**; p &amp;lt; .001), cognitive emotional regulation (r = .398**; p &amp;lt; .001), dejection (r = .226**; p &amp;lt; .001), interpersonal conflict (r = .352**; p &amp;lt; .001), anxiety (r =.316**; p &amp;lt; .001), sexuality (r =.305*; p &amp;lt; .001) and social support (r = .534; p &amp;lt; .001). There were also significant correlations among the independent variables. Conclusion: Psychosocial factors are potent predictors of life satisfaction among married women with breast cancer. Based on the findings, it was recommended that psycho-social intervention based on the factors identified as causative agents of life satisfaction should be developed and implemented for married individuals. Note: This abstract was not presented at the meeting. Citation Format: Chioma Asuzu, Ngozi Efosa-Urhoghide. Psychosocial predictors of life satisfaction among married women with breast 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 2765. doi:10.1158/1538-7445.AM2017-2765
Abstract 15: Suppression of adaptive responses to targeted therapies by transcriptional inhibition
Authors: Maria Rusan, Kapsok Li, Yvonne Li, Camilla L. Christensen, Brian J. Abraham, Nicholas Kwiatkowski, Kevin Buczkowski, Bruno Bockorny, Ting Chen, Shuai Li, Haikuo Zhang, Hideko Terai, Tiffany Tavares, Tinghu Zhang, Tae Jung Kim, Michael Silkes, Tenny Mudianto, Li Tan, Takeshi Shimamura, Matthew Meyerson, Hideo Watanabe, Nathanael S. Gray, Richard A. Young, Kwok-Kin Wong, Peter S. Hammerman
Journal: Cancer Research (2017)

Abstract Tumor cells become dependent on the expression of key genes that drive hallmark tumor traits, but these “addictions” also represent potential vulnerabilities for therapeutic intervention. Treating tumor cells with a small molecule inhibitor of the transcriptional kinase CDK7 selectively suppresses expression of key dependency genes in multiple cancers. Our previous work showed responses to the CDK7 inhibitor THZ1 were especially noteworthy in T cell leukemias, small cell lung cancers, and triple-negative breast cancers—tumor types where the prognoses are especially unfavorable. The genes whose expression is most sensitive to CDK7 inhibition and whose expression is essential for tumor cell survival are often associated with super-enhancers—clusters of constituent enhancers that are bound by unusually large amounts of transcription apparatus including CDK7 itself. This “Achilles’ cluster” of super-enhancer-associated genes thus represents the set of addictions of tumor cells whose expression is important for tumor cell survival. Transcriptional inhibition synergizes with targeted therapies in models of multiple tumor types. Treating tumors with therapies that target kinase proteins such as EGFR, FGFR, and KRAS leads to resistance, which is concurrent with changes in the activities of enhancers and super-enhancers and gene expression programs of resistant cells. Treating cells with a transcriptional inhibitor in addition to targeted therapies prevents “rewiring” of the gene expression program and increases cell death in tumor models. Thus transcriptional inhibition represents a promising avenue in both monotherapy and combination settings where drug resistance is acquired. Citation Format: Maria Rusan, Kapsok Li, Yvonne Li, Camilla L. Christensen, Brian J. Abraham, Nicholas Kwiatkowski, Kevin Buczkowski, Bruno Bockorny, Ting Chen, Shuai Li, Haikuo Zhang, Hideko Terai, Tiffany Tavares, Tinghu Zhang, Tae Jung Kim, Michael Silkes, Tenny Mudianto, Li Tan, Takeshi Shimamura, Matthew Meyerson, Hideo Watanabe, Nathanael S. Gray, Richard A. Young, Kwok-Kin Wong, Peter S. Hammerman. Suppression of adaptive responses to targeted therapies by transcriptional inhibition [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 15. doi:10.1158/1538-7445.AM2017-15
Abstract 4713: Deubiquitination and stabilization of programmed cell death-ligand 1 by CSN5
Authors: Seung-Oe Lim, Chia-Wei Li, Mien-Chie Hung
Journal: Cancer Research (2017)

Abstract Chronic inflammation in cancer is often associated with disease aggressiveness. Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of antitumor immunity and enhanced tumor cell survival. In the current study, we identified TNFα as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNFα-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. The role of CSN5 in modulating PD-L1 stabilization prompted us to use CSN5 inhibitor, curcumin, to show that it could destabilize PD-L1. Curcumin reduced CSN5 activity to attenuate TNFα-mediated PD-L1 stabilization and enhanced anti-tumor immunity. Preclinical data demonstrated inhibition of CSN5 sensitized cancer cells to anti-CTLA4 therapy, suggesting CSN5 inhibitor may be a useful adjuvant to enhance immune-based therapies. Note: This abstract was not presented at the meeting. Citation Format: Seung-Oe Lim, Chia-Wei Li, Mien-Chie Hung. Deubiquitination and stabilization of programmed cell death-ligand 1 by CSN5 [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 4713. doi:10.1158/1538-7445.AM2017-4713
Abstract 2604: The Georgetown Database of Cancer (G-DOC): A web-based data sharing platform for precision medicine
Authors: Krithika Bhuvaneshwar, Anas Belouali, Shruti Rao, Adil Alaoui, Yuriy Gusev, Robert Clarke, Louis M. Weiner, Subha Madhavan
Journal: Cancer Research (2017)

Abstract Introduction An overarching goal of biomedical research is to improve the use and dissemination of rapidly growing biomedical datasets to support precision medicine. Individualized molecular profiling and the identification of predictive biomarkers can powerfully inform the choice of therapies for cancer patients. However, both require integration of extensive molecular, clinical, and pharmacological data, often from disparate and diverse sources. The Georgetown Database of Cancer (G-DOC) was designed and engineered to be a unique multi-omics data analysis platform to enable translational research and precision medicine. Methods G-DOC is home to 61 datasets that contain data from over 10,000 patients across 14 diseases (10 cancers and 4 non-cancers). 1700+ researchers from over 48 different countries worldwide currently use the platform. The data and tools in the G-DOC system have enabled over 40 research publications. G-DOC has the largest public collection of brain cancer patients from NCI Rembrandt dataset (671 patients).G-DOC integrates clinical, transcriptomic, metabolomic, microRNA, next generation sequencing (NGS) data, and MRI medical images with systems-level analysis tools into a single, user-friendly platform. The “Variant Search” feature in G-DOC currently enables exploratory analysis of mutations based on genes, chromosomes, and functional location. A researcher can use this feature to 1) identify clinically actionable mutations in their dataset 2) identify pathways that may be affected by these mutations, and 3) identify novel mutations in their dataset and explore their potential impact on protein function. Results and Conclusion We are currently working on developing features to support the import, integration, search, and retrieval of CLIA/CAP-certified cancer molecular diagnostic (molDx) data. This will enhance G-DOC’s interoperability with clinical and patient molecular profiling data that may be already stored in other databases. Our vision is to continuously improve and expand G-DOC with the long-term vision of supporting integration of informatics techniques into everyday research and practice. Citation Format: Krithika Bhuvaneshwar, Anas Belouali, Shruti Rao, Adil Alaoui, Yuriy Gusev, Robert Clarke, Louis M. Weiner, Subha Madhavan. The Georgetown Database of Cancer (G-DOC): A web-based data sharing platform for precision medicine [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 2604. doi:10.1158/1538-7445.AM2017-2604
Abstract 3190: Using a genome-wide shRNA screen to investigate the mechanism of stroma-conferred gemcitabine resistance in pancreatic ductal adenocarcinoma
Authors: Graham D. Mills, Nicolas Erard, Frances M. Richards, Gregory J. Hannon, Duncan I. Jodrell
Journal: Cancer Research (2017)

Abstract The purpose of this study is to identify mechanisms of resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) using an in vitro coculture system. The inherent resistance of PDAC to first line treatments such as gemcitabine has been attributed to the dense fibrotic stroma. Targeting stromal components, in particular cancer-associated fibroblasts (CAFs), the activated form of pancreatic stellate cells (PSCs), is a promising avenue for therapeutic intervention. We have demonstrated previously the induction of gemcitabine resistance when co-culturing KRAS G12D; p53 R172H; Pdx-cre (KPC) mouse PDAC-derived tumour cells with αSMA+ fibroblast-like cells from PDAC tumour (FLCs), in comparison to PDAC cells co-cultured with PSCs or in monoculture. This resistance-inducing effect is specific to cells of mesenchymal phenotype, is transient in nature and a product of cell-cell contact. To investigate the exact mechanism by which PDAC cells become resistant to gemcitabine in coculture, we undertook a genome-wide shRNA depletion viability screen, infecting KPC mouse PDAC cells with a pooled shERWOOD UltramiR shRNA library both in mono- and co-culture with FLCs, in the presence and absence of gemcitabine. Next-generation sequencing and differential expression analysis, using DESeq2, identified shRNAs depleted through 6 cycles of gemcitabine treatment in coculture, indicating they target genes driving the resistance effect. Pathway analysis of differential expression using MetaCore implicated DNA damage repair and protein modification pathways in the gemcitabine resistance effect. Depletion of p97, ATR, or Chk1 all sensitised PDAC cells to gemcitabine in coculture, corroborating findings with translational value in previous studies. Further evaluation is ongoing using validation shRNA dropout assays in combination with targeted literature reviews to collate a candidate list of targetable genes with translational value in preventing and combating chemotherapy resistance in patients with PDAC. Citation Format: Graham D. Mills, Nicolas Erard, Frances M. Richards, Gregory J. Hannon, Duncan I. Jodrell. Using a genome-wide shRNA screen to investigate the mechanism of stroma-conferred gemcitabine resistance in pancreatic ductal adenocarcinoma [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 3190. doi:10.1158/1538-7445.AM2017-3190
Syk inhibitors in clinical development for hematological malignancies
Authors: Delong Liu, Aleksandra Mamorska-Dyga
Journal: Journal of Hematology & Oncology (2017)

Spleen tyrosine kinase (Syk) is a cytosolic non-receptor protein tyrosine kinase (PTK) and is mainly expressed in hematopoietic cells. Syk was recognized as a critical element in the B-cell receptor signaling pathway. Syk is also a key component in signal transduction from other immune receptors like Fc receptors and adhesion receptors. Several oral Syk inhibitors including fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659 are being assessed in clinical trials. The second generation compound, entospletinib, showed promising results in clinical trials against B-cell malignancies, mainly chronic lymphoid leukemia. Syk inhibitors are being evaluated in combination regimens in multiple malignancies.
Abstract 146: The PI3K inhibitor, taselisib, has a unique mechanism of action that leads to enhanced potency in PIK3CA mutant models
Authors: Kyung W. Song, Kyle A. Edgar, Donald S. Kirkpatrick, Lilian Phu, Stephen Schmidt, Michelle Nannini, Rebecca Hong, Eric Cheng, Lisa Crocker, Amy Young, Deepak Sampath, Lori Friedman
Journal: Cancer Research (2017)

Abstract Activating mutations in PIK3CA are commonly found in a wide variety of human cancers, and the dysregulation of the phosphoinositide-3 kinase (PI3K) signaling pathway has been implicated in tumor cell growth and survival. Taselisib (GDC-0032), a novel, oral, selective inhibitor of p110alpha, sparing inhibition of p110beta, is more potent in cancer cells bearing PIK3CA mutants than those with wildtype PIK3CA. Preclinical studies demonstrate that taselisib induces more apoptotic cell death in PIK3CA mutant cancer cells than other PI3K inhibitors. We have discovered that taselisib has a dual mechanism of action, both blocking PI3K signaling, and inducing a decrease in p110a protein levels. Mass spec analysis reveals that taselisib treatment leads to the specific depletion of mutant p110alpha without significant change in wildtype p110alpha protein levels. This drug-induced p110a protein depletion is rescued by E1 inhibitors and by proteasome inhibitors. Other clinical PI3K inhibitors, including p110alpha selective and pan-PI3K inhibitors, are unable to induce the depletion of mutant p110 alpha protein. Furthermore, we have discovered that taselisib more effectively maintains pathway suppression in PIK3CA mutant cells at 24 hrs in response to feedback. In comparison to other clinical-stage PI3K inhibitors administered at a maximum tolerated dose, taselisib has superior efficacy with increased tumor regressions in PIK3CA mutant xenograft models. In summary, these preclinical studies indicate that PI3K inhibitors, which have the ability to trigger degradation of mutant p110a protein, can more effectively suppress the signaling pathway, which may result in greater anti-tumor activity and improved therapeutic index in PIK3CA mutant tumors. Citation Format: Kyung W. Song, Kyle A. Edgar, Donald S. Kirkpatrick, Lilian Phu, Stephen Schmidt, Michelle Nannini, Rebecca Hong, Eric Cheng, Lisa Crocker, Amy Young, Deepak Sampath, Lori Friedman. The PI3K inhibitor, taselisib, has a unique mechanism of action that leads to enhanced potency in PIK3CA mutant models [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 146. doi:10.1158/1538-7445.AM2017-146