tbuckley/cabot-search huggingface dataset:
Abstract 3906: Targeting a novel G-protein coupled receptor (GPCR) for elimination of leukemia stem cells (LSC)
Authors: Florida Voli, Hangyu Yi, Estrella Gonzales-Aloy, Jenny Yingzi Wang
Journal: Cancer Research (2017)

Abstract Acute myeloid leukemia (AML) is a lethal blood cancer. Clinical evidence has highlighted the critical role for leukemic stem cells (LSCs) in the high relapse rate of AML patients. Understanding the signaling pathways critical for LSC function will facilitate the development of new therapies to target LSCs. G protein-coupled receptors (GPCRs) are the most successful drug targets with approximately 36% of currently marketed drugs targeting human GPCRs (Rask-Andersen et al., Nat Rev Drug Discov 2011). Aberrant expression of GPCRs has been observed in various cancers and the importance of GPCRs in cancer stem cells has begun to be appreciated. In this study, our gene expression profiling analysis identified a novel GPCR (hereafter named NG), which was suppressed in LSCs compared to normal hematopoietic stem cells. Overexpression of NG in pre-LSCs severely impaired leukemia initiation and progression in mice, whereas knockdown of NG significantly accelerated the disease onset. Our data also showed that NG overexpression substantially downregulated several well-known Wnt/β-catenin targets (e.g., Tcf7l2, c-Fos and Ccnd1). These data support a tumor suppressive role for NG in inhibiting leukemogenesis via downregulation of Wnt/β-catenin signaling. Consistent with these observations, treatment with an agonist that specifically activates the NG signaling pathway induced a marked decrease in cell viability and growth in murine LSCs and in human AML THP-1 cells, but had no effects on human AML MOLM-13 cells. This agrees with our finding that NG specifically targets the Wnt/β-catenin signaling, and the inhibitory effect of the agonist might largely depend on β-catenin expression levels in human AML cells, wherein THP-1 has been reported to express endogenous β-catenin but MOLM-13 exhibits no detectable β-catenin expression (Man CH. et al. Blood 2015). In summary, our data support a tumour suppressor role for NG in leukemogenesis and the forced expression of NG may provide a means to eradicate LSCs. Thus, restoring NG by the agonist treatment represents a promising therapeutic strategy for AML treatment. Citation Format: Florida Voli, Hangyu Yi, Estrella Gonzales-Aloy, Jenny Yingzi Wang. Targeting a novel G-protein coupled receptor (GPCR) for elimination of leukemia stem cells (LSC) [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 3906. doi:10.1158/1538-7445.AM2017-3906
Abstract 956: Novel oral small molecule CXCR4 inhibitor improves activity of immune checkpoint blockade in ovarian cancer mouse model
Authors: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros
Journal: Cancer Research (2017)

Abstract Ovarian cancer continues to be the most lethal gynecologic malignancy with no real cure for patients presenting with advanced stage disease. Immune check point blockade showed modest clinical response in patient with recurrent ovarian cancer, thus additional therapeutic strategies for combination therapy are needed. As chemokines and their receptors drive both immune cell migration and tumor growth, angiogenesis and metastasis formation, they are an attractive target for combinatorial cancer therapy. CXCR4 is the most highly expressed chemokine receptor in advanced stage high grade serous ovarian cancer, thus the objective of this study was to evaluate the efficacy of a novel oral small molecule CXCR4 inhibitor (X4-136) alone and in combination with immune checkpoint inhibition and the anti-angiogenic agent bevacizumab, and characterize the changes in circulating immune cells during treatment in murine ovarian cancer model. The ID8 cell line was used in C57BL/6J mice to establish an immune competent murine model and to compare single agent and combination therapy with oral X4-136 CXCR4 inhibitor, bevacizumab, and anti-PD1. During treatment blood sampling was performed and immune cells were analyzed by flow cytometry. Our results demonstrated that single agent therapies alone with either drug had no significant effect on tumor progression or survival. Combination therapy with the CXCR4 inhibitor and anti-PD1 improved survival compared to control animals and the other combination therapy groups. The addition of bevacizumab to the dual combination did not further prolong survival. Analysis of circulating immune cells revealed elevations in CD11b+Ly6C+ and the ratio of CD11b+Ly6C+ to CD11b+Ly6G+ in groups treated with the CXCR4 inhibitor, indicating an increase in circulating myeloid cells. Bevacizumab had no activity in this mouse model as a single agent, and did not have synergistic effect in combination therapy. For the first time we demonstrated that novel CXCR4 inhibitor X4-136 in combination therapy with anti-PD1 showed improved survival in murine ovarian cancer model. CXCR4 blockade increased the proportion of circulating myeloid cells during active treatment, thus further investigation into this novel therapeutic approach is warranted. Citation Format: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. Novel oral small molecule CXCR4 inhibitor improves activity of immune checkpoint blockade in ovarian cancer mouse model [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 956. doi:10.1158/1538-7445.AM2017-956
Abstract 5706: Gene expression profile of peripheral blood mononuclear cells in breast cancer patients may be contribute to the identification and the immunological classification of breast cancer patients by blood test
Authors: Eiji Suzuki, Kosuke Kawaguchi, Masahiro Sugimoto, Fengling Pu, Ryuji Uozumi, Ayane Yamaguchi, Mariko Nishie, Moe Tsuda, Takeshi Kotake, Satoshi Morita, Masakazu Toi
Journal: Cancer Research (2017)

Abstract It is reported that gene expression profile of peripheral blood mononuclear cells (PBMCs) exhibits unique gene expression signature in cancer patients including renal cell carcinoma, pancreatic cancer and lung cancer. Since pancreatic cancer diagnosis is difficult in not only early detection of the disease but also in the diagnosis itself, development of novel diagnostic tools in addition to conventional diagnostic strategy has been awaited. On the other hand, in breast cancer, because early diagnosis by mammography and ultra sound examination on breast is established successfully, exploration of gene expression profile of PBMCs may be important in terms of insight to host antitumor immune response aspects. In the current study, we performed RNA sequencing (RNA-seq) analysis on RNA of PBMCs from 3 healthy volunteers, 6 early and 7 metastatic breast cancer patients including all phenotypes defined by ER, PgR and HER2. Genes that showed FDR&amp;lt;0.05 and fold change of &amp;lt;0.5 and 2.0&amp;lt; in comparison of healthy volunteers and breast cancer patients were applied to clustering analysis by Ward method. We found significant unique gene expression signature between healthy volunteers and breast cancer patients. Furthermore, it was shown that HER2 overexpressing breast cancer patients, which breast cancer patients were divided into 3 clusters including HER2 type and other 2 different groups, seemed to be classified into healthy group different from other phenotypes of breast cancer patients. These findings suggested that evaluation of gene expression patterns of PBMCs of breast cancer patients might distinguish breast cancer patients from healthy subjects and the gene expression signature of PBMCs which divided breast cancer patients into 3 groups might reveal immunologically important biologic properties such as response prediction of cancer immunotherapy including immune checkpoint inhibition treatment. Citation Format: Eiji Suzuki, Kosuke Kawaguchi, Masahiro Sugimoto, Fengling Pu, Ryuji Uozumi, Ayane Yamaguchi, Mariko Nishie, Moe Tsuda, Takeshi Kotake, Satoshi Morita, Masakazu Toi. Gene expression profile of peripheral blood mononuclear cells in breast cancer patients may be contribute to the identification and the immunological classification of breast cancer patients by blood test [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 5706. doi:10.1158/1538-7445.AM2017-5706
Abstract 2471: Role of PALB2-BRCA1 interaction in tumor suppression
Authors: Amar H. Mahdi, YanYing Huo, Bing Xia
Journal: Cancer Research (2017)

Abstract Homologous recombination (HR) is the only error-free pathway for the repair of DNA double strand breaks (DSBs). BRCA1 and BRCA2, the two major breast cancer suppressor proteins, play essential roles in HR-mediated repair of DSBs by promoting the recruitment of RAD51, the recombination enzyme, to DNA damage sites for the initiation of HR. PALB2 (partner and localizer of BRCA2) plays a key role in this pathway by acting as a chromatin adaptor for BRCA2 and a linker between BRCA1 and BRCA2. Like BRCA1 and BRCA2, PALB2 is a tumor suppressor gene itself. Germline, heterozygous mutations in the gene increase the risk of breast, ovarian and pancreatic cancers. However, its mechanism is not fully understood. To investigate the in vivo role of the PALB2-BRCA1 interaction, we previously generated a Palb2 knockin mouse strain which contains a mutation that disrupts BRCA1 binding. This mouse model also allows us to bypass the embryonic lethality of the Palb2 KO mice. In this study, we hypothesized that the direct communication between the two proteins is critical for proper DNA damage repair and response in vivo and for suppression of tumorigenesis. Indeed, both immunohistochemistry (IHC) and immunofluorescence (IF) demonstrated that different tissues of the mutant mice have higher levels of endogenous DSBs (γH2AX foci) and slower DSB repair kinetics after ionizing radiation (IR). Yet, mutant cells were more resistant to cell death. When aged under normal conditions, mutant mice showed increased tumor incidence in multiple tissues, particularly in the liver. When challenged by IR, mutant mice quickly developed thymic lymphoma and later in other tissues including liver and ovary, etc. Interestingly, when crossed with Trp53 mutant mice, the resulting Palb2m/m;Trp53+/- mice showed greatly accelerated development of thymic lymphoma and osteosarcoma, which are typically associated with Trp53 but not Palb2 mutations. Exome sequencing revealed focal deletion of the wild-type allele of Trp53 in the majority of the tumors, suggesting that disruption of BRCA1-PALB2/BRCA2 axis promotes regional genomic deletions that may lead to loss of other tumor suppressors such as p53. Our results underscore the importance of the BRCA1-PALB2/BRCA2 pathway for tumor suppression and suggest a potentially novel mechanism for BRCA1/PALB2-mediated tumor suppression, which is by preventing Trp53/TP53 loss of heterozygosity (LOH), which allows for tumor development. Citation Format: Amar H. Mahdi, YanYing Huo, Bing Xia. Role of PALB2-BRCA1 interaction in tumor suppression [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 2471. doi:10.1158/1538-7445.AM2017-2471
Abstract 1923: Paired isolation and expansion of CSC and CTC from primary small cell lung cancer patient tissue and blood using the 3DKUBE bioreactor platform
Authors: Melissa Millard, Alina Lotstein, Lillia Holmes, David Schammel, Ki Chung, Jeff Edenfield, Hal E. Crosswell, Tessa DesRochers
Journal: Cancer Research (2017)

Abstract Surgical resection is rarely an option for small cell lung cancer (SCLC) patients as the majority present with extensive disease at diagnosis. This scarcity of patient samples suitable for research presents a significant road block for the development of SCLC targeted-therapeutics. To address the problem of tissue scarcity, we have developed a method for the isolation and expansion of cancer stem cells (CSC) and circulating tumor cells (CTC) from primary tissues and blood of SCLC patients using the 3DKUBE™ perfusion microbioreactor. We have established a label-free, combined chemical and functional selection method for the isolation of CSCs from SCLC samples, solid tumor as well as blood, that does not rely upon the bias imposed by marker-based selection. Cells enriched in this manner were further purified and expanded under optimized conditions (growth factors, ECM, scaffolding and oxygen tension) within the 3DKUBE™ perfusion microbioreactor. These isolated and expanded CSCs have maintained resistance to cisplatin and etoposide, stabilized the expression of traditional CSC markers, and been validated in vitro through serial spheroid formation assays. These CSCs are currently being characterized and compared to parental tissue through correlative genomic and phenomic analysis and validated through in vivo tumorigenesis models. These cells will be utilized to generate 3D microtumors to accurately predict SCLC drug response in vitro, a determination that is not accurately performed in conventional 2D cell culture and is inhibited by both cost and time in patient-derived xenografts (PDX) Citation Format: Melissa Millard, Alina Lotstein, Lillia Holmes, David Schammel, Ki Chung, Jeff Edenfield, Hal E. Crosswell, Tessa DesRochers. Paired isolation and expansion of CSC and CTC from primary small cell lung cancer patient tissue and blood using the 3DKUBE bioreactor platform [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 1923. doi:10.1158/1538-7445.AM2017-1923
Abstract 350: Pregnancy at early age is associated with a reduction of progesterone-responsive cells and epithelial Wnt signaling in human breast tissue
Authors: Robert Mechera, Simone Münst, Silvio Däster, Salvatore Piscuoglio, Charlotte Ng, Fabienne Meier-Abt, Walter P. Weber, Savas D. Soysal
Journal: Cancer Research (2017)

Abstract Background: Pregnancy at early age is the most significant modifiable factor which consistently decreases lifetime breast cancer risk. However, the underlying mechanisms haven’t been conclusively identified. Studies in mice suggest a reduction in progesterone-receptor (PR) sensitive epithelial cells as well as a downregulation of the Wnt signaling pathway as being one of the main mechanisms for the protective effect of early pregnancy. The aim of our study was to validate these findings in humans. Methods: We collected benign breast tissue of 123 women who had been stratified according to age at first pregnancy and the occurrence of subsequent breast cancer, and performed immunohistochemistry for PR, Wnt4 and the Wnt-target Versican. Results: The number of PR positive epithelial cells was significantly lower in the group of women with early pregnancy and no subsequent breast cancer compared to the group of nulliparous women with subsequent invasive breast cancer (p=0.017). In women with early pregnancy, expression of Versican and Wnt4 was significantly lower compared to nulliparous women (p=0.0064 and p=0.0156 respectively), and Versican expression was also significant lower compared to women with late pregnancy (p&amp;lt;0.0001). Discussion: Our results confirm prior observations in mice and suggest a role of downregulation of epithelial Wnt signaling in the protective effect of early pregnancy in humans. This results in a decreased proliferation of stem/progenitor cells; therefore, the Wnt signaling pathway may represent a potential target for breast cancer prevention in humans. Citation Format: Robert Mechera, Simone Münst, Silvio Däster, Salvatore Piscuoglio, Charlotte Ng, Fabienne Meier-Abt, Walter P. Weber, Savas D. Soysal. Pregnancy at early age is associated with a reduction of progesterone-responsive cells and epithelial Wnt signaling in human breast tissue [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 350. doi:10.1158/1538-7445.AM2017-350
Abstract 5560: Systemic map of protein phosphatase 2A (PP2A)-regulated phosphotargets and drug responses in cancer cells
Authors: Otto Kauko, Susumu Imanishi, Evgeny Kulesskiy, Teemu D. Laajala, Laxmana Yetukuri, Artur Padzik, Mikael Jumppanen, Pekka Haapaniemi, Bhagwan Yadaw, Veronika Suni, Taru Varila, Garry Corthals, Wennerberg Krister, Tero Aittokallio, Jukka Westermarck
Journal: Cancer Research (2017)

Abstract Despite the pivotal role of phosphatases in cancer cell signalling, systemic understanding of phosphatase targets is still at infancy. Protein phosphatase 2A (PP2A) is a human tumor suppressor complex. PP2A inhibition is a requirement for human cell transformation and PP2A regulates many cancer critical signalling pathways. Importantly, emerging data indicates that reactivation of PP2A tumor suppressor activity could provide entirely novel approach for cancer therapy. Here, we present first systemic analysis of phosphoprotein targets (dephosphorylome) regulated by PP2A in cancer cells. Based on data, PP2A regulates cancer critical signalling pathways, including entire EGFR-RAS-RAF-MEK-ERK cascade, and functions as a master regulator of MYC function. At network level, PP2A targets critical cellular processes such as chromosome organization, RNA splicing, and nuclear envelope assembly. Surprisingly, soft clustering of PP2A dephosphorylome revealed that most phospho-target residues are subject to only unidirectional regulation in cancer cells. Moreover, targets show intracellular gradient where phosphatase inhibition dominates nuclear phosphorylation balance. Since phosphoregulation is critical for cancer drug responses, dephosphorylome was correlated with cancer cell responses to over 300 drugs. Importantly, cancer therapies could be broadly classified based on their dephosphorylome, both at quantitative and qualitative manner. Finally, we demonstrate the utility of this large dataset by validating the role of PP2A in MEK inhibitor resistance in KRAS mutant cancer cells via regulation of RAF, mTor and MYC. The study presents first systemic resource to understand potential of PP2A manipulation in cancer cell signalling and drug responses. The study also uncovers generally important insights to phosphoregulation. Citation Format: Otto Kauko, Susumu Imanishi, Evgeny Kulesskiy, Teemu D. Laajala, Laxmana Yetukuri, Artur Padzik, Mikael Jumppanen, Pekka Haapaniemi, Bhagwan Yadaw, Veronika Suni, Taru Varila, Garry Corthals, Wennerberg Krister, Tero Aittokallio, Jukka Westermarck. Systemic map of protein phosphatase 2A (PP2A)-regulated phosphotargets and drug responses in cancer cells [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 5560. doi:10.1158/1538-7445.AM2017-5560
Abstract 5624: Characterization of proliferation in multiple T-cell subsets in the CT26 murine colon carcinoma model by multi-color flow cytometry
Authors: Matt Thayer, Alden Wong, David Draper, Dan Saims, Scott C. Wise
Journal: Cancer Research (2017)

Abstract The efficacy of immune-modulating anti-cancer therapeutic antibodies that have been FDA-approved in recent years, such as anti-CTLA-4, anti-PD-1 and anti-PD-L1, has altered the paradigm of cancer treatment. Subsequently, the growing interest in the development of new single agent and combination therapies with immune-modulatory effects has generated a need for more powerful immunophenotyping techniques capable of in-depth cell characterization and proliferation assessment. To this end, using the CT26 syngeneic murine colorectal cancer model we have developed an 8 color flow cytometry antibody panel that focuses on the identification of lymphocyte subsets and analysis of proliferation within them utilizing the high-throughput-capable 4-laser, 14-color Attune NxT Flow Cytometer (Thermo Fisher Scientific). Splenocytes from tumor-naïve and CT26 tumor-bearing C57BL/6 mice were stained with CFSE (carboxyfluorescein succinimidyl ester), an amine-reactive fluorescent dye which enables generational tracking for up to seven rounds of cell division, allowing for proliferation to be quantified. Splenocytes from these mice were then stimulated with anti-CD3, anti-CD28, and IL-2. After stimulation for four days, cells were stained with antibodies against CD45, CD3, CD19, CD49b, CD335, CD4, CD8, and FoxP3. We were able to identify differential proliferative capacity between naïve and tumor-bearing mice in CD4+ T-cell, CD8+ T-cell, regulatory T-cell, and B-cell populations. Finally, we show that the accuracy of analysis is enhanced by the use of fluorescence minus-one (FMO) controls to identify those markers that generate dim signals, as well as a viability dye used to exclude dead cells from analysis. Identification of potentially responsive immune compartments, as well as characterizing proliferation, will facilitate identification and development of potential combination therapies by expanding the depth of our ability to provide mechanistic descriptions of drug function and efficacy. Following this proof-of-concept work, we will also present data from tumor-bearing mice treated with immune checkpoint inhibitors in order to identify potential differences in proliferation after treatment with immune-modulating agents. Citation Format: Matt Thayer, Alden Wong, David Draper, Dan Saims, Scott C. Wise. Characterization of proliferation in multiple T-cell subsets in the CT26 murine colon carcinoma model by multi-color flow cytometry [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 5624. doi:10.1158/1538-7445.AM2017-5624