tbuckley/cabot-search huggingface dataset:
Abstract 2365: Dual inhibition of the PI3k/Akt and MEK5/ERK5 pathways in tamoxifen resistant breast cancer
Authors: Thomas D. Wright, Mahmud Hasan, Paula Witt-Enderby, Jane Cavanaugh
Journal: Cancer Research (2017)

Abstract Approximately 70% of breast cancers are considered estrogen receptor alpha (ER) and/or progesterone receptor (PR) positive, and their growth is primarily driven by the hormone estrogen. Initially these cancers are responsive to endocrine therapies such as tamoxifen. However, over time patients become resistant to conventional endocrine therapy and treatment becomes more difficult. Tamoxifen resistance occurs due to several mechanisms: loss of ER expression, gain of function mutations, pharmacological tolerance, alterations of co-activators, and ligand independent activation of ER by various kinase cascades. Aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. The crosstalk between PI3K/Akt and MEK1/2/ERK1/2 has been characterized in several systems. However, new evidence suggests that MEK5/ERK5, a member of the MAPK family, is a key component in the proliferation and survival of therapy resistant cancers. MEK5/ERK5 has been shown to promote ER alpha driven transcription in ER+ breast cancers and actin reorganization and metastasis in ER- breast cancers. Furthermore, MEK5/ERK5 promotes hormone independent tumorigenesis in breast cancer. Our lab has previously investigated these pathways in hormone independent breast cancers, TNBC (triple negative breast cancer). Our previous results indicate that combinations of PI3k/Akt and MEK5/ERK5 blockade are promising because they inhibit both the pro-proliferative and pro-metastatic pathways in TNBC. Additionally, PI3k/Akt and MEK5/ERK5 inhibition was shown synergistically reduce viability in a diverse panel of cell lines (TNBC, ER+, and Triple Positive). Based on these initial results we hypothesize that PI3k/Akt and MEK5/ERK5 inhibition decreases viability via a hormone independent mechanism: perhaps by reducing the cytosolic sequestration of Bad. In this study we investigate the utility PI3k/Akt and MEK5/ERK5 inhibition in a MCF-7 TamR cell line. The goal of our study is to elucidate the roles of PI3k/Akt/mTOR and MEK5/ERK5 in endocrine resistant breast cancer and broaden the scope of a dual inhibition strategy. Citation Format: Thomas D. Wright, Mahmud Hasan, Paula Witt-Enderby, Jane Cavanaugh. Dual inhibition of the PI3k/Akt and MEK5/ERK5 pathways in tamoxifen resistant 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 2365. doi:10.1158/1538-7445.AM2017-2365
Abstract 2811: Comparative study of anti-PD1 and CSF1R inhibition on tumor-infiltrating lymphocytes and macrophage populations across a panel of syngeneic tumor models
Authors: Yuki Kato Maves, Hooman Izadi, Elvira C. Talaoc, Deborah Yan, Charlene Echegaray, Andrew Calinisan, Krystal Moya, Heather Venant, Mitchell Garland, Radhika Iyer, Shounak Gosh, Stephanie Songco, Jayant Thatte, Tommy Broudy
Journal: Cancer Research (2017)

Abstract Immunotherapy represents an extremely promising treatment approach for cancer patients. The success in this field has been signified by multiple recent approvals of checkpoint inhibitors across a range of cancer types. Subsequently, there is an increasing need to understand why certain patients and diseases benefit from these treatments while others do not, as well as how to maximize the benefits from these treatments. To address some of these questions, we used an in vivo screening platform, MuScreen, which allows for evaluation of multiple syngeneic models and treatment modalities.We have characterized baseline and treated tumor immune infiltrates for a panel of syngeneic models using flow cytometry. The correlation between responsiveness and effects of checkpoint inhibitors (e.g., anti-PD-1), and macrophage targeted agents (e.g., CSF1R inhibition) on immune infiltrates including tumor-associated macrophages (TAMs) were investigated in 6 syngeneic models. Furthermore, M1/M2 polarization of macrophages was investigated to explore the potential role of these cells in establishing an immunosuppressed tumor microenvironment that may affect response to therapy. Here, we show that the baseline immune cell population varies across models, and that immune checkpoint inhibitors and macrophage-targeted agents had variable efficacy across different tumor models. We also present the correlation of immune cell infiltration, including tumor infiltrating lymphocytes (TILs), TAMs, and responsiveness to immunotherapy intervention. Having an in-depth understanding of the immune make up of a model in which an immunomodulatory compound is screened is paramount for successful translation into the clinic. A well-characterized and fully profiled panel of syngeneic models such as the MuScreen platform allows for finding the right model for screening test compounds to be used alone or in combination with immunotherapy. Citation Format: Yuki Kato Maves, Hooman Izadi, Elvira C. Talaoc, Deborah Yan, Charlene Echegaray, Andrew Calinisan, Krystal Moya, Heather Venant, Mitchell Garland, Radhika Iyer, Shounak Gosh, Stephanie Songco, Jayant Thatte, Tommy Broudy. Comparative study of anti-PD1 and CSF1R inhibition on tumor-infiltrating lymphocytes and macrophage populations across a panel of syngeneic tumor 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 2811. doi:10.1158/1538-7445.AM2017-2811
Abstract 1620: Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenic CD4+ T-cells and induction of antitumor CD8+ T-cell activity
Authors: TAO GU, Magdia DeJesus, Thomas P. Burris, Nejat K. Egilmez
Journal: Cancer Research (2017)

Abstract An oral sustained-release formulation of Interleukin-10 suppressed tumor growth and enhanced survival in the APCmin/+ / Bacteroides fragilis spontaneous colon cancer model. Therapeutic benefit was associated with a 5-fold reduction in CD4+RORγt+Foxp3-IL-17+ T-helper cell, CD4+RORγt+Foxp3+IL-17+ pathogenic T-regulatory cell (pgTreg) and CD4+RORγt-Foxp3+IL-17- conventional T-regulatory cell (cTreg) numbers; and a concurrent enhancement of CD8+ T-cell cytotoxicity in the colonic lamina propria. Selective subset depletion and functional blockade studies demonstrated that CD4+RORγt+IL-17+ T-cell subsets and CD4+Foxp3+ cTreg supported tumorigenesis/tumor progression whereas CD8+ cytotoxic T-lymphocytes suppressed tumor growth. These findings establish the utility of oral particulate IL-10 as a potential new therapeutic in the management of colon cancer and shed light on the cellular mechanisms that underlie its antitumor activity. Note: This abstract was not presented at the meeting. Citation Format: TAO GU, Magdia DeJesus, Thomas P. Burris, Nejat K. Egilmez. Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenic CD4+ T-cells and induction of antitumor CD8+ T-cell activity [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 1620. doi:10.1158/1538-7445.AM2017-1620
Abstract CT061: Novel safety of high dose ascorbic acid and induction chemotherapy for high risk pancreatic cancer
Authors: Howard W. Bruckner, Azriel Hirschfeld, Daniel Gurell, King Lee
Journal: Cancer Research (2017)

Abstract Background: High dose ascorbic acid has been reported to have in vitro anticancer activity. Low dose combination chemotherapy with GFLIP (gemcitabine, 5fu, leucovorin, irinotecan, oxaliplatin) is an effective regimen for patients with pancreatic cancer. Combining high dose ascorbic acid with GFLIP may be a synergistic and well tolerated treatment regimen. Methods: High dose ascorbic acid with a range of 75-100 grams IV given on an average 1-2 times per week was combined with GFLIP given on a 2 week schedule for patients with pancreatic cancer. Eligibility criteria include locally advanced, unresectable, recurrent and metastatic disease. Patients who progressed on prior treatment, ECOG 0-2, were also included. There was no age cut off. Results: 26 patients were treated, 9 patients were ≥ 70 years of age (35%). 25 out of 26 patients had stage IV disease (96%). Nine out of 26 patients had received at least one prior chemotherapy regimen (35%). Five out of 26 patients had a grade 3 neutropenia (19%) there was no grade 4 neutropenia. One out of 26 patients (4%) had a grade 3 anemia and thrombocytopenia. There was no neutropenic fever and no limiting gastrointestinal (diarrhea, stomatitis) toxicity. This study included patients with a performance status of 2, patients who had progressed on prior chemotherapy and older patients. Conclusion: High dose ascorbic acid combined with GFLIP chemotherapy is a safe and well tolerated treatment regimen for high risk patients with pancreatic cancer. This level of safety justifies the further study of this treatment regimen especially for high risk patients who would not be eligible for standard high dose combination chemotherapy in pancreatic cancer. Citation Format: Howard W. Bruckner, Azriel Hirschfeld, Daniel Gurell, King Lee. Novel safety of high dose ascorbic acid and induction chemotherapy for high risk pancreatic 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 CT061. doi:10.1158/1538-7445.AM2017-CT061
Abstract 5114: Design, synthesis, and biological evaluation of tricyclic thieno[2,3- <i>d</i>]pyrimidines as microtubule targeting antitumor agents
Authors: Farhana Islam, Aleem Gangjee, Xin Zhang, Xilin Zhou, Susan L. Mooberry
Journal: Cancer Research (2017)

Abstract Microtubules are dynamic structures that, together with actin microfilaments and intermediate filaments, constitute the cellular cytoskeleton. Besides their well-known roles in cell division, their functions involve maintenance of cell shape and morphology, cellular motility, and trafficking of organelles and vesicles. Recently, we reported a compound AG 370 as a microtubule targeting agent, that circumvented the Pgp and βIII-tubulin mediated drug resistance mechanisms that limit the efficacy of paclitaxel, docetaxel, and the vinca alkaloids. Molecular modeling and docking studies of the parent compound (AG 370) in the colchicine binding site (PDB: 402B) suggest that the C-5 and C-6 of parent compound are oriented towards the hydrophobic pockets with the side chain of Ala316, Val315, Leu255 and Met259. However, this binding pocket in tubulin is relatively large. To further explore the hydrophobic pocket, an additional cyclohexene ring was introduced at C-5 and C-6 of AG370. In the molecular modeling study, the resulting tricyclic scaffold showed hydrophobic interactions with the amino acids of the colchicine binding site. The 2-Me substituent of the tricyclic scaffold was replaced with a 2-H and a 2-NH2 group and 4-position of the scaffold was replaced with appropriate anilines. The 2-amino- N4-methoxyphenyl moiety (AG61) was found to be the most potent analog in the tricyclic series in both antiproliferative assay in human melanoma cancer cell line (MDA-MB-435 cell line, IC50 = 9.0 ± 0.2 nM) and in microtubule depolymerization assay in A-10 cells (EC50= 19 nM). Thus, we identified tricyclic thieno[2,3-d]pyrimidines as a novel structural scaffold with potent antiproliferative activity as well as microtubule depolymerizing activity. These analogs are selected for preclinical development. Citation Format: Farhana Islam, Aleem Gangjee, Xin Zhang, Xilin Zhou, Susan L. Mooberry. Design, synthesis, and biological evaluation of tricyclic thieno[2,3- d]pyrimidines as microtubule targeting antitumor agents [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 5114. doi:10.1158/1538-7445.AM2017-5114
Abstract 2407: Inhibition of gene expression during non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis is mediated by histone H4 lysine 16 deacetylation
Authors: Kostiantyn Dreval, Aline de Conti, Orish Ebere Orisakwe, Frederick A. Beland, Igor P. Pogribny
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers and the incidence is steadily increasing worldwide. The molecular mechanisms leading to the development of HCC consist of genetic and epigenetic aberrations, including changes in global and gene-specific DNA methylation and altered expression of several classes of non-coding RNAs. While changes in DNA methylation and microRNA expression during the development of HCC are well-studied, the role of aberrant post-translational histone modifications remains unexplored. Using a mouse Stelic Animal Model (STAM) of NASH-associated liver carcinogenesis, we have investigated alterations in hepatic histone modifications at steatotic (6 weeks), fibrotic (12 weeks), and full-fledged HCC (20 weeks) stages of the HCC development. NASH-related liver carcinogenesis was characterized by a progressive decrease in the levels of histone H4 lysine 20 trimethylation (H4K20me3) and histone H4 lysine 16 acetylation (H4K16ac), with the greatest decrease occurring in full-fledged tumors. Mechanistically, the deacetylation of H4K16ac was associated with nuclear protein 1 (Nupr1)-mediated inhibition of histone lysine acetyltransferase KAT8. In addition to a global loss of hepatic H4K16ac, there was a significant decrease of gene-specific H4K16ac, as indicated by a reduced level of H4K16ac in 16 out of 25 critical cancer-related genes. More importantly, the changes in the extent of gene-specific H4K16 deacetylation were positively correlated with the level of gene transcription (r = 0.965, p &amp;lt; 0.01). These results indicate that a reduction of global and gene-specific of H4K16ac is a key pathophysiological mechanism contributing to the development of NAFLD-derived HCC. Citation Format: Kostiantyn Dreval, Aline de Conti, Orish Ebere Orisakwe, Frederick A. Beland, Igor P. Pogribny. Inhibition of gene expression during non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis is mediated by histone H4 lysine 16 deacetylation [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 2407. doi:10.1158/1538-7445.AM2017-2407
Abstract 3062: Metformin inhibits TGFβ-induced stromal ECM remodeling to impede invasion in ovarian cancer
Authors: Peter C. Hart, Shermeen Sheikh, Ernst Lengyel, Iris Romero
Journal: Cancer Research (2017)

Abstract Recently, our group has elucidated that metformin, the commonly used medication for type 2 diabetes, has anti-ovarian cancer (OvCa) effects in preclinical models and use of the drug is associated with improved OvCa survival in retrospective epidemiological studies. While the cytotoxic effects of metformin in ovarian cancer cell lines is well demonstrated, the impact of metformin on tumor-stromal interactions in the tumor microenvironment is not well defined. Currently, our work has focused on the impact of metformin on the tumor microenvironment and cancer cell behavior in physiologic models of tumor metastasis. Using a 3D organotypic model, we demonstrate that OvCa cell invasion is inhibited by metformin. In evaluating the molecular mechanism mediating this effect we show that OvCa cells co-cultured with stromal cells or stimulated with TGFβ1 upregulate the production of the extracellular matrix (ECM) proteins fibronectin and collagen 1 and that this effect is attenuated by metformin. Interestingly, metformin’s inhibition of ECM production was not dependent on AMP-activated kinase (AMPK), a common metformin target. To expand on this finding we performed label-free shotgun proteomics and identified collagens, fibronectin and TGFBR2 to be among the proteins most highly repressed in response to metformin exposure in OvCa cells. Finally, we identified that this repression of ECM remodeling by metformin was associated with an overall reduction in TGFBR2 expression and consequent SMAD/STAT3 activity. Taken together, our data indicate that metformin may have novel targets in the tumor microenvironment where it targets pro-tumorigenic effects of the stromal compartment by repressing TGFβ-dependent stromal cell ECM secretion, thereby inhibiting ovarian cancer invasion and metastasis. Citation Format: Peter C. Hart, Shermeen Sheikh, Ernst Lengyel, Iris Romero. Metformin inhibits TGFβ-induced stromal ECM remodeling to impede invasion in ovarian 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 3062. doi:10.1158/1538-7445.AM2017-3062
Abstract 3064: Retinoic acid: An effective therapy for basal-like breast cancer
Authors: Krysta Mila Coyle, Cheryl A. Dean, Dejan Vidovic, Ian C. Weaver, Carman A. Giacomantonio, Paola Marcato
Journal: Cancer Research (2017)

Abstract We have identified a novel strategy to identify breast cancer patients who will benefit from an existing anti-cancer agent, retinoic acid (RA). While RA has not yet achieved success in the treatment of breast cancers, we hypothesized that it can be an effective therapy for a subset of triple-negative breast cancer (TNBC) patients. TNBC is among the most aggressive breast cancers, and lacks targeted therapies. TNBCs can be further subtyped into basal-like and claudin-low, which differ in gene expression and drug sensitivities. Understanding the molecular basis of these subtypes will lead to the development of more effective treatment options for TNBC. To test this hypothesis, we performed tumor growth assays on TNBC cell lines and patient-derived xenografts (PDXs). We found that RA treatment decreased the tumor growth of four basal-like TNBC cell lines (MDA-MB-468, HCC70, SUM149, HCC1937). In contrast, RA increased the tumor growth of two claudin-low TNBC cell lines (MDA-MB-231, MDA-MB-436). Gene expression and methylation analysis of these affected cell lines revealed subtype-specific expression of RA-inducible genes due to silencing by DNA methylation, e.g. of the RA-inducible tumor-suppressor gene RARRES1. RARRES1 is silenced by methylation in claudin-low cell lines, but is hypomethylated and expressed in basal-like cells. Use of the subtype-specific expression and methylation profiles allowed us to accurately predict the response of 4 PDXs to RA treatment. Continued classification of TNBCs into these two subtypes will enable clinical use of RA, in part due to the subtype-specific hypomethylation of RA-inducible tumor suppressor genes including RARRES1. We have identified additional subtype-specific biomarkers which can predict the response of patient tumors to RA treatment, thus identifying a novel targeted therapy strategy for TNBCs. Citation Format: Krysta Mila Coyle, Cheryl A. Dean, Dejan Vidovic, Ian C. Weaver, Carman A. Giacomantonio, Paola Marcato. Retinoic acid: An effective therapy for basal-like 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 3064. doi:10.1158/1538-7445.AM2017-3064
Abstract 5446: Tumor-derived miR-200c and 141 contribute to high levels of plasma microRNA-200c and 141 through exosomes
Authors: Lizhong Wang, Runhua Liu, Song Gao, Yicun Wang, Meng Wang, Zhi Li
Journal: Cancer Research (2017)

Abstract Circulating microRNAs (miRs) have potential as cancer biomarkers, but their regulatory mechanisms remain elusive. Here we used a breast cancer model (Foxp3 heterozygous Scurfy mutant female mice, Foxp3sf/+) for identification of circulating miR biomarkers, and the formation and regulation of these miRs were investigated. Aging Foxp3sf/+ female mice developed spontaneous breast cancers and lung metastases. Levels of miR-200c and 141 were lower in the Foxp3sf/+ breast cancer cells than in normal breast epithelial cells, but plasma levels of miR-200c and 141 in the Foxp3sf/+ mice increased during tumor progression, especially during metastasis to the lung. Likewise, 259 participants, including patients with breast cancer or benign breast tumors, members of breast cancer families, and matched normal healthy controls, were assessed for circulating levels of candidate miRs. The results showed that: 1) the levels of miR-200c and 141 were lower in the FOXP3low breast cancer cells relative to those with FOXP3high, especially for late-stage and metastatic cancer cells; 2) the levels of miR-200c and 141 were higher in plasma of patients with metastatic breast cancer than in plasma of those with localized breast cancer, with benign breast tumors, with a family history of breast cancer, or normal healthy controls. Furthermore, in Foxp3sf/+ mice, plasma miR-200c and 141 were released from tumor cells through exosomes. Thus, plasma levels of miR-200c and 141 are potential biomarkers for early detection of metastases. MiR-200c and 141 appear to be released from breast cancer cells, through exosomes, into the circulation. Citation Format: Lizhong Wang, Runhua Liu, Song Gao, Yicun Wang, Meng Wang, Zhi Li. Tumor-derived miR-200c and 141 contribute to high levels of plasma microRNA-200c and 141 through exosomes [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 5446. doi:10.1158/1538-7445.AM2017-5446