tbuckley/cabot-search huggingface dataset:
Divergent evolution of temozolomide resistance in glioblastoma stem cells is reflected in extracellular vesicles and coupled with radiosensitization
Authors: Delphine Garnier, Brian Meehan, Thomas Kislinger, Paul Daniel, Ankit Sinha, Bassam Abdulkarim, Ichiro Nakano, Janusz Rak
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is almost invariably fatal due to failure of standard therapy. The relapse of GBM following surgery, radiation, and systemic temozolomide (TMZ) is attributed to the ability of glioma stem cells (GSCs) to survive, evolve, and repopulate the tumor mass, events on which therapy exerts a poorly understood influence. Here we explore the molecular and cellular evolution of TMZ resistance as it emerges in vivo (xenograft models) in a series of human GSCs with either proneural (PN) or mesenchymal (MES) molecular characteristics. We observed that the initial response of GSC-initiated intracranial xenografts to TMZ is eventually replaced by refractory growth pattern. Individual tumors derived from the same isogenic GSC line expressed divergent and complex profiles of TMZ resistance markers, with a minor representation of O6-methylguanine DNA methyltransferase (MGMT) upregulation. In several independent TMZ-resistant tumors originating from MES GSCs we observed a consistent diminution of mesenchymal features, which persisted in cell culture and correlated with increased expression of Nestin, decline in transglutaminase 2 and sensitivity to radiation. The corresponding mRNA expression profiles reflective of TMZ resistance and stem cell phenotype were recapitulated in the transcriptome of exosome-like extracellular vesicles (EVs) released by GSCs into the culture medium. Intrinsic changes in the tumor-initiating cell compartment may include loss of subtype characteristics and reciprocal alterations in sensitivity to chemo- and radiation therapy. These observations suggest that exploiting therapy-induced changes in the GSC phenotype and alternating cycles of therapy may be explored to improve GBM outcomes.
Abstract 1605: Combined oral cytokine therapy effectively treats colon cancer in a murine model
Authors: Neal Bhutiani, Qingsheng Li, Charles D. Anderson, Tao Gu, Nejat K. Egilmez
Journal: Cancer Research (2017)

Abstract Background: Regardless of its etiology, colorectal cancer development is intimately associated with dysregulation of the intestinal immune system. Sustained release, orally delivered IL-10 not only inhibits colon tumor growth but restores T cell homeostasis both locoregionally and systemically. However, it does not induce tumor regression. We aimed to combine orally delivered IL-12, a potent immunostimulatory molecule with robust anti-tumor effect, with oral IL-10 therapy to induce tumor regression. Methods: 6 week old APCmin mice were inoculated with enterotoxic Bacteroides fragilis (serotype 086) after five days of intestinal flora depletion with antibiotics dissolved in drinking water. 7-10 days after bacterial inoculation, mice were treated three times weekly with either 1) blank polylactic acid microspheres for 3 weeks, 2) IL-10 containing microspheres (0.5 microgram/dose) for 3 weeks, 3) IL-12 containing microspheres (0.25 micrograms/dose) for 3 weeks, or 4) IL-10 containing microspheres for 1 week followed by a combination of IL-10 and IL-12 containing microspheres for 2 weeks. After euthanasia, colons were assessed for polyp counts and select polyps were isolated for confocal microscopy analysis. Mesenteric lymph node lymphocytes were isolated and analyzed using flow cytometry. Results: Mice treated with oral IL-10 and IL-12 demonstrated a reduction in polyp number compared to those mice treated with IL-10 alone, and both groups had fewer polyps than mice treated with either IL-12 or blank microspheres. Addition of IL-12 resulted in increased CD8+ T cell numbers and IFN-γ production compared to treatment with IL-10 alone. IL-10 retained its effect on CD4+ T cells when combining it with IL-12, resulting in a decrease in conventional regulatory T cells (FoxP3+ RORγT -) as well as pathogenic regulatory T cells (FoxP3+ RORγT+) and IL-17 producing CD4+ T cells. Conclusions: The addition of IL-12 to IL-10 therapy augments the therapeutic effect of oral cytokine treatment on colon adenocarcinoma in the APCmin B. fragilis model. The effect appears additive and mediated by both IL-10’s effect on regulatory T cell populations and IL-12’s effect on CD8+ T cells. Further studies in the setting of more advanced disease, including liver metastases, will elucidate the therapeutic potential of combination oral cytokine therapy with IL-10 and IL-12 for treatment of colorectal cancer. Citation Format: Neal Bhutiani, Qingsheng Li, Charles D. Anderson, Tao Gu, Nejat K. Egilmez. Combined oral cytokine therapy effectively treats colon cancer in a murine 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 1605. doi:10.1158/1538-7445.AM2017-1605
Abstract 2535: MicroRNA-518c-5p promotes the metastasis of oral cancer
Authors: Makoto Kinouchi, Daisuke Uchida, Nobuyuki Kuribayashi, Yuske Komiyama, Shuji Tsuchida, Hitoshi Kawamata
Journal: Cancer Research (2017)

Abstract We have demonstrated that CXCR4 system is involved in the metastatic process of oral cancer. Recently, we identified the miR-518c-5p as a downstream target of the CXCR4 system. In this study, we examined the function of miR-518c-5p on the metastasis of oral cancer. We transfected miR-518c expression vector into oral cancer cells, B88 and CAL27, and isolated stable transfectants, B88-518c and CAL27-518c, respectively. The growth and migration of both cells were significantly enhanced in compared with those of mock cells. LNA-based miR-518c-5p inhibitor significantly impaired the enhanced cell growth and migration of these cells, indicating that these phenomena were dependent on the expression of miR-518c-5p, not on that of miR-518c-3p. Next, we examined the function of miR-518c-5p in vivo. miR-518c or mock transfectants were inoculated into the masseter muscle or the blood vessels of nude mice. Tumor volume, lymph nodes metastasis, and lung metastasis were significantly increased in the mice inoculated with miR-518c transfectants. Furthermore, we examined the mRNA expression induced by miR-518c-5p using B88 cells and B88-518c cells by cDNA microarray analysis. Consequently, some of the genes involved in the cell growth and metastasis were upregulated in the B88-518c cells. These results indicate that CXCR4 system regulates the metastases of oral cancer via induction of miR-518c-5p. Citation Format: Makoto Kinouchi, Daisuke Uchida, Nobuyuki Kuribayashi, Yuske Komiyama, Shuji Tsuchida, Hitoshi Kawamata. MicroRNA-518c-5p promotes the metastasis of oral 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 2535. doi:10.1158/1538-7445.AM2017-2535
Abstract 3621: Characterization of the effects of estrogen receptor alpha Y537S and D538G mutations on receptor pharmacology
Authors: Steven J. Hartman, Tracy Kleinheinz, Jonathan White, Stephen Daly, Ria Goodwin, Wei Zhou, Jun Liang, Xiaojing Wang, Daniel F. Ortwine, Lori Friedman, Martin O’Rourke, Ciara Metcalfe, Robert A. Blake
Journal: Cancer Research (2017)

Abstract The frontline therapy for estrogen receptor alpha (ERα) positive Breast Cancer (ER+BC) involves various forms of endocrine therapy, consisting of either Selective Estrogen Receptor Modulators (SERMs) or aromatase inhibitors. An emerging mechanism of ER+BC resistance to endocrine therapy, and consequently disease relapse, has been associated with a set of “hotspot” mutations in and near to helix-12 of the ERα ligand binding domain. Selective Estrogen Receptor Degraders/Down-regulators (SERDs) represent an important pharmacological strategy being applied to develop treatments for resistant ER+BC. Here, we compare 2 of the most frequent ERα hotspot mutations (Y537S and D538G), with ERα wildtype (WT) and the ability of a set of SERM/SERDs and other ERα ligands to bind, antagonize, degrade/stabilize ERα and affect cell proliferation. Common themes that emerged included the observation that the concentration of each drug required to bind, antagonize or degrade ERα Y537S or ERα D538G was typically higher than that required for ERα WT, although the extent of the shift varied between drugs and the type of measurement. An unexpected observation was that 4-hydroxy-tamoxifen (a major active metabolite of tamoxifen) stabilized nuclear ERα Y537S protein. This represents a potential mechanism that may limit the efficacy of Tamoxifen in treating ERα Y537S ER+BC. Citation Format: Steven J. Hartman, Tracy Kleinheinz, Jonathan White, Stephen Daly, Ria Goodwin, Wei Zhou, Jun Liang, Xiaojing Wang, Daniel F. Ortwine, Lori Friedman, Martin O’Rourke, Ciara Metcalfe, Robert A. Blake. Characterization of the effects of estrogen receptor alpha Y537S and D538G mutations on receptor pharmacology [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 3621. doi:10.1158/1538-7445.AM2017-3621
Abstract 4067: BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in an <i>in vivo</i> C6 rat glioma model and synergizes with temozolomide
Authors: Stephane Gesta, Semma Nagpal, Tulin Dadali, Milton Merchant, Taichang Jan, Anne R. Diers, Michael Kiebish, Joaquin Jiminez, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan, Lawrence Recht
Journal: Cancer Research (2017)

Abstract BPM31510, a parenteral nanodispersion of ubidecarenone that is in clinical testing for solid tumors, effectuates an anti-cancer effect in highly metabolic cancers by eliciting an anti-Warburg effect. Intraperitoneal (i.p.) administration of BPM31510 reverses paraplegia in a rat CNS leukemia model demonstrating the bioavailability of the drug to the central nervous system. The study describes data demonstrating the therapeutic utility of BPM31510 in glioblastoma multiforme (GBM). BPM31510 decreased cell proliferation rates in patient derived GBM cell lines compared to temozolamide (TMZ), pretreatment with BPM31510 followed by TMZ challenge was associated with significant synergy in reducing cell proliferation compared to monotherapy. In a C6 glioma allograft rat model treatment with BPM31510 alone (n=30/group) (i.p., 50mg/kg, b.i.d) increased overall survival compared to untreated control group. BPM31510 in combination with procarbazine (oral, 60mg/kg; d 8, 21) and vincristine (IV, 1.4mg/kg; d 8, 29) significantly improved overall survival compared to BPM31510 alone or chemotherapy. Furthermore, long term survival was achieved in four of twenty rats with C6 gliomas receiving BPM31510 doses between 10 and 50 mg/kg compared with none treated with either vehicle or irradiation (P &amp;lt; 0.02, Fisher exact test). Interestingly, the long term survival persisted for over two months after all treatment was discontinued; MR imaging confirmed the presence of static masses in these long term survivors. Collectively, the data demonstrate that BPM31510 has a robust effect in a preclinical model of GBM. Intravenous BPM31510 is currently in Phase 1/2 clinical trial for TMZ+BEV refractory GBM patients. Citation Format: Stephane Gesta, Semma Nagpal, Tulin Dadali, Milton Merchant, Taichang Jan, Anne R. Diers, Michael Kiebish, Joaquin Jiminez, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan, Lawrence Recht. BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in an in vivo C6 rat glioma model and synergizes with temozolomide [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 4067. doi:10.1158/1538-7445.AM2017-4067
Abstract 5813: Rab GTPase 3C promotes colon cancer metastasis via regulation of IL-6 secretion and STAT3 signaling pathway
Authors: Chi-Long Chen
Journal: Cancer Research (2017)

Abstract RAB GTPases is involved in membrane trafficking vesicle formation and cell motility. Recently, exocytotic RABs received growing attention in cancer research. However, the molecular mechanism of exocytotic RABs in colorectal tumorigenicity remains unclear. In this study, we found RAB GTPase 3C (RAB3C) has the most significant association with higher pathological stage, tumor recurrence, frequent distant metastasis, and poor prognosis in 215 colorectal adenocarcinoma cohort using tissue microarray (TMA) analysis. In multivariate analyses, high RAB3C expression retained its independently prognostic significance for both overall survival (p=0.001) and disease-free survival (p &amp;lt; 0.001). Further experimental results showed increased migration and invasion ability in RAB3C overexpressing colon cancer cells compared with control group in vitro and in vivo. The cell culture medium collected from RAB3C overexpressing model could promote parental colon cancer cells further indicated that the metastasis-promoting role of RAB3C is exocytosis dependent. We then integrated the results from previously microarray and proteomics datasets and discovered that increased production of multiple cytokines in RAB3C overexpressing cell lines. Of these cytokines, IL-6 pathway is the top pathway corresponding to gene expression changes after RAB3C overexpression. Blocking of IL-6 function with IL-6 antibody or IL-6 knockdown significantly reduced the migration ability in RAB3C overexpressing colon cancer cells. Furthermore, secretion of IL-6 after RAB3C overexpression promoted the JAK2-STAT3 signaling with increased STAT3 phosphorylation levels to promote migration. In addition, Ruxolitinib, a JAK2 inhibitor, was found to significantly inhibited RAB3C induced colon cancer cell migration through blocking STAT3 phosphorylation. In conclusion, our study showed that RAB3C overexpression promoted tumor metastasis and is associated with poor prognosis of colon cancer patients through modulating the IL6 exocytosis of cancer cells to activate JAK2-STAT3 pathway. These findings suggest a new therapeutic strategy through the inhibition of STAT3 signaling pathway in RAB3C-IL-6 axis by Ruxolitinib to prevent metastasis of colon cancer. Note: This abstract was not presented at the meeting. Citation Format: Chi-Long Chen. Rab GTPase 3C promotes colon cancer metastasis via regulation of IL-6 secretion and STAT3 signaling pathway [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 5813. doi:10.1158/1538-7445.AM2017-5813
Abstract 4060: Pharmacological targeting of the Aurora A and Histone 3 lysine 9 methyltransferase pathways in pancreatic cancer induces mitotic catastrophe
Authors: Angela Mathison, Ann Salmonson, Mckenna Missfeldt, Thiago de Assuncao, Jennifer Bintz, Trace Christensen, Sarah Kossak, Asha Nair, Juan Iovanna, Robert Huebert, Gwen Lomberk
Journal: Cancer Research (2017)

Abstract By regulating gene expression networks that mediate neoplastic behavior, epigenetic protein complexes are the ultimate effectors of oncogenic pathways. This hierarchical position of epigenetic pathways within the mechanisms that regulate cancer makes them ideal candidates for therapeutic targets. The current work was designed to characterize the role of the K9H3 Histone Methyltransferase (HMT) pathway in mediating oncogenic signals downstream of Aurora Kinase A (AurkA), with the goal of designing efficient combinatorial therapies against PDAC. Affinity protein purification, combined with mass spectrometry, demonstrates that HP1γ isolated from mitotic cells interacts with AurkA and the HMTs, G9a and GLP. We also find that this complex is critical for mitotic progression and cell proliferation. Congruently, treatment of PDAC cells with individual drugs against AurkA or HP1-HMT inhibits cell growth by inducing senescence, a cytostatic response. However, the combination of these agents has a synergistic effect of reducing cell growth in both, monolayer and spheroid cultures to result in a cytotoxic effect. Confocal and electron microscopy, along with cell cycle analysis, demonstrate that the cytotoxic effect of this combination is due to induction of mitotic catastrophe, a distinct form of cell death that occurs during mitosis. Molecularly, the combination of AurkA and HP1-HMT inhibition bypasses G2/M arrest with downregulation of the Chk1-Cdc25c pathway. In vivo treatment of PDAC orthotopic xenografts with the HP1-HMT inhibitor alone demonstrated reduced PDAC growth, and increased efficacy in PDAC growth reduction was observed in combination with the AurkA inhibitor over either individual treatment. Thus, our data demonstrate a novel AurkA-HP1-HMT mitotic pathway that holds promise for potential pharmacological targeting in combinatorial therapy for this malignancy. Citation Format: Angela Mathison, Ann Salmonson, Mckenna Missfeldt, Thiago de Assuncao, Jennifer Bintz, Trace Christensen, Sarah Kossak, Asha Nair, Juan Iovanna, Robert Huebert, Gwen Lomberk. Pharmacological targeting of the Aurora A and Histone 3 lysine 9 methyltransferase pathways in pancreatic cancer induces mitotic catastrophe [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 4060. doi:10.1158/1538-7445.AM2017-4060
Abstract 2191: Multiple imaging reporter labeled acid-degradable dextran nanopolymer as a COX-2 siRNA carrier for COX-2 specific downregulation
Authors: Zhihang Chen, Balaji Krishnamachary, Marie-France Penet, Zaver M. Bhujwalla
Journal: Cancer Research (2017)

Abstract Cyclooxygenase-2 (COX-2) as a target has attracted interest for multiple degenerative diseases and cancers. COX-2 siRNA provides specific and effective down-regulation of COX-2. However, because artificial cationic polymers can induce proinflammatory signals that increase COX-2 expression, there are few if any reports about the use of artificial cationic polymers as siRNA carrier to downregulate COX-2 in cancer cells. Here we developed a method to efficiently synthesize a multiple imaging reporter labeled biodegradable dextran to use as an efficient cationic polymer carrier for COX-2 siRNA delivery. Amine function groups were conjugated to the dextran platform through acetal bonds. Acetal bonds were broken at acidic conditions that occur in cancer and endocytosis compartments. Rhodamine was labeled to the amine groups to detect degradation and removal of these groups from the cell, while the dextran scaffold was labeled with Cy5.5. The rapid cleavage and release of amine groups minimized the proinflammatory side effects of the positively charged amine groups.Colorimetric assay of Cy5.5 and rhodamine in different pH buffer indicated that the amine group was cleaved at pH 5.5 buffer but was stable in pH 7.4 buffer. Fluorescence imaging showed that the dextran siRNA nanoplex entered the cells through endocytosis that provided acidic conditions for the breaking of the amine group. For the first time, the intracellular breaking of acetal bonds was clearly visualized by multiple imaging reporters. Because the rapid cleavage and release of amine groups minimized the proinflammatory side-effects, quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay indicated that this dextran COX-2 siRNA nanoplex could downregulate COX-2 expression efficiently. Prostaglandin E2 level decreased significantly with COX-2 siRNA/dextran treatment. In vivo imaging demonstrated that the COX-2 siRNA/dextran nanoplex accumulated in MDA-MB-231 tumors. QRT-PCR and western blot assays of COX-2 levels in tumor tissue demonstrated that this nanoplex significantly downregulated COX-2 expression in vivo efficiently and within 24h. This dextran nanopolymer can be used as a safe, reproducible, and biocompatible siRNA carrier to effectively reduce COX-2 expression in cancer cells and tumors. Citation Format: Zhihang Chen, Balaji Krishnamachary, Marie-France Penet, Zaver M. Bhujwalla. Multiple imaging reporter labeled acid-degradable dextran nanopolymer as a COX-2 siRNA carrier for COX-2 specific downregulation [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 2191. doi:10.1158/1538-7445.AM2017-2191
Abstract SY06-02: Macrophage-targeted cancer immunotherapy
Authors: Carola Ries
Journal: Cancer Research (2017)

Abstract Combining immunotherapies that harness cytotoxic T cells to fight cancer has become a major effort in treating metastatic cancer patients. We present data on an example of cancer immunotherapy combination targeting innate immune cells, in particular tumor-associated macrophages (TAMs), that is currently being tested in the clinic. Combination of a TAM-depleting anti-CSF-1R antibody with an activating anti-CD40 agonist demonstrated synergistic antitumoral efficacy resulting in complete tumor remission in preclinical mouse cancer models. Ex vivo RNA sequencing of sorted TAM revealed that only the combination treatment induced a transient, profound repolarization of TAMs towards an immunostimulatory M1 phenotype. However, these TAM populations are ultimately eliminated. The central role of macrophages was further substantiated by complete loss of therapeutic benefit when TAMs were depleted prior to combinational treatment. Furthermore, rechallenge and depletion experiments demonstrated that tumor rejection is finally mediated by an antitumoral T-cell response. In colorectal cancer patients coexpression of human CSF1R and CD40 on TAMs was detected, providing the basis to explore this combination in the clinic. Citation Format: Carola Ries. Macrophage-targeted cancer immunotherapy [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 SY06-02. doi:10.1158/1538-7445.AM2017-SY06-02