tbuckley/cabot-search huggingface dataset:
Abstract 1999: Regulation of the oncogenic, invasion-promoting transcription factor myeloid zinc finger-1 (MZF1) in breast cancer by microRNAs
Authors: Tuula Kallunki, Siri A. Tvingsholm, Knut K. Bundgaard Clemmensen, Ditte M. Brix, Bo Rafn, José Moreira, Lisa Frankel, Anders Lund, Riku Louhimo, Sampsa Hautaniemi, Irina Gromova, Marja Jäättelä
Journal: Cancer Research (2016)

Abstract INTRODUCTION: Myeloid Zinc Finger 1 (MZF1) is a transcription factor that is normally involved in myeloid differentiation. MZF1 can also be found in epithelial cancers, where it functions as an invasion and metastasis promoting oncogene. MZF1 is a central node of the invasive signaling network activated by HER2/ErbB2 in breast cancer, where MZF1 mobilizes and activates lysosomes and increases the expression of cysteine cathepsin B to promote invasion and metastasis. Thus, maintaining the sufficient expression level of MZF1 is important for the invasive signaling of breast cancer cells. RESULTS AND EXPERIMETAL PROCHEDURES: Here we show that MZF1 is essential for the invasion of breast cancer cells in 3-dimensional cultures. We also describe a possible mechanism that regulates MZF1 levels in breast cancer. By using available micro-RNA (miRNA) binding site prediction programs (www.microrna.org/), specific microRNA mimics, corresponding miRNA inhibitors e.g. locked nucleic acids, luciferase reporter assays, immunofluorescense, quantitative PCR and 3-dimensional invasion assays we show that some breast cancer specific miRNAs can regulate MZF1 RNA and protein levels and revert the malignant and invasive cellular phenotype of breast cancer cells by altering the invasion promoting functions of lysosomes. These results are supported by the analysis of breast cancer patient data from the cancer genome atlas (http://cancergenome.nih.gov) showing that MZF1 expression correlates negatively with the expression of the identified miRNAs, when using data collected from over 600 primary breast cancer tumors. SUMMARY: This study shows that MZF1 is an oncogene whose sufficient expression levels are central for breast cancer cell invasion and whose specific miRNA-mediated downregulation can inhibit breast cancer malignancy by modifying the expression of its lysosomal target genes. CONCLUSION: Cancer-associated upregulation of MZF1 increases the breast cancer malignancy. Thus finding ways to downregulate MZF1 expression or inhibit its activity can be beneficial for breast cancer therapy. Citation Format: Tuula Kallunki, Siri A. Tvingsholm, Knut K. Bundgaard Clemmensen, Ditte M. Brix, Bo Rafn, José Moreira, Lisa Frankel, Anders Lund, Riku Louhimo, Sampsa Hautaniemi, Irina Gromova, Marja Jäättelä. Regulation of the oncogenic, invasion-promoting transcription factor myeloid zinc finger-1 (MZF1) in breast cancer by microRNAs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1999.
Abstract 1883: Treatment with histone deacetylase (HDAC) and BRAF inhibitors upregulates the expression of the plasma membrane Ca2+ pump, PMCA4b and alters intracellular Ca2+ handling in BRAF mutant melanoma cells
Authors: Luca Hegedus, Tamas Garay, Eszter Molnar, Karolina Varga, Rita Padanyi, Katalin Paszty, Balazs Hegedus, Mathias Wolf, Michael Grusch, Eniko Kallay, Agnes Enyedi
Journal: Cancer Research (2016)

Abstract The aim of our study was to test the effects of histone deacetylase (HDAC) and BRAF inhibitors on the expression and activity of the plasma membrane Ca2+ pump isoform 4b (PMCA4b) in BRAF mutant melanoma cell lines. Remodeling of Ca2+ homeostasis during malignancy is caused by the rearrangement of the Ca2+ signaling machinery, including Ca2+ pumps, Na+/Ca2+ exchangers and channels. Plasma membrane calcium ATPases (ATP2B - or PMCA) maintain the resting low intracellular calcium concentration by pumping out excess calcium from the cytosol. Changes in PMCA expression during malignant transformation have been described previously in colorectal and breast cancer cells, and most recently by our group in melanomas. We found that in BRAF mutant melanoma cells the PMCA 4b protein level was markedly elevated by BRAF inhibitor treatment. Overexpression of PMCA4b suppressed motility and metastatic potential. Previously, it was shown that HDAC inhibitors-induced differentiation up-regulated PMCA4b expression in gastric, colon and breast cancer cells. In the present study we treated BRAF mutant and BRAF wild type melanoma cells with HDAC inhibitors (SAHA (suberanilohydroxamic acid) or valproic acid) and tested the changes in abundance, localization and function of PMCA4b. Expression levels of the PMCA proteins were analyzed by qRT-PCR and Western Blotting. Subcellular localization of the PMCAs and the effects of treatments on cytosolic Ca2+ signaling were analyzed by confocal microscopy. We found that treatment with the HDAC inhibitors increased the level of PMCA4b expression at both mRNA and protein levels in both BRAF wild type and BRAF mutant cell types. The increased PMCA4b level was coupled with enhanced plasma membrane localization and with a faster Ca2+ clearance after stimulation. Our results show that in melanoma cells the expression of PMCA4b is under epigenetic control and HDAC inhibitors efficiently enhanced PMCA4b expression independent of the BRAF status of cells. Citation Format: Luca Hegedus, Tamas Garay, Eszter Molnar, Karolina Varga, Rita Padanyi, Katalin Paszty, Balazs Hegedus, Mathias Wolf, Michael Grusch, Eniko Kallay, Agnes Enyedi. Treatment with histone deacetylase (HDAC) and BRAF inhibitors upregulates the expression of the plasma membrane Ca2+ pump, PMCA4b and alters intracellular Ca2+ handling in BRAF mutant melanoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1883.
Abstract CT121: Demographics of clinical trial participants for new molecular entity (NME) oncology drugs and biologics approved by FDA CDER in 2015
Authors: Hilary Wright, Merina Elahi, Ayomide Igun, Greg Soon, Alice Chen, Anne Pariser, Emmanuel Fadiran
Journal: Cancer Research (2016)

Abstract Background: In 2015, approximately 810,100 new cancer cases were diagnosed in females in the US. To facilitate the assessment of efficacy and safety of medical products in the diverse populations who might use them after approval, the Food and Drug Administration (FDA) has implemented guidance and regulations to encourage greater participation of women and minorities in clinical trials (CTs). Objectives: To assess demographics in oncology CTs submitted in support of “new drugs” (i.e., New Molecular Entity New Drug Applications (NME NDAs) and original Biologics License Applications (BLAs)) approved by the FDA's Center for Drug Evaluation and Research (CDER) in 2015. Methods: Participation by sex, race, and age (&amp;lt;65 years, ?65 years) and presence of sex-based efficacy and safety analyses were assessed from sponsors’ final clinical study reports for new oncology drugs for adult indications approved in 2015. Sex-based analyses were coded as exploratory or conclusive as previously reported., Results: Fourteen new oncology drugs were approved by CDER in 2015. One BLA and one NDA were excluded from the analysis because they were for pediatric or sex-specific indications. For the 12 remaining drugs, there were 188 trials (phase 1, 2, or 3) that included a total of 17,702 subjects, 48.1% of whom were women. Of the subjects for which race was reported (94.2% of the total), 78.0% were Caucasian, and of those for which age group was reported (75.3% of all subjects), 33.4% were ?65 years of age. Women were 43.1%, 53.2%, and 53.9% of subjects in phase 1, 2, and 3 CTs, respectively. PPR, defined as the Ratio of the Proportion of women in the indicated disease population in the CTs to the Proportion of women in the disease population, was ?0.8 for 11 new drugs and &amp;lt;0.8 for one new drug. Eleven new drugs included both efficacy and safety sex-based analyses, and one new drug included only efficacy sex-based analysis. Conclusions: Relative to their proportion in the disease population, female participation was comparable to (i.e., PPR between 0.8 and 1.2) or greater than men's in late-phase trials for 11 of the 12 oncology drugs examined. Female participation in early-phase CTs was lower than in late-phase CTs; however, late-phase clinical trials are typically where FDA's risk-benefit assessments are made. Citation Format: Hilary Wright, Merina Elahi, Ayomide Igun, Greg Soon, Alice Chen, Anne Pariser, Emmanuel Fadiran. Demographics of clinical trial participants for new molecular entity (NME) oncology drugs and biologics approved by FDA CDER in 2015. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT121.
Abstract 1541: Heterogeneous response to platinum in metastatic ovarian cancer detectable by biodynamic imaging
Authors: Daniel Merrill, Hao Sun, Daniela Matei, Bakhtiyor Yakubov, John Turek, David Nolte
Journal: Cancer Research (2016)

Abstract The mechanisms by which tumors develop multi-drug resistance are not well understood. Biodynamic imaging (BDI) is a label-free assay that detects phenotypic response of ex vivo tissue to chemotherapeutic drugs. In the current study, we used BDI to measure the response of primary and metastatic ovarian tumors to cisplatin. Xenografts from two human ovarian cancer cell lines, A2780 and SKOV3, were grown orthotopically in the ovaries of nude mice and allowed to metastasize in the peritoneal space. Primary and metastatic tumors were harvested and tested for response to 25 μM cisplatin by using BDI. Sensitivity was assessed through selected response biomarkers. Metastatic tumors of the platinum-sensitive A2780 cell line showed 20% decrease in sensitivity to cisplatin compared with the response of the primary tumors, while the less sensitive SKOV3 tumors exhibited a 6% decrease in response of metastatic vs. primary tumors. In parallel, RNA sequencing profiled primary ovarian and metastatic implants. Differential gene expression was detected in primary tumors vs. metastatic sites. Genes upregulated in metastases include TIMP3, WNT2, OSR1, elastin (SKOV3 tumor model) and MMP1, MMP3, MMP10, MET, EGFR, PDGF-C (A2780 tumor model). The study demonstrates the ability of BDI to detect differences in drug sensitivity between primary and metastatic tumors and provides support for the association of metastasis and chemoresistance in ovarian cancer. Supported by NIH R01 EB016582. Citation Format: Daniel Merrill, Hao Sun, Daniela Matei, Bakhtiyor Yakubov, John Turek, David Nolte. Heterogeneous response to platinum in metastatic ovarian cancer detectable by biodynamic imaging. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1541.
Abstract 3085: The BET family bromodomain inhibitor ABBV-075 targets multiple pathogenesis factors in multiple myeloma and exhibits robust in vivo efficacies as a single agent and in combination with bortezomib
Authors: Tamar Uziel, Xiaoyu Lin, Emily Faivre, Aparna Sarthy, Daniel H. Albert, Leiming Li, Denise Wilcox, Xiaoli Huang, Terry Magoc, Lloyd Lam, Steven W. Elmore, Keith McDaniel, Warren Kati, Yu Shen
Journal: Cancer Research (2016)

Abstract Small molecule inhibitors of the bromodomain and extraterminal domain (BET) proteins represent a potential new class of cancer therapeutic agents. ABBV-075 is a potent and selective BET family bromodomain inhibitor that was recently advanced to Phase 1 studies. Here we report the in vitro and in vivo characterization of ABBV-075 in preclinical models of multiple myeloma. ABBV-075 exhibited significant anti-proliferative activities and triggered robust apoptosis across many multiple myeloma cell lines, including cell lines that were engineered to become resistant to bortezomib. As reported for other BET inhibitors, ABBV-075 potently inhibited super-enhancer regulated potential cancer drivers such as Myc, IRF8 etc. In addition to directly impacting multiple myeloma cell growth and survival, ABBV-075 also diminished stroma cell derived IL-6 secretion and prevented HUVEC cell proliferation in vitro. Given the importance of angiogenesis and the survival factor IL-6 for multiple myeloma pathogenesis, ABBV-075 could potentially produce significant therapeutic benefits in myeloma by simultaneously targeting multiple critical pathogenesis mechanisms for this disease. ABBV-075 caused significant tumor growth delay in the OPM2 flank tumor model as a monotherapy. Combining ABBV-075 with Bortezomib provided further therapeutic benefit compared with the treatment of either of the two agents individually. Taken together, our results suggest that ABBV-075 could be a promising option to explore for the treatment of multiple myeloma. Citation Format: Tamar Uziel, Xiaoyu Lin, Emily Faivre, Aparna Sarthy, Daniel H. Albert, Leiming Li, Denise Wilcox, Xiaoli Huang, Terry Magoc, Lloyd Lam, Steven W. Elmore, Keith McDaniel, Warren Kati, Yu Shen. The BET family bromodomain inhibitor ABBV-075 targets multiple pathogenesis factors in multiple myeloma and exhibits robust in vivo efficacies as a single agent and in combination with bortezomib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3085.
Biomarker-driven access to crizotinib in ALK-, MET-, or ROS1-positive malignancies in adults and children: Feasibility of the French National Acsé Program.
Authors: Gilles Vassal, Natalie Hoog Labouret, Marie-Cécile Le Deley, Marta Jimenez, Frederique Nowak, Denis Moro-Sibilot, Yann Godbert, Luc Taillandier, Jean-Yves Blay, Herve R. Bonnefoi, David Malka, Roch Houot, Thomas Aparicio, Bernard J. Escudier, Christophe Tournigand, Isabelle Ray Coquard, Pierre Laurent-Puig, Frederique Madeleine Penault-Llorca, Fabien M. Calvo, Agnes Buzyn
Journal: Journal of Clinical Oncology (2014)

TPS2647 Background: Crizotinib (czb) is registered only for the treatment of patients (pts) with ALK+ lung cancer. Czb targets (ALK, MET, ROS1) are also altered (translocation, amplification, mutation) in a wide range of malignancies in adults and children. To avoid off label use and allow for a nationwide safe and controlled access to czb for pts with an ALK, MET or ROS1 positive tumor, the French National Cancer Institute (INCa) launched the AcSé program: access to tumor molecular diagnosis in the 28 INCa molecular genetic centers along with an exploratory phase II trial. Methods: Biomarker identification is proposed to pts ≥ 1 year with an advanced disease among more than 15 malignancies (such as colon, gastric, liver, thyroid, renal and breast cancers, cholangiocarcinoma, lymphoma, neuroblastoma, sarcomas, and ROS1 or MET lung cancer) (such as colon, gastric, liver, thyroid, renal and breast cancers, cholangiocarcinoma, lymphoma, neuroblastoma, sarcomas, and ROS1 lung cancer) known from literature to harbor a genomic alteration in a czb target. If not eligible for any other academic or industry trial targeting the same alteration, a patient with an ALK, MET or ROS1 positive tumor may enter one of the 22 specified cohorts defined as a disease and a type of target alteration, and receives czb (adult: 250 mg x 2; child: 280 mg/m2 x 2). Pts with an altered czb target as evidenced through a pangenomic tumor profiling program are also eligible. Tumor response is evaluated every 2 months using RECIST criteria. Three statistical 2-stage designs are considered for cohorts to anticipate 3 situations in terms of expected response rate and incidence. Accrual stops if 0 response / N1 pts; else N2 additional pts are recruited. 10,000 to 15,000 molecular tests and 490 pts treated in 150 centers are planned over 3 years. From Aug. 2013 to Jan. 2014, 22 pts have been accrued. The AcSé program is currently being expanded to other targeted drugs. Clinical trial information: NCT02034981. P0 P1 α β N1 N2 Common case 10% 30% 10% 10% 11 14 Very rare disease, eg neuroblastoma 10% 30% 15% 15% 8 12 Optimistic case, eg ROS1+ lung cancer 20% 40% 10% 10% 7 30
Combination efficacy of mTOR and MEK inhibitor in malignant pleural mesothelioma (MPM).
Authors: Seiji Matsumoto, Hayato Orui, Ayumi Kuroda, Masaki Hashimoto, Kazue Yoneda, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa
Journal: Journal of Clinical Oncology (2013)

e18557 Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor and poor prognosis. Active new agents is an urgent priority for patients with MPM. PI3K/AKT/mTOR pathway inhibitors in MPM have reported, but, the results has limited. Because PI3K/AKT/mTOR pathway inhibitors will make signaling feedback loops and cross-talk between signaling pathways. Combining PI3K/AKT/mTOR pathway inhibitors with other inhibitors might improve efficacy. Activation of RTKs stimulates both the PI3K/AKT/mTOR and RAS/RAF/MEK signaling pathways, and some study shows that inhibition of both pathways may be more effective than targeting either alone. We speculated that simultaneous inhibition both of mTOR and MEK by everolimus and selumetinib might improve the treatment of MPM. Methods: At first, we examined the growth inhibitory effects of everolimus or selumetinib alone on MPM cell lines. Next we examined combination efficacyofeverolimus with selumetinib on MPM cell lines, H226 was examined by computer-assisted analysis using the CalcuSyn software. We next confirmed the in vivo efficacy of everolimus or selumetinib alone, and the combination of both compounds in H226 MPM xenograft model. Results: Everolimus inhibited the growth of MPM cell lines with IC 50 values 1.19-21.5 μM. Selumetinib also inhibited the growth of MPM cell lines with IC 50 values 4.68-88.2μM. Next we examined combination efficacyofeverolimus with selumetinib on MPM cell lines, H226 was examined by computer-assisted analysis using the CalcuSyn software. With H226, the combination index (CI) at fraction (Fa) 0.5 and 0.8 were (0.56 ± 0.30) and (0.76 ± 0.48), respectively, indicating everolimus and selumetinib act synergistic, respectively. Everolimus or selumetinib alone showed significant antitumor activity, and the combination of everolimus and selumetinib enhanced the individual antitumor activity in H226 MPM xenograft model. (p&lt;0.05). Conclusions: These findings indicate that the combination of everolimus and selumetinib is effective in MPM growth inhibition not only in vitro but in vivo and chemotherapy regimens involving the combination of everolimus and selumetinib may be new molecular target therapy for MPM patients
Admitting the Patient With Acute Stroke to the Right House—Lessons From the Sorting Hat of Hogwarts
Authors: Lee H. Schwamm
Journal: JAMA Internal Medicine (2016)

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Abstract LB-208: First-in-class steroidal leukemia inhibitory factor (LIF) inhibitor in targeted cancer therapy
Authors: Hareesh B. Nair, Bindu Santhamma, Surya Viswanadhapa, Klaus J. Nickisch
Journal: Cancer Research (2016)

Abstract The leukemia inhibitory factor (LIF), an IL-6 family member, is a pleotropic cytokine has been demonstrated as an oncogene and involved in multiple cellular mechanisms during the initiation and progression of various human malignancies. Overexpression of LIF was significantly correlated with advanced tumor stage, larger tumor size and worse relapse free survival rate. In the present study EC330, a novel steroidal LIF inhibitor showed cytotoxicity in various cancer cell lines and NCI-60 cell line panel at low nano-molar range. EC330 blocked formation of colonies in soft agar and inhibited angiogenesis (tube formation) in human umbilical vein endothelial cells. EC330 binds to LIF/LIFR complex by insilico docking studies and reduced the STAT3 phosphorylation in a dose dependent manner through blocking LIF-JAK-STAT signaling. EC330 showed marked specificity in MCF-7 cells overexpressing LIF verses MCF-7 cells. The compound further showed cytoskeletal disruption and targeting cancer associated fibroblasts (CAFs). EC330 treatment (0.5 and 2.5mg/kg) dose dependently reduced tumor burden in ovarian (IGROV-1) and triple negative breast cancer (MDA-MB-231) cell xenografted mouse models. These findings establish EC330 as a novel LIF inhibitor having targeted therapeutic perspectives for patients with aggressive primary tumors. LIF targeting may result in the blockade of cancer fibroblast associated pro invasive tumor microenvironment in regular as well as therapy resistant tumors. Citation Format: Hareesh B. Nair, Bindu Santhamma, Surya Viswanadhapa, Klaus J. Nickisch. First-in-class steroidal leukemia inhibitory factor (LIF) inhibitor in targeted cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-208.
Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model
Authors: Guangfu Li, Dai Liu, Timothy K. Cooper, Eric T. Kimchi, Xiaoqiang Qi, Diego M. Avella, Ningfei Li, Qing X. Yang, Mark Kester, C. Bart Rountree, Jussuf T. Kaifi, David J. Cole, Don C. Rockey, Todd D. Schell, Kevin F. Staveley-O’Carroll
Journal: Journal of Hepatology (2016)