tbuckley/cabot-search huggingface dataset:
Activity of sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): A phase II trial of the University of Chicago Phase II Consortium
Authors: L. Wiebe, K. E. Kasza, R. G. Maki, D. R. D’Adamo, W. A. Chow, J. L. Wade III, E. Agamah, W. M. Stadler, E. E. Vokes, H. L. Kindler
Journal: Journal of Clinical Oncology (2008)

10502 Background: Therapeutic options are limited in GIST pts who have progressed on IM and SU. Sorafenib inhibits KIT, VEGFR and PDGFR-β kinases. In vitro, SOR inhibits KIT kinase activity and cell growth of multiple IM-RES Ba/F3 KIT mutants (Guo, CCR 2007). In a randomized phase II discontinuation trial of SOR, 2 pts with IM-RES GIST developed partial responses (PR) lasting 11 months (mo). Methods: We are conducting a multicenter phase II trial of SOR in PS 0–2 pts with unresectable, c-kit-expressing GIST that progressed on IM per RECIST criteria. In 2/07, after FDA approval of SU for IM-RES GIST, the study was amended to require progression after both IM and SU. Primary endpoint: response. Simon minimax 2-stage design requires 1 response in 18 pts for 2nd stage, and 4 responses in 32 IM/SU RES pts. Pts receive SOR 400 mg orally twice daily. CT scans: Q2 28-day cycles. Results: 26 pts (6 IM-RES, 20 IM/SU-RES) enrolled 1/06–12/07 at 5 sites. Pt characteristics: male 54%; median age 57 (range 42–85); PS 0/1/2: 38%/54%/8%. Cycles: 119 (median 4, range 1–14). 25 pts are evaluable for toxicity (1 too early) and 24 for response (2 too early) in this ongoing trial. 3 pts (13%) (1 IM-RES, 2 IM/SU-RES) have PR (1 unconfirmed); 14 pts (58%) (3 IM-RES, 11 IM/SU-RES) have stable disease (SD). Disease control rate (PR + SD): 71%. Median progression-free survival: 5.3 mo (95% CI: 3.2, ∞). Median survival 13.0 mo (95% CI: 5.1, ∞), estimated 1-year survival 62%. Grade 3 toxicities (% pts): hand-foot syndrome 28%, hypertension 24%, rash 20%, diarrhea 12%, GI bleed 8%, fatigue 8%, perforation 4%, anemia 4%. Grade 4 toxicity: thrombosis 4%. Conclusions: These preliminary data suggest that SOR is active and well-tolerated in pts with IM-and SU-resistant GIST. Supported by NCI grant N01-CM-62201. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, Onyx Bayer Bayer
Hypermethylation of Bcl6 Is a Potential Cause of Development of Lymphoma with Tfh Features in Tet2 Knockdown Mice
Authors: Hideharu Muto, Mamiko Sakata-Yanagimoto, Yasuyuki Miyake, Genta Nagae, Terukazu Enami, Yuhei Kamada, Kazumi Suzukawa, Naoya Nakamura, Hiroyuki Aburatani, Seishi Ogawa, Shigeru Chiba
Journal: Blood (2013)
Abstract 5094: Acid-induced collagen remodeling promotes cancer progress as a result of niche engineering competition between cancer and stroma cells
Authors: Mehdi Damaghi, Tinjan Chen, Josef Johnson, Robert J. Gillies
Journal: Cancer Research (2016)

Abstract Early carcinogenesis is an avascular and hypoxic disease that makes tumor cells export metabolically derived acid through glycolysis. Even in presence of oxygen cancer cells keep the glycolytic phenotype (Warburg effect) that acidifies the environment more and constantly. Hence the physical microenvironment of solid tumors is profoundly acidic. Pre-malignant cells within this niche must adapt to acidosis in order to survive this hostile microenvironment. We think pre-malignant cells adapt to acidosis to not only survive in this hostile microenvironment but also to acquire an advantage that helps them to outcompete the others and eventually help them to invade. Recently many evidences have been provided showing the collaboration of tumor associated stroma cells such as Fibroblasts (TAF) with tumor cells in cancer progress. Here we also show how these cells use acidification and acid adaptation as a strategy to construct and engineer their niche in their own favor for growth and proliferation. In this study we focused on collagen as major proteins of extra cellular matrix (ECM) and even arguably the most dominant one. The unique mechanical properties of fibrillar collagen are mainly controlled by its structure and any change in it can lead to ECM induced tumor growth. ECM unique compositions and topographies are generated through a dynamic biochemical and biophysical interplay between the various cells and the evolving microenvironment. In this study we developed the window chamber and intra vital microscopy to study the collagen remodeling lively. Later we used 3D cell culture and co-culture to validate our findings. Finally we used proteomics to understand molecular mechanism behind the changes in acid adapted versus non-adapted cancer cells and TAfs. We found cancer cells take different strategy than TAFs, although both changes promote cancer progression. In conclusion, there are evolutionary advantages behind acid production and adapting to it for cancer and cancer associated cells. We discuss how acquiring these advantages can helps us to design new therapeutics against these unique phenotypes. Citation Format: Mehdi Damaghi, Tinjan Chen, Josef Johnson, Robert J. Gillies. Acid-induced collagen remodeling promotes cancer progress as a result of niche engineering competition between cancer and stroma 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 5094.
Abstract 945: Tissue tranglutaminase-2 promotes gastric cancer progression via ERK1/2 pathway
Authors: Liping Su, Xiaofeng Wang, Quan Zhou, Xiongyan Wu, Bingya Liu
Journal: Cancer Research (2016)

Abstract Gastric cancer is one of the most common tumors worldwide with extensive local tumor invasion, metastasis and poor prognosis. Thus, understanding the mechanisms regulating progression of gastric cancer is the key for developing effective therapeutic strategies. Tissue tranglutaminase-2 (TG2), a multifunctional member of the transglutaminase (TGase) family, has already been proved to play an important role in tumor initiation and progression. However, the specific role and underlying molecular mechanisms of TG2 in the progression of gastric cancer (GC) remain unknown. Here we showed that TG2 was highly expressed in GC tissues and positively associated with depth of tumor invasion and late TNM stage. With gain and lose-of function approaches, we found that TG2 promotes GC cell proliferation, migration and invasion, as well as tumorigenesis and peritoneal metastasis in vivo. These events were associated with activating of ERK1/2 pathway, and ERK1/2 inhibitor U0126 inhibited cell proliferation, migration and invasion induced by overexpression of TG2. Taken together, these findings suggest that TG2 contributes to tumorigenesis and progression of GC by activating the ERK1/2 signaling pathway and is a potential therapeutic target of metastatic gastric cancer. Citation Format: Liping Su, Xiaofeng Wang, Quan Zhou, Xiongyan Wu, Bingya Liu. Tissue tranglutaminase-2 promotes gastric cancer progression via ERK1/2 pathway. [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 945.
Abstract 2176: Targeting eEF-2Kinase by thymoquinone in triple negative breast cancer
Authors: Nashwa N. Kabil, Recep Bayraktar, Nermin Kahraman, Bulent Ozpolat
Journal: Cancer Research (2016)

Abstract Triple-negative breast cancers (TNBCs) constitute a heterogeneous subtype of breast cancers that present a significant challenge for the treatment and management, and have a poor clinical outcome. Eukaryotic elongation factor-2 kinase (eEF-2K) is an atypical calcium/calmodulin (Ca2++/CaM)-dependent Ser/Thr-kinase that regulates peptide chain elongation by phosphorylating its substrate elongation factor 2 (eEF2), resulting in decreased protein translation. Recently, we have reported that eEF-2K expression is significantly upregulated in TNBC cell lines and is associated with poor survival and worse prognosis, indicating that eEF-2K is a potential therapeutic target in TNBC. Moreover, we demonstrated that eEF-2K promotes TNBC cell proliferation, invasion/migration, and tumorigenesis. Its inhibition by systemically administered liposomal siRNA resulted in marked inhibition of tumor growth and enhancement in the efficacy of chemotherapy in orthotopic TNBC mouse models (Tekedereli 2012). Currently, there are no reported inhibitors of eEF-2K. Natural dietary poly phenolic compounds have been shown to inhibit various cancers by regulating various kinases and molecular targets, with both in-vitro and in-vivo activity. Thymoquinone (TQ) is an active ingredient isolated from Nigella sativa and has been investigated for its antioxidant, anti-inflammatory, and anticancer activities in several in-vitro and in-vivo models. However, the mechanism by which TQ mediates its effects not well understood. Here, we investigated if TQ inhibits eEF-2K in TNBC cells. We demonstrated, for the first time, that treatment with TQ decreases the expression of eEF-2K in a dose dependent manner as wells as its downstream targets, resulting in decreased proliferation, colony formation, migration, and invasion of TNBC cells. Furthermore, eEF-2K knockdown by siRNA recapitulates the effects of TQ, including cell proliferation, migration/invasion, and correlated events. Additionally, TQ treatment inhibits Src activity and other molecular targets, and induces significant apoptosis in TNBC cells in a caspase independent manner. Currently, we are investigating the downstream effects of TQ by RPPA analysis and its in-vivo efficacy in orthotopic xenograft mouse models of TNBC. Overall, our studies suggest that TQ could present a novel therapeutic strategy in targeting eEF-2K and inhibition of TNBCs. Citation Format: Nashwa N. Kabil, Recep Bayraktar, Nermin Kahraman, Bulent Ozpolat. Targeting eEF-2Kinase by thymoquinone in triple negative breast cancer. [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 2176.
Case 1-1971
Authors: Richard C. Cabot, Benjamin Castleman, Betty U. McNeely, Bernard M. Jacobson, Benjamin Castleman
Journal: New England Journal of Medicine (1971)

Presentation of CaseA 70-year-old woman entered the hospital because of a cough and fever.She had been well until three years previously, when acute pericarditis developed. A pericardiocentesis was performed; smears and cultures of the fluid showed no mycobacteria or other micro-organisms, and L.E.-cell tests on the pericardial fluid and the blood were negative. A needle biopsy of the pericardium revealed no evidence of tumor. A tuberculin skin test (intermediate-strength PPD) was negative. A complete blood count was normal. An x-ray film of the chest demonstrated cardiac enlargement and slight fullness of the anterior mediastinum. Review of films taken . . .
Abstract 2009: Role of FOXO1 in oncogenic program of B cell precursor acute lymphoblastic leukemia (BCP-ALL)
Authors: Fan Wang, Alexey Ushmorov, Thomas Wirth
Journal: Cancer Research (2016)

Abstract Although treatment of B cell precursor acute lymphoblastic leukemia (BCP-ALL) in children has shown eminent progress over the past decades, about 15% of patients can still not be cured, however. Therefore, new therapeutic strategies are warranted. FOXO1 together with other transcription factors including EBF1, PAX5 and TCF3 plays a central role in differentiation of pre-B-cells. In cooperation with PAX5 and other B-cell transcription factors, FOXO1 induces expression of SYK, BLNK, RAG1, RAG2, AICDA and IL7RA genes. Of note, SYK and IL7RA signaling contribute to the oncogenic program of BCP-ALL, which utilize pre-B cell survival and proliferation program. In this study, we demonstrate that FOXO1 is highly expressed in most of the BCP-ALL cell lines. By using immunofluorescence assays we show that FOXO1 is localized in the nucleus of BCP-ALL cells. Overexpression of constitutively active AKT1 (inactivating FOXO1) negatively regulates the growth of BCP-ALL cells. Inhibition of FOXO1 by shRNA results in cell death in the RS4;11 BCP-ALL cell line. BCP-ALL cells are more sensitive to growth arrest and apoptosis induced by a small molecular FOXO1 inhibitor AS1842856 than other classical Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. Gene expression profiling of BCP-ALL cells after treatment with the FOXO1 inhibitor for 24h shows the significantly down-regulation of FOXO target genes including VPREB3, IL1B, KLHL24 and BNIP3L. Interestingly, at the same time, some FOXO targets like NOXA, RUNX2 and PRDM1 were found upregulated, indicating a complex effect of the FOXO1 inhibitor. We conclude that FOXO1 expression is critical for the BCP-ALL oncogenic program and its targeting represents a novel therapeutic approach. Citation Format: Fan Wang, Alexey Ushmorov, Thomas Wirth. Role of FOXO1 in oncogenic program of B cell precursor acute lymphoblastic leukemia (BCP-ALL). [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 2009.
Abstract 1869: Dislodgement of K-Ras from plasma membranes, induction of apoptosis and tumor regression by PCAIs, a novel class of polyisoprenylated small molecules
Authors: FELIX AMISSAH, ELIZABETH NTANTIE, ROSEMARY A. POKU, AUGUSTINE T. NKEMBO, OLUFISAYO O. SALAKO, HERNAN FLORES-ROZAS, NAZARIUS S. LAMANGO
Journal: Cancer Research (2016)

Abstract Although mutation-induced dysregulation of Ras signaling constitutes the biochemical change that drives some of the most difficult-to-manage cancers, directly targeting the constitutively active mutant Ras GTPases has not resulted in clinically useful drugs. Therefore, modulating Ras activity for targeted treatment of cancer remains an urgent healthcare need. In the current study, we investigated a novel class of compounds, the polyisoprenylated cysteinyl amide inhibitors (PCAIs), for their anticancer molecular mechanisms using the NSCLC cell panel with K-Ras and/or other mutant genes. Treatment of the lung cancer cells with PCAIs, NSL-RD-035, NSL-BA-036, NSL-BA-040, NSL-BA-055 and NSL-BA-040 resulted in concentration-dependent cell death in both K-Ras mutant (A549 and NCI-H1573), N-Ras mutant (NCI-H1299) and other (NCI-H661, NCI-H460, NCI-H1975, NCI-H1563) NSCLC cells. The PCAIs at sub- to low micromolar 1.0 -10 μM concentrations induced the degeneration of 3D spheroid cultures, inhibited, clonogenic cell growth, and induced marked apoptosis and cell cycle arrest, together with a significant increase in active caspase 3 (p&amp;lt;0.001). NSL-BA-040 at 5 μM prominently dislodged YFP-tagged K-Ras, but not H-Ras and N-Ras from the plasma membranes of transfected A549 and NCI-H661 cells. NSL-RD-035 attenuated the tumor growth of A549 cells in xenografted athymic mice in vivo. Taken together, PCAIs likely suppress NSCLC cell growth by disrupting growth signaling through the dislodgement of K-Ras the plasma membrane. Citation Format: FELIX AMISSAH, ELIZABETH NTANTIE, ROSEMARY A. POKU, AUGUSTINE T. NKEMBO, OLUFISAYO O. SALAKO, HERNAN FLORES-ROZAS, NAZARIUS S. LAMANGO. Dislodgement of K-Ras from plasma membranes, induction of apoptosis and tumor regression by PCAIs, a novel class of polyisoprenylated small molecules. [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 1869.
Abstract 2150: Alternative treatment strategies to overcome MAPK inhibitor resistance in melanoma
Authors: Eva Goetz, Bokang Rabasha, Levi Garraway
Journal: Cancer Research (2016)

Abstract Inhibitors of the BRAF/MEK/ERK pathway have promise in the treatment of BRAF mutant melanoma and other MAPK activated cancers. Treatment of metastatic melanoma patients with the combination of RAF + MEK inhibitor has extended progression free survival over single agent therapy. However, in a large subset of patients, resistance invariably develops. Most clinical models show reactivation of the MAPK pathway in resistant samples, suggesting further downregulation of MAPK signaling might be beneficial. Therefore, we took BRAF mutant melanoma grown to resistance by continuous culture in dabrafenib plus trametinib (RAF + MEK inhibitor) or SCH772984 (ERK inhibitor), and treated them with a triple combination of RAF+MEK+ERK inhibitors. We found cells resistant to RAF+MEK inhibitors were cross-resistant to ERK inhibitor, but sensitive to RAF+MEK+ERK inhibitors. Conversely, cells resistant to the ERK inhibitor were cross-resistant to RAF+MEK inhibitor, but sensitive to the triple combination. However, given the possible deleterious side effects of a triple combination in patients, we explored whether alternative dosing and timing strategies could delay development of resistance. We compared chronic dosing of RAF+MEK or ERK inhibitors to weekly exposures alternating between RAF+MEK and ERK inhibitors. This alternative dosing strategy delayed development of resistance in vitro over chronic dosing, while also resulting in a slower proliferation rate in resistant cells. In addition, cells exposed to a higher dose of inhibitor for a shorter period of time was equivalent to chronic exposure. These studies suggest that alternative dosing strategies (other than chronic exposure) may prevent development of resistance, and allow for treatment of patients with higher order combinations and less side effects. Citation Format: Eva Goetz, Bokang Rabasha, Levi Garraway. Alternative treatment strategies to overcome MAPK inhibitor resistance in melanoma. [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 2150.
Phase 2 study of tarloxotinib bromide (TRLX) in patients (pts) with EGFR-Mutant, T790M-Negative NSCLC progressing on an EGFR TKI.
Authors: Stephen V. Liu, Charu Aggarwal, Christina Brzezniak, Robert Charles Doebele, David E. Gerber, Barbara Gitlitz, Leora Horn, Benjamin J. Solomon, Tom Stinchcombe, Liza Cosca Villaruz, Howard Jack West, Stew Kroll, Tillman E. Pearce, D. Ross Camidge
Journal: Journal of Clinical Oncology (2016)

TPS9100 Background: Additional treatment options are needed for pts with EGFR-mutant (MT) NSCLC who develop non-T790M-mediated resistance to EGFR TKIs. Sensitizing EGFR mutations are often heterozygous with co-expression of both wild type (WT) and MT EGFR, a genotype associated with poorer response to EGFR TKIs. Hypoxia-induced activation of WT EGFR signaling may be a mechanism of EGFR-TKI resistance in NSCLC. TRLX is a hypoxia-activated prodrug that releases an irreversible pan-ErbB TKI targeting WT EGFR, MT EGFR and HER2. Hypoxic tumor targeting using TRLX may allow a greater therapeutic index with greater intratumoral TKI exposure and less dose-limiting systemic toxicity compared to currently available EGFR TKIs. In xenograft models of NSCLC that co-express MT and WT EGFR, TRLX monotherapy reverses resistance to EGFR TKIs. A Phase 1 study in pts with advanced solid tumors established the maximum tolerated dose of 150 mg/m2 TRLX as a 1-hour weekly intravenous (IV) infusion. The most common treatment-related adverse events were dose-dependent and included rash, QT prolongation, nausea, infusion reaction, vomiting, diarrhea and fatigue. Methods: A multicenter Phase 2 trial is evaluating the safety and efficacy of single-agent TRLX in pts with EGFR-MT, T790M-negative NSCLC after progression on an EGFR TKI (NCT02454842). Eligible patients will have documentation of a sensitizing EGFR mutation and progression on EGFR TKI therapy with no evidence of T790M on a post-progression biopsy. Eligible patients must also have adequate pre-therapy tumor tissue available to enable tumor biomarker assessment, including assessment of EGFR signaling status using an EGFR-GRB2 proximity-ligation assay. TRLX (150 mg/m2) is administered by IV infusion over 60 minutes on Days 1, 8, 15 and 22 of a 28-day cycle. The primary endpoint is RECIST 1.1 response rate. Secondary endpoints include PFS, duration of response, OS, PK and safety, as well as evaluation of hypoxia PET imaging with [18F]HX-4, serum, and tissue biomarkers. The study design incorporates a Simon two-stage design (alpha = 0.10; beta = 0.10); up to 37 patients will be enrolled. Recruitment is ongoing. Clinical trial information: NCT02454842.
PTU-063 Effect of intra-operative methylprednisolone on post liver transplant intensive care unit course: further evidence for the existence of hepato-adrenal syndrome?: Abstract PTU-063
Authors: R Broomhead, D W M Patch, D Thorburn, A K Burroughs, J P O'Beirne
Journal: Gut (2010)

<h3>Introduction</h3> Adrenal insufficiency is associated with increased fluid and vasopressor requirements in liver failure and treatment with hydrocortisone improves survival in cirrhotic patients with septic shock.1 Previous data from our unit suggest a high incidence of adrenal insufficiency in patients undergoing liver transplant (LT).2 Adrenal insufficiency appears to be more common in liver transplant programs that use steroid free immunosuppressive regimens but the effect of intraoperative corticosteroids on the outcome of liver transplantation has never been assessed.3 <h3>Methods</h3> We conducted a retrospective analysis of prospectively collected data from 90 consecutive patients undergoing first elective LT, before (Group 1 n=45) and after (Group 2-n=45) the administration of 1000 mg methylprednisalone in the anhepatic phase became standard practise. No other changes to LT treatment protocols were made during the study period. Baseline demographic data and post operative requirements for fluids (12 h and total ITU crystalloid and colloid requirement), vasopressors, renal replacement therapy, ventilation and total stay on the intensive care unit (ITU) were compared between groups. <h3>Results</h3> Indication, MELD score and age at time of LT were not significantly different between groups. There were significantly reduced requirements for fluid, vasopressors, renal replacement therapy, invasive ventilation and ITU stay in group 2 compared with group 1. <h3>Conclusion</h3> Compared to patients undergoing LT in a steroid free regimen, the adminstration of intrapoerative methylprednisolone to patients undergoing LT results in improved post operative haemodynamics and the need for organ support. This finding supports the notion that the common finding of adrenal insufficiency in patients with cirrhosis has clinical importance and that corticosteroid replacement can improve outcome.
Women’s Health and Abortion Rights
Authors: Rebecca B. Reingold, Lawrence O. Gostin
Journal: JAMA (2016)

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