tbuckley/cabot-search huggingface dataset:
Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy
Authors: Wennan Zhao, Yuling Qiu, Dexin Kong
Journal: Acta Pharmaceutica Sinica B (2016)

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Class I PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin (mTOR) to play key roles in carcinogenesis. Therefore, PI3K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3K inhibitor for cancer therapy. Dozens of other PI3K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers, etc. This review provides an introduction to PI3K and summarizes key advances in the development of PI3K inhibitors.
Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis
Authors: Eli M Miloslavsky, Ray P Naden, Johannes W J Bijlsma, Paul A Brogan, E Sherwood Brown, Paul Brunetta, Frank Buttgereit, Hyon K Choi, Jean-Francois DiCaire, Jeffrey M Gelfand, Liam G Heaney, Liz Lightstone, Na Lu, Dedee F Murrell, Michelle Petri, James T Rosenbaum, Kenneth S Saag, Murray B Urowitz, Kevin L Winthrop, John H Stone
Journal: Annals of the Rheumatic Diseases (2016)

To develop a Glucocorticoid Toxicity Index (GTI) to assess glucocorticoid (GC)-related morbidity and GC-sparing ability of other therapies.Nineteen experts on GC use and outcome measures from 11 subspecialties participated. Ten experts were from the USA; nine from Canada, Europe or Australia. Group consensus methods and multicriteria decision analysis (MCDA) were used. A Composite GTI and Specific List comprise the overall GTI. The Composite GTI reflects toxicity likely to change during a clinical trial. The Composite GTI toxicities occur commonly, vary with GC exposure, and are weighted and scored. Relative weights for items in the Composite GTI were derived by group consensus and MCDA. The Specific List is designed to capture GC toxicity not included in the Composite GTI. The Composite GTI was evaluated by application to paper cases by the investigators and an external group of 17 subspecialists.Thirty-one toxicity items were included in the Composite GTI and 23 in the Specific List. Composite GTI evaluation showed high inter-rater agreement (investigators κ 0.88, external raters κ 0.90). To assess the degree to which the Composite GTI corresponds to expert clinical judgement, participants ranked 15 cases by clinical judgement in order of highest to lowest GC toxicity. Expert rankings were then compared with case ranking by the Composite GTI, yielding excellent agreement (investigators weighted κ 0.87, external raters weighted κ 0.77).We describe the development and initial evaluation of a comprehensive instrument for the assessment of GC toxicity.
Biweekly cabazitaxel as a safe treatment option for metastatic castration resistant prostate cancer (mCRPC) patients post-docetaxel: Final analysis of Prosty II trial.
Authors: Pirkko-Liisa Kellokumpu-Lehtinen, Timo Marttila, Antti Pekka Jekunen, Petteri Hervonen, Katariina Klintrup, Vesa V Kataja, Tapio Utriainen, Marjaana Luukkaa, Markku Leskinen, Kalevi Pulkkanen, Ilari Lehtinen, Mikko Taalikka, Anna-Liisa Kautio
Journal: Journal of Clinical Oncology (2016)

e16523 Background: In our Prosty I trial biweekly docetaxel (D) was better tolerated and yielded longer overall survival than standard triweekly D (Kellokumpu-Lehtinen et al. Lancet Oncol 2013;14:117-124). Our aim in Prosty II trial (NCT01558219) was to evaluate the safety of biweekly cabazitaxel (C) as post-docetaxel for mCRPC. Methods: Atotal of 60patients (pts) with mCRPC received C 16 mg/m² i.v. on day 1 and day 14 at 4 week cycles plus daily prednisone. The inclusion criteria; mCRPC post-D, WHO performance status (PS) < 2, age > 18 yrs and adequate bone marrow, liver and renal functions. The exclusion criteria; prior anti-cancer therapy or radioisotopes within 4-6 weeks, other malignant disease, use of inhibitors/inducers of cytochrome P450 3A4/5 or other serious illness. The primary endpoint was safety. Results: At baseline, WHO PS was 0 in 30%, 1 in 67% and 2 in 3% of the pts. The median serum PSA was 305 µg/L (range 3.7-2425) and the mean age 67 (range 50-79) yrs, 50% of pts had primarily mPC and 50% of pts had received prior abiraterone (n = 28) or enzalutamide (n = 2) in addition to D. A total of 253 cycles of C (twice biweekly dosing) were administered. No prophylactic G-CSF was used. The most common Grade 3/4 adverse events (CTCAE) were neutropenia 16.6%, pain 13.3%, fatigue 10.0%, anemia 5.0%, infection without neutropenia 10.0%, leucopenia 3.3%, neutropenic infection 1,7%, mucositis 1.7%, elevated ALP and limb edema both 1.7% of the pts. In addition one pulmonary embolism, one intracerebral hemorrhage and one bone fracture occurred (all Grade 4 AEs). Altogether in up to11 cycles Grade 1 AEs were reported in 3 (5.0%), Grade 2 AEs in 28 (46.7%), Grade 3 AEs in 23 (38.3%) and Grade 4 AEs in 6 pts (10.0%). Most of the patients (61%) discontinued the treatment due to progression. A confirmed PSA response ≥ 50% was recorded in 6 (10.2%) and best overall response as PR in 2 (3.4%) and as SD in 17 pts (28.8), clinical benefit ratio being 32.2%. The median survival was 12.8 months, and 19 pts (31.7%) were still alive at the end of the study. Conclusions: Our results show that biweekly cabazitaxel is a manageable treatment option for these heavily pretreated patients with advanced mCRPC. Clinical trial information: NCT01558219.
Abstract LB-231: An optide (optimized knottin-peptide) that inhibits tumor cell growth In vitro and accumulates in sarcoma flank tumors in vivo
Authors: Theo Sottero, Emily J. Girard, Colin Correnti, Mark R. Stroud, Brandon L. Kier, Andrew J. Mhyre, James Olson
Journal: Cancer Research (2016)

Abstract Antibody-drug conjugates (ADCs) have been FDA approved for the targeted delivery of chemotherapy to cancer. However, ADCs are limited for solid tumors and brain cancer by their poor penetration and inability to cross the blood-brain-barrier. A number of groups have shown that cystine-knot peptides (knottins) can be modified in ways that allow them to target cancer cells. Our lab demonstrated that an optide (optimized knottin-peptides) conjugate such as chlorotoxin-Cy5.5 are able to accumulate throughout tumors and cross an intact blood-brain barrier. However, chlorotoxin-Cy5.5 accumulates in mouse liver - a potential liability if used as a peptide-drug conjugate. We sought to identify a novel peptide that is capable of delivering chemotherapy selectively to tumor cells in vitro and in vivo. Our group has developed a mammalian protein expression system that is able to produce &amp;gt;20mg scale, endotoxin-free knottins and can rapidly generate variants of those peptides. We went in vivo to investigate if there was selective accumulation of our novel peptide-dye conjugates in sarcoma flank xenografts. Mice were injected intravenously with conjugate and accumulation was quantified in a number of tissues using IVIS imaging. We identified a novel peptide that accumulated in sarcoma flank tumors &amp;gt;10-fold relative to liver. We tested the ability of this peptide to deliver cytotoxic chemotherapy in vitro as a peptide-drug conjugate. We identified a novel conjugate capable of efficiently inhibiting the growth of a number of tumor cell lines in vitro. We tested the ability of various endocytosis inhibitors to prevent the uptake of this peptide and showed that inhibitors of GPI-anchored protein endocytosis prevented this accumulation. To verify tumor accumulation in preparation for efficacy studies we tracked the distribution of a radiolabeled form of the peptide in a whole body autoradiography model and observed sustained tumor uptake. Our novel peptide-conjugate is able to potently inhibit the growth of a number of tumor cell lines in vitro and the endocytosis of GPI-anchored proteins is involved in this accumulation. Additionally, this peptide accumulates in tumor tissue in vivo. Optide-drug conjugates may offer enhanced tumor penetration over antibody-drug conjugates and therefore increase the therapeutic index in delivering cytotoxic chemotherapy. Citation Format: Theo Sottero, Emily J. Girard, Colin Correnti, Mark R. Stroud, Brandon L. Kier, Andrew J. Mhyre, James Olson. An optide (optimized knottin-peptide) that inhibits tumor cell growth In vitro and accumulates in sarcoma flank tumors in vivo. [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-231.
Abstract 4101: Stromal cell-induced alterations in the response of colorectal cancer cell to demethylating agents
Authors: Viswanath Das, Svetlana Skolekova, Khushboo Agrawal, Jan Gursky, Lucia Kučerová, Marián Hajdúch
Journal: Cancer Research (2016)

Abstract Epigenetic mechanisms such as DNA hypermethylation, that results in gene silencing, is closely associated with resistance to platinum-based chemotherapy for colorectal cancer (CRC). DNA methyltransferase inhibitors (DNMTi) that reactivate and induce reexpression of silenced gene have the potential to improve the outcome of platinum-based and other therapies in CRC. In fact, non-cytotoxic concentrations of azacitidine, a clinically used DNMTi, has been reported to resensitize platinum-resistant ovarian cells to carboplatin. Hypomethylating agents, such as azacitidine and decitabine have shown significant promise in hematologic malignancies; however, studies on their application to CRC and other solid tumors have yielded ambivalent results potentially due to the complexities of the tumor microenvironment that result from the numerous cell type interactions. In this study, we analyzed the impact of different tumor-stroma ratios on cancer cell response to azacitidine, decitabine, and two lead compounds identified by in vitro screens in two-dimensional (2D) and three-dimensional (3D) co-cultures of colorectal HCT116 carcinoma demethylation reporter cells and adipose-derived mesenchymal stromal cells (MSCs) isolated from healthy individuals undergoing elective lipoaspiration. Each subject provided informed consent. Activity of hypomethylating drugs was examined in 2D and 3D cultures of different tumor-stroma ratios using confocal microscopy, flow cytometry, and MTT analyses. Our preliminary flow cytometry results show an altered response of hypomethylating agents in cocultures of HCT116 and MSCs compared to monocultures of HCT116 cells alone. There was an increase in demethylation of HCT116 cells in 3D cultures containing a higher ratio of stromal cells following treatment with low concentration of decitabine. Furthermore, confocal analysis 3D co-cultures at various z-plane heights revealed increased demethylation at low concentrations of all drugs in cultures with high stromal cell numbers. These results indicate that intratumoral stroma may alter the sensitivity of cancer cells to demethylating agents and warrant further studies. Citation Format: Viswanath Das, Svetlana Skolekova, Khushboo Agrawal, Jan Gursky, Lucia Kučerová, Marián Hajdúch. Stromal cell-induced alterations in the response of colorectal cancer cell to demethylating agents. [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 4101.
Abstract 2185: Sann-Joong-Kuey-Jian-Tang can inhibit human breast cancer cells through dural- blocking both the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways
Authors: CHIN CHENG SU.
Journal: Cancer Research (2016)

Abstract Sann-Joong-Kuey-Jian-Tang (SJKJT) consists of 17 species of medicinal herbs, is a traditional Chinese medicine prescription, and has been used as complementary medication for a number of types of solid cancer in Taiwan. Transmembrane tyrosine kinase has been strongly implicated in the growth, survival, and metastasis of a wide variety of human tumors. The phosphoinositide-3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) and RAS/RAF/MEK/ERK pathways are two of the most frequently dysregulated kinase cascades in human cancer were well documented. Both pathways represent important signal transduction mechanisms that facilitate the proliferation and survival of cancers driven by growth factor receptors, such as vascular endothelial growth factor receptor (VEGFR), insulin-like growth factor-I receptor (IGF-IR), human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR).The individual downstream components of these signaling cascades either through somatic mutation or epigenetic modification, are also known to be frequently altered in cancer, thus contributing to tumorigenesis and resistance to anticancer therapies. Targeting both the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR Pathways for suppressing Inhibitor Resistant Cells is necessary. In the present study, the human breast cancer BT-20 and MCF-7 cells were treated with SJKJT in vitro. The cytotoxicity of SJKJT were evaluated by 3–(4,5–dimethylthiazol–2–y1)–2,5–diphenyltetrazolium bromide (MTT) assay. The effects of SJKJT on the protein expressions of VEGFR, IGF-IR, PI3K, AKT, mTOR, Ras, Raf, MEK and ERK and β-actin in the BT-20 and MCF-7 cells were examined by western blot analysis. The results showed that SJKJT can induce the proliferation inhibition with time and dose dependent. As a potential mechanism, it was noted that SJKJT treatment significantly inhibited the activity of the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways, which played a protective role against the cytotoxicity. In addition, it was demonstrated that SJKJT treatment inhibited the protein expressions of VEGFR, EGFR and IGF-IR significantly. These results suggest that one of the molecular mechanisms for SJKJT to inhibit breast cancer BT-20 and MCF-7 cells maybe through inhibiting the protein expressions of VEGFR, EGFR, IGF-IR and both Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways. The use of traditional chinese medicine prescription SJKJT may become a feasible novel therapy option. Further studies are warranted to fully elucidate its mechanisms of action. Citation Format: CHIN CHENG SU. Sann-Joong-Kuey-Jian-Tang can inhibit human breast cancer cells through dural- blocking both the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways. [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 2185.
Abstract 77: Establishment of lung cancer patient derived xenograft model from circulating tumor cells: Identification of somatic mutations associated with metastatic potentials
Authors: Chansu Lee, Youngwook Kim, Eunkyung Bae, Sunghoon Cho, Sohyun Youn, Kwang-Sung Ahn, Bong-Seog Kim
Journal: Cancer Research (2016)

Abstract Carcinoma metastasis is initiated by a subpopulation of circulating tumor cells (CTCs) found in the blood of patients. However, the existence and genetic alternations of metastasis-initiating cells (MICs) among CTCs has not been experimentally demonstrated. The establishment of xenograft model using CTCs should help us to understand the biologic behaviors and genetic alternations of MICs associated the promotion of metastasis. Here, we demonstrate that xenograft model can be established by CTCs obtained from lung cancer patients and somatic mutations analyzed from xenograft model in which MICs develop metastatic tumor. After injecting mononuclear cells of lung cancer patients via tail vein, mouse was sacrificed at four weeks. After primary cultured cells were isolated from mouse lung tissues, the MICs were selected by using FASC sorting (EpCam+) and then re-injected via tail vein. And tumor formations in mouse were examined at 8 weeks. For identifying somatic mutations, target sequencing with NGS was performed in tumor DNA and cell free DNA (CF DNA) of lung cancer patients bloods. Our results indicated that nonsynonymous IDH, EGFR, KIT, ABL1, PTEN, ATM, P53, and SMAD4 were found in both tumor tissues and CF DNA of lung cancer patients’ bloods. IDH and EGFR was alternative homo. Others newly found in CF DNA. For further examination of the biologic behaviors of tumor cells which harvested from xenograft model using CTCs, we cultured primary cells from lung tissues and analyzed the anti-cancer drug resistance. Our results showed that primary cultured cells (BH-007) were resistant against cisplatin and erlotinib. In assay of migration and invasion, BH-007 cells possessed high metastatic potential when compared with A549 and H23 cell lines. These data suggested that several somatic mutations affect the anti-cancer drug resistance in lung cancer patients. Our future researches will include development of patient-derived xenograft models for preclinical testing of novel therapeutics. And we develop the possible integration of CF DNA analysis and PDX model from CTCs in the design of co-clinical studies for testing in individual lung cancer patients. Citation Format: Chansu Lee, Youngwook Kim, Eunkyung Bae, Sunghoon Cho, Sohyun Youn, Kwang-Sung Ahn, Bong-Seog Kim. Establishment of lung cancer patient derived xenograft model from circulating tumor cells: Identification of somatic mutations associated with metastatic potentials. [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 77.
Association of a Biomarker of Glucose Peaks, 1,5-Anhydroglucitol, With Subclinical Cardiovascular Disease
Authors: Menglu Liang, John William McEvoy, Yuan Chen, A. Richey Sharrett, Elizabeth Selvin
Journal: Diabetes Care (2016)

1,5-Anhydroglucitol (1,5-AG) is a biomarker of glucose peaks and has been associated with clinical cardiovascular disease. However, the association between 1,5-AG and subclinical cardiovascular disease is unknown. We investigated the association of 1,5-AG with subclinical myocardial damage (assessed by high-sensitivity cardiac troponin T [hs-cTnT]) and atherosclerosis (assessed by carotid intima-media thickness [CIMT] and carotid plaque).We measured 1,5-AG, hs-cTnT, CIMT, and carotid plaque among 10,072 people without diabetes and 681 with diabetes who attended the second examination of the Atherosclerosis Risk in Communities (ARIC) Study (baseline, 1990-1992). We used Poisson regression to characterize the associations between 1,5-AG and prevalent elevated hs-cTnT, thick CIMT, or carotid plaque. Among 9,145 people with a second hs-cTnT measurement 6 years later, we used multinomial logistic regression to assess associations with incident elevation in hs-cTnT.We found that in people with diabetes, lower 1,5-AG (<6 μg/mL) was cross-sectionally associated with elevated hs-cTnT (prevalence ratio 2.06, 95% CI 1.23-3.46) compared with higher 1,5-AG (≥10 μg/mL). Associations in people without diabetes and with thick CIMT or the presence of carotid plaque were less robust. Low 1,5-AG was prospectively associated with the 6-year incident elevation in hs-cTnT (relative risk 2.90, 95% CI 1.23-6.85) in people with diabetes. All associations were strongly attenuated with further adjustment for HbA1c.In people with diabetes, 1,5-AG was associated with subclinical cardiovascular disease, particularly chronic subclinical myocardial damage. Nonetheless, whether observed associations are truly independent of average glycemia is unclear.
Augmented endoscopic resection for fibrotic or recurrent colonic polyps using an ablation and cold avulsion technique
Authors: Zacharias Tsiamoulos, Rajaratnam Rameshshanker, Sachin Gupta, Brian Saunders
Journal: Endoscopy (2016)

Severe submucosal tethering can occur at the base of a polyp because of previous failed endoscopic attempts, extensive biopsies, de-novo fibrosis of flat polyps, or tattoo ink being placed inadvertently at the base of the polyp. A scarred submucosa limits the depth and effectiveness of the lifting solution used when resecting a polyp, which makes snare capture of fibrotic polyp segments impossible and risks the resection being incomplete [1] [2]. Japanese authors have suggested endoscopic submucosal dissection (ESD) en bloc resection of fibrotic polyps; however this is technically difficult and carries a higher risk of perforation [3] [4]. Supplementary ablative techniques such as the use of either argon plasma coagulation (APC) with prior submucosal injection or hot avulsion using electrocautery biopsy forceps are alternative, simpler, and lower risk strategies [2] [5]. The depth of tissue destruction is, however, difficult to accurately judge and viable polyp tissue remains below the cauterized surface when thermal energy alone is used.
Bax Degradation Activity Is a Novel Poor Prognosis Marker of Chronic Lymphocytic Leukemia.
Authors: Samir G. Agrawal, Feng-Ting Liu, Catherine Wiseman, Sima Shirali, Hongxiang Liu, Debra Lillington, Ming Qing Du, Denise Syndercombe Court, Adrian C. Newland, John G. Gribben, Li Jia
Journal: Blood (2007)