P276-00, a flavone that inhibits cyclin-dependent kinases, has been identified by us recently as a novel antineoplastic agent. In this study, we have selected a panel of human tumor cell lines and xenografts to allow determination of selectivity and efficacy of P276-00. When tested against a panel of 16 cisplatin-sensitive and cisplatin-resistant cell lines, the antiproliferative potential of P276-00 was found to be f30-fold higher than cisplatin. Studies to show tumor sensitivity using clonogenic assay in 22 human xenografts indicated that P276-00 was f26-fold more potent than cisplatin, and further, it was also found to be active against cisplatin-resistant tumors of central nervous system, melanoma, prostate, and renal cancers. Further, we studied the effects of P276-00 on cell cycle progression by flow cytometry using asynchronous and synchronous population of tumor and normal cells.

We present here recent work at NPAC aimed at developing WebFlow – a general purpose Web‐based visual interactive programming environment for coarse grain distributed computing. We follow the 3‐tier architecture with the central control and integration WebVM layer in tier‐2, interacting with the visual graph editor applets in tier‐1 (front‐end) and the legacy systems in tier‐3. WebVM is given by a mesh of Java Web servers such as Jeeves from JavaSoft or Jigsaw from MIT/W3C. All system control structures are implemented as URL‐addressable servlets which enable Web browser‐based authoring, monitoring, publication, documentation and software distribution tools for distributed computing. We view WebFlow/WEbVM as a promising programming paradigm and co‐ordination model for the exploding volume of Web/Java software, and we illustrate it in a set of ongoing application development activities. © 1997 John Wiley & Sons, Ltd.

Bhonde MR, Gupte RD, Dadarkar SD, Jadhav MG, Tannu AA, Bhatt P, Bhatia DR, Desai NK, Deore V, Yewalkar N, Vishwakarma RA, Sharma S, Kumar S, Dagia NM. A novel mTOR inhibitor is efficacious in a murine model of colitis.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the USA by 2030. Immune checkpoint inhibitors fail to control most PDAC tumors because of PDAC’s extensive immunosuppressive microenvironment and poor immune infiltration, a phenotype also seen in other non-inflamed (ie, ‘cold’) tumors. Identifying novel ways to enhance immunotherapy efficacy in PDAC is critical. Dipeptidyl peptidase (DPP) inhibition can enhance immunotherapy efficacy in other cancer types; however, the impact of DPP inhibition on PDAC tumors remains unexplored.MethodsWe examined the effects of an oral small molecule DPP inhibitor (BXCL701) on PDAC tumor growth using mT3-2D and Pan02 subcutaneous syngeneic murine models in C57BL/6 mice. We explored the effects of DPP inhibition on the tumor immune landscape using RNAseq, immunohistochemistry, cytokine evaluation and flow cytometry. We then tested if BXCL701 enhanced anti-programmed cell death protein 1 (anti-PD1) efficacy and performed immune cell depletion and rechallenged studies to explore the relevance of cytotoxic immune cells to combination treatment efficacy.ResultsIn both murine models of PDAC, DPP inhibition enhanced NK and T cell immune infiltration and reduced tumor growth. DPP inhibition also enhanced the efficacy of anti-PD1. The efficacy of dual anti-PD1 and BXCL701 therapy was dependent on both CD8+ T cells and NK cells. Mice treated with this combination therapy developed antitumor immune memory that cleared some tumors after re-exposure. Lastly, we used The Cancer Genome Atlas (TCGA) to demonstrate that increased NK cell content, but not T cell content, in human PDAC tumors is correlated with longer overall survival. We propose that broad DPP inhibition enhances antitumor immune response via two mechanisms: (1) DPP4 inhibition increases tumor content of CXCL9/10, which recruits CXCR3+ NK and T cells, and (2) DPP8/9 inhibition activates the inflammasome, resulting in proinflammatory cytokine release and Th1 response, further enhancing the CXCL9/10-CXCR3 axis.ConclusionsThese findings show that DPP inhibition with BXCL701 represents a pharmacologic strategy to increase the tumor microenvironment immune cell content to improve anti-PD1 efficacy in PDAC, suggesting BXCL701 can enhance immunotherapy efficacy in ‘cold’ tumor types. These findings also highlight the potential importance of NK cells along with T cells in regulating PDAC tumor growth.

The present work describes the anticancer activity of Ophiobolin A isolated from the endophytic fungus Bipolaris setariae. Ophiobolin A was isolated using preparative HPLC and its structure was confirmed by HRMS, (1)H NMR, (13)C NMR, COSY, DEPT, HSQC and HMBC. It inhibited solid and haematological cancer cell proliferation with IC50 of 0.4-4.3 μM. In comparison, IC50 against normal cells was 20.9 μM. It was found to inhibit the phosphorylation of S6 (IC50 = 1.9 ± 0.2 μM), ERK (IC50 = 0.28 ± 0.02 μM) and RB (IC50 = 1.42 ± 0.1 μM), the effector proteins of PI3K/mTOR, Ras/Raf/ERK and CDK/RB pathways, respectively. It induced apoptosis and inhibited cell cycle progression in MDA-MB-231 cancer cells with concomitant inhibition of signalling proteins. Thus, this study reveals that anticancer activity of Ophiobolin A is associated with simultaneous inhibition of multiple oncogenic signalling pathways namely PI3K/mTOR, Ras/Raf/ERK and CDK/RB.

BackgroundLung cancer is the major cause of cancer-related deaths and many cases of Non Small Cell Lung Cancer (NSCLC), a common type of lung cancer, have frequent genetic/oncogenic activation of EGFR, KRAS, PIK3CA, BRAF, and others that drive tumor growth. Some patients though initially respond, but later develop resistance to erlotinib/gefitinib with no option except for cytotoxic therapy. Therefore, development of novel targeted therapeutics is imperative to provide improved survival benefit for NSCLC patients. The mTOR cell survival pathway is activated in naïve, or in response to targeted therapies in NSCLC.MethodsWe have discovered P7170, a small molecule inhibitor of mTORC1/mTORC2/ALK1 and investigated its antitumor efficacy using various in vitro and in vivo models of human NSCLC.ResultsP7170 inhibited the phosphorylation of AKT, S6 and 4EBP1 (substrates for mTORC2 and mTORC1) levels by 80-100% and growth of NSCLC cells. P7170 inhibited anchorage-independent colony formation of NSCLC patient tumor–derived cells subsistent of disease sub-types. The compound also induced apoptosis in NSCLC cell lines. P7170 at a well-tolerated daily dose of 20 mg/kg significantly inhibited the growth of NSCLC xenografts independent of different mutations (EGFR, KRAS, or PIK3CA) or sensitivity to erlotinib. Pharmacokinetic-pharmacodynamic (PK-PD) analysis showed sub-micro molar tumor concentrations along with mTORC1/C2 inhibition.ConclusionsOur results provide evidence of antitumor activity of P7170 in the erlotinib –sensitive and –insensitive models of NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-259) contains supplementary material, which is available to authorized users.

Cell cycle deregulation is one of the first steps that transform normal cells into tumor cells. Cyclin-dependent kinases (Cdks) related alterations such as overexpression and amplification of cell-cycle activators or inactivation of cell cycle inhibitors are among the most common genetic changes in human tumors. The pursuit for drugs that inhibit Cdks has been an intense area of research for more than 15 years. A number of Cdk inhibitors are being evaluated in clinical trials for the treatment of cancer. P1446A-05 has been identified as a Cdk4-D1, Cdk1-B and Cdk9-T inhibitor. P1446A-05 exhibited greater selectivity to Cdk4-D1 and Cdk1-B that are involved in the G1 and G2/M phase of the cell cycle respectively. The IC50 values were 0.09 and 0.025 μM for Cdk4-D1 and Cdk1-B respectively. P1446A-05 also inhibited Cdk9-T, which plays a role in transcription, with an IC50 of 0.022 μM. P1446A-05 was inactive against many non-Cdks with an IC50 of more than 50 μM. In cytotoxicity assay using 30 human cancer cell lines P1446A-05 showed IC50 in the range of 0.5 to 3.9 μM, whereas the cytotoxicity for unstimulated normal human PBMNCs was > 10 μM. P1446A-05 arrested cell cycle progression at G1 and G2 phases and induced apoptosis in human cancer cell lines such as non-small-cell lung cancer (H-460), colorectal carcinoma (HCT-116) and prostate cancer (PC-3) in a dose and time dependent manner. Furthermore, P1446A-05 affected the proteins involved in cell cycle and apoptosis. It down-regulated cyclin D1, inhibited Cdk4 specific phosphorylation (ser780 of retinoblastoma), induced the tumor suppressor protein p53, and reduced the levels of the anti-apoptotic protein Bcl-2. Pharmacokinetic studies revealed that P1446A-05 exhibited an absolute oral bioavailability of 82.48% in mice and 79.07% in rats. It showed dose-dependent increase in 1446A-05 levels in plasma of mice and rats. In in vivo efficacy studies, orally administered P1446A-05 significantly (p<0.001) inhibited the tumor growth in two xenograft models that of colon cancer (Colo-205) and non-small cell lung cancer (H-460) in SCID mice. These data demonstrated that P1446A-05 is an orally active inhibitor of Cdk with a unique target profile that may have therapeutic potential in human malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3054. doi:1538-7445.AM2012-3054

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