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TIE
TIE/angiopoietins
angiopoientins(3)
Angs are protein growth factors that promote angiogenesis.(1-3) There are four Angs: Ang1, Ang2, Ang3, and Ang4.(4) Ang-1, expressed in many adult tissues, binds to Tie2 receptor as an agonist and causes Tie2 autophosphorylation, resulting in a facilitated connection between endothelial cells and mural cells. Ang-1/Tie2 signaling promotes endothelial cell proliferation when endothelial cells are isolated, in contrast with promoting vessel stabilization when endothelial cells contact each other.(3) Ang-2 is an antagonist for Tie2 by competing with Ang-1. The Angs are the secreted ligands of the TIE family of protein RTKs. The TIE receptors are TYKs.(4) Tie1 and Tie2 receptors are endothelial cell-specific receptors expressed in vascular and lymphatic endothelial cells. There is no ligand identified for Tie1 receptor. Tie2 dimerizes upon Ang-1/Ang-2 binding.(1, 3, 6)
In the presence of endogenous VEGF-A, Ang-2 increases tumor angiogenesis by promoting vessel destabilization, whereas Ang-2 promotes endothelial cell death and vessel regression in the absence of VEGF-A.(1, 3, 5)

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References

1. Ichihara E KK TM. Targeting angiogenesis in cancer therapy. . Acta Med Okayama. 2011;65(6):353-62. PMCID: 22189475.

2. LDJaBF FJ. Growth and metastasis of tumor in organ culture. Cancer. 1963;16:453-67.

3. Ichihara E KK, Tanimoto M. Targeting angiogenesis in cancer therapy. Acta Med Okayama. 2011;65(6):353-62. PMCID: 22189475.

4. Bogenrieder T HM. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene. 2003;22:6524-36.

5. BPaLR LI. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci U S A. 2002;99:11205-10.

6. Popkov M JN MD, Rader C and Barbas CF 3rd. Targeting tumor angiogenesis with adenovirus-delivered anti-Tie-2 intrabody. . Cancer Res. 2005;65:972-81.



News


Friday, October 21, 2016 2:06 PM|Thomas Brodowicz; Antoine Italiano; Jennifer Wallet; Jean-Yves Blay; François Bertucci; Christine Chevreau; Sophie Piperno-Neumann; Emmanuelle Bompas; Sébastien Salas; Christophe Perrin; Corinne Delcambre; Bernadette Liegl-Atzwanger; Maud Toulmonde; Sarah Dumont; Isabelle Ray-Coquard; Stéphanie Clisant; Sophie Taieb; Cécile Guillemet; Maria Rios; Olivier Collard; Laurence Bozec; Didier Cupissol; Esma Saada-Bouzid; Christine Lemaignan; Wolfgang Eisterer; Nicolas Isambert; Loïc Chaigneau; Axel Le Cesne; Nicolas Penel|JournalTOCs API - The Lancet Oncology (50 articles)|Labels: ANG, sarcoma, clinical trial

Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial
Olivier Mir Thomas Brodowicz; Antoine Italiano; Jennifer Wallet; Jean-Yves Blay; François Bertucci; Christine Chevreau; Sophie Piperno-Neumann; Emmanuelle Bompas; Sébastien Salas; Christophe Perrin; Corinne Delcambre; Bernadette Liegl-Atzwanger; Maud Toulmonde; Sarah Dumont; Isabelle Ray-Coquard; Stéphanie Clisant; Sophie Taieb; Cécile Guillemet; Maria Rios; Olivier Collard; Laurence Bozec; Didier Cupissol; Esma Saada-Bouzid; Christine Lemaignan; Wolfgang Eisterer; Nicolas Isambert; Loïc Chaigneau; Axel Le Cesne; Nicolas Penel
The Lancet Oncology, Vol. , No. (2016) pp. -
Publication date: Available online 14 October 2016 Source:The Lancet Oncology Author(s): Olivier Mir, Thomas Brodowicz, Antoine Italiano, Jennifer Wallet, Jean-Yves Blay, François Bertucci, Christine Chevreau, Sophie Piperno-Neumann, Emmanuelle Bompas, Sébastien Salas, Christophe Perrin, Corinne Delcambre, Bernadette Liegl-Atzwanger, Maud Toulmonde, Sarah Dumont, Isabelle Ray-Coquard, Stéphanie Clisant, Sophie Taieb, Cécile Guillemet, Maria Rios, Olivier Collard, Laurence Bozec, Didier Cupissol, Esma Saada-Bouzid, Christine Lemaignan, Wolfgang Eisterer, Nicolas Isambert, Loïc Chaigneau, Axel Le Cesne, Nicolas Penel Background Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline. Methods In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov, NCT01900743. Findings From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9–2·3) with regorafenib versus 1·7 months (0·9–1·8) with placebo (HR 0·89 [95% CI 0·48–1·64] p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5–5·0) with regorafenib versus 1·8 (1·0–2·8) months with placebo (HR 0·46 [95% CI 0·46–0·80] p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4–11·6) with regorafenib versus 1·0 (0·8–1·4) with placebo (HR 0·10 [95% CI 0·03–0·35] p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0–7·8) with regorafenib versus 1·0 (0·9–1·9) with placebo (HR 0·46 [95% CI 0·25–0·81] p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 [19%] events in the 89 patients in the regorafenib group vs two [2%] events in the 92 patients in the placebo group), hand and foot skin reaction (14 [15%] vs no events) and asthenia (12 [13%] vs six [6%]). One treatment-related death occurred in the regorafenib group due to liver failure. Interpretation Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib. Funding Bayer HealthCare.

Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ANG, Bcr-Abl, FGFR, childhood cancer, clinical trial
Although regorafenib was approved for use in patients who had progressive GIST despite imatinib and/or sunitinib on the basis of phase II and phase III data, it has not been examined in a systematic fashion in patients with other forms of sarcoma. Given the activity of sorafenib, sunitinib and pazopanib in soft tissue sarcomas, and evidence of activity of sorafenib in osteogenic sarcoma and possibly Ewing/Ewing-like sarcoma, there is precedent to examine SMOKIs (small molecule oral kinase inhibitors) such as regorafenib in sarcomas other than GIST. It is also recognized that SMOKIs (small molecule oral kinase inhibitors)such as regorafenib, sorafenib, pazopanib, and sunitinib have overlapping panels of kinases that are inhibited simultaneously. While not equivalent, most of these SMOKIs (small molecule oral kinase inhibitors) block vascular endothelial growth factor and platelet derived growth factors receptors (VEGFRs and PDGFRs), speaking to a common mechanism of action of several of these agents.
Wednesday, October 12, 2016 3:26 PM|Li Xu, Wei-Lin Liao, Qi-Jue Lu, Chun-Guang Li, Yang Yuan, Zhi-Yun Xu, Sheng-Dong Huang, He-Zhong Chen|Journal of Cancer|Labels: ANG, lung cancer

Objective: To determine the mechanism of Angiogenin(ANG) function involved in the carcinogenesis of lung squamous cell carcinoma.

Methods: 12 patients' normal tissue and cancerous tissue were collected. ANG expression in the squamous cell carcinoma of the lung was evaluated by qRT-PCR and western-blot. The regulation of ANG on proliferation, migration, invasion, and apoptosis of SK-MES-1 cells were analyzed by Cell Counting Kit-8, Transwell migration chamber, Transwell invasion chamber, and Annexin V-FITC assay, respectively. PCR array was utilized for screening potential target genes of ANG. Chromatin immunoprecipitation(ChIP) assays and luciferase assay were adopted for investigation of ANG's direct regulation on HMGA2.

Results: ANG expression is increased in the squamous cell carcinoma of the lung tissue. In vitro experiments results indicated that overexpression of ANG promotes proliferation and invasion capability of SK-MES-1 cells. The candidate proliferation, migration, and invasion related ANG target gene found was HMGA2, expression levels of which were also enhanced in lung squamous cell carcinoma tissue. The direct regulation of ANG on HMGA2 was verified by ChIP and luciferase assay results. Furthermore, down-regulating HMGA2 significantly alleviated the suppression effects of ANG on proliferation, migration, and invasion of SK-MES-1 cells.

Conclusions: Our data illustrated the mechanisms that ANG promoted the cell of SQCLC proliferation, migration, and invasion capacity via directly up-regulating HMGA2.

Wednesday, October 12, 2016 3:26 PM|Jinlong Li, Jie Luo, Dongsheng Gu, Feilong Jie, Nana Pei, Andrew Li, Xinglu Chen, Yanling Zhang, Hongyan Du, Baihong Chen, Weiwang Gu, Colin Sumners, Hongwei Li|Journal of Cancer|Labels: ANG, RAS, prostate cancer

The renin-angiotensin system (RAS) plays important roles in tumorigenesis and is involved with several hallmarks of cancer. Evidence shows that angiotensin II (AngII) type 1 receptor (AT1R) blockers may be associated with improved outcome in prostate cancer patients. Furthermore, our previous studies indicate that increased expression of Ang II type 2 receptor (AT2R) alone induced apoptosis in human prostate cancer lines, an effect that did not require Ang II. This study aimed to investigate the effects of AT2R on tumor growth in vivo and we hypothesized that AT2R over-expression would inhibit proliferation and induce apoptosis in vivo. Human prostate cancer DU145 xenograft mouse model was used to assess the effect of AT2R on tumor growth in vivo. Mice bearing a palpable tumor were chosen and divided randomly into three treatment groups: AT2R, GFP, and PBS. Then we directly injected into the xenograft tumors of the mice every three days with recombinant adenoviruses encoding AT2R (Ad5-CMV-AT2R-EGFP), EGFP (Ad5-CMV-EGFP) and PBS, respectively. The tumor sizes of the tumor bearing mice were then measured. Immunohistochemical Ki-67 staining and TUNEL assay were performed to examine the inhibitory effect of AT2R on tumor cell proliferation. The results showed that AT2R overexpression can inhibit tumor growth of prostate cancer in vivo by inhibiting proliferation and inducing apoptosis of tumor cells. GADD45A is involved in the AT2R-induced antitumor activity. This suggests that AT2R is a potentially useful gene for prostate gene therapy.

Wednesday, July 27, 2016 1:11 PM|SUEDA, T., SAKAI, D., KUDO, T., SUGIURA, T., TAKAHASHI, H., HARAGUCHI, N., NISHIMURA, J., HATA, T., HAYASHI, T., MIZUSHIMA, T., DOKI, Y., MORI, M., SATOH, T.|Anticancer Research recent issues|Labels: ANG, CRC

Background: Regorafenib and TAS-102 are novel antitumor agents for patients with metastatic colorectal cancer (mCRC) whose disease has progressed after standard therapies. In randomized trials, regorafenib and TAS-102 prolonged survival in patients with mCRC. However, the appropriate selection of regorafenib or TAS-102 in treatment strategy has not yet been established. Patients and Methods: We performed a retrospective analysis, between March 2013 and July 2015, on the efficacy and safety of regorafenib or TAS-102. Results: Thirty-seven patients with mCRC treated with regorafenib or TAS-102 were included. Of these 37 patients, 23 first received regorafenib and 14 received TAS-102. The median progression-free survival and overall survival were 3.0 and 5.8 months, respectively, in the regorafenib group and 2.1 and 6.3 months, respectively, in the TAS-102 group. Drug-related adverse events (AEs) and grade ≥3 AEs were 23 (100%) and 10 (43.5%), respectively, in the regorafenib group and 13 (92.9%) and 2 (14.3%), respectively, in the TAS-102 group. The most frequent grade ≥3 AEs were hepatotoxicity (17.4%) and hand-foot syndrome (13.0%) in the regorafenib group, and neutropenia (14.3%) in the TAS-102 group. In subgroup analysis, the median overall survival was 11.5 months in patients receiving crossover treatment with regorafenib to TAS-102, and 7.6 months in those receiving crossover treatment with TAS-102 to regorafenib. Conclusion: Our results showed that regorafenib and TAS-102 have comparable efficacy but different toxicity profiles in patients with mCRC. Both are considered new salvage treatment options. Differences in the toxicity profiles between the two treatments will help in choosing regorafenib or TAS-102.

Thursday, June 30, 2016 12:40 PM|News-Medical.Net Gastrointestinal Cancer News Feed|Comments|Labels: ANG, liver cancer, clinical trial
Oral multikinase inhibitor regorafenib achieves significantly improved survival rates compared to placebo in patients with hepatocellular carcinoma, according to data from the phase III RESORCE trial, presented at the ESMO 18th World Congress of Gastrointestinal Cancer in Barcelona, Spain.