The purpose of the study is to evaluate whether the novel anti-cancer drug OXY111A is safe and tolerated in patients with primary and secondary hepato-pancreato-biliary and gastrointestinal neoplasia as measured by exploring the maximum tolerated dose (MTD). At level of MTD, additional patients will be included aimed for assessing the efficacy profile in these neoplasia entities.

开始日期2014-02-01

申办/合作机构

University of Zurich

100 项与 Myoinositol Trispyrophosphate 相关的临床结果

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100 项与 Myoinositol Trispyrophosphate 相关的转化医学

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100 项与 Myoinositol Trispyrophosphate 相关的专利（医药）

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项与 Myoinositol Trispyrophosphate 相关的文献（医药）

2021-07-01·International Journal of Radiation Oncology*Biology*Physics2区 · 医学

Tumor Oxygenation by Myo-Inositol Trispyrophosphate Enhances Radiation Response

2区 · 医学

Article

作者: Borgeaud, Nathalie ; Pruschy, Martin ; Grgic, Ivo ; Gupta, Anurag ; Tschanz, Fabienne ; Guckenberger, Matthias ; Clavien, Pierre-Alain ; Graf, Rolf

PURPOSETumor hypoxia is a major limiting factor for successful radiation therapy outcomes, with hypoxic cells being up to 3-fold more radiation resistant than normoxic cells; tumor hypoxia creates a tumor microenvironment that is hostile to immune response. Thus, pharmaceutical-induced tumor oxygenation before radiation therapy represents an interesting method to enhance the efficacy of radiation therapy. Myo-inositol trispyrophosphate (ITPP) triggers a decrease in the affinity of oxygen to hemoglobin, which leads to an increased release of oxygen upon tissue demand, including in hypoxic tumors.METHODS AND MATERIALSThe combined treatment modality of high-dose bolus ITPP with a single high-dose fraction of ionizing radiation (IR) was investigated for its mechanics and efficacy in multiple preclinical animal tumor models in immunocompromised and immunocompetent mice. The dynamics of tumor oxygenation were determined by serial hypoxia-oriented bioimaging. Initial and residual DNA damage and the integrity of the tumor vasculature were quantified on the immunohistochemical level in response to the different treatment combinations.RESULTSITPP application did not affect tumor growth as a single treatment modality, but it rapidly induced tumor oxygenation, as demonstrated by in vivo imaging, and significantly reduced tumor growth when combined with IR. An immunohistochemical analysis of γH2AX foci demonstrated increased initial and residual IR-induced DNA damage as the primary mechanism for radiosensitization within initially hypoxic but ITPP-oxygenated tumor regions. Scheduling experiments revealed that ITPP increases the efficacy of ionizing radiation only when applied before radiation therapy. Irradiation alone damaged the tumor vasculature and increased tumor hypoxia, which were both prevented by combined treatment with ITPP. Interestingly, the combined treatment modality also promoted increased immune cell infiltration.CONCLUSIONSITPP-mediated tumor oxygenation and vascular protection triggers immediate and delayed processes to enhance the efficacy of ionizing radiation for successful radiation therapy.

2021-04-01·Journal of Cellular and Molecular Medicine2区 · 医学

Tumour angiogenesis normalized by myo‐inositol trispyrophosphate alleviates hypoxia in the microenvironment and promotes antitumor immune response

2区 · 医学

ArticleOA

作者: Majewska, Aleksandra ; El Hafny‐Rahbi, Bouchra ; Klimkiewicz, Krzysztof ; Kieda, Claudine ; Brodaczewska, Klaudia ; Delalande, Anthony ; Collet, Guillaume ; Grillon, Catherine

AbstractPathologic angiogenesis directly responds to tumour hypoxia and controls the molecular/cellular composition of the tumour microenvironment, increasing both immune tolerance and stromal cooperation with tumour growth. Myo‐inositol‐trispyrophosphate (ITPP) provides a means to achieve stable normalization of angiogenesis. ITPP increases intratumour oxygen tension (pO2) and stabilizes vessel normalization through activation of endothelial Phosphatase‐and‐Tensin‐homologue (PTEN). Here, we show that the tumour reduction due to the ITPP‐induced modification of the tumour microenvironment by elevating pO2 affects the phenotype and properties of the immune infiltrate. Our main observations are as follows: a relative change in the M1 and M2 macrophage‐type proportions, increased proportions of NK and CD8+T cells, and a reduction in Tregs and Th2 cells. We also found, in vivo and in vitro, that the impaired access of PD1+NK cells to tumour cells is due to their adhesion to PD‐L1+/PD‐L2+ endothelial cells in hypoxia. ITPP treatment strongly reduced PD‐L1/PD‐L2 expression on CD45+/CD31+ cells, and PD1+ cells were more numerous in the tumour mass. CTLA‐4+ cell numbers were stable, but level of expression decreased. Similarly, CD47+ cells and expression were reduced. Consequently, angiogenesis normalization induced by ITPP is the mean to revert immunosuppression into an antitumor immune response. This brings a key adjuvant effect to improve the efficacy of chemo/radio/immunotherapeutic strategies for cancer treatment.

2016-12-01·BMC Cancer2区 · 医学

Development of OXY111A, a novel hypoxia-modifier as a potential antitumor agent in patients with hepato-pancreato-biliary neoplasms - Protocol of a first Ib/IIa clinical trial

2区 · 医学

ArticleOA

作者: Stupp, Roger ; Lehn, Jean-Marie ; Pestalozzi, Bernhard ; Humar, Bostjan ; Kron, Philipp ; Clavien, Pierre-Alain ; Samaras, Panagiotis ; Graf, Rolf ; Dutkowski, Philipp ; Linecker, Michael ; Nicolau, Claude ; Petrowsky, Henrik ; Jetter, Alexander ; Schlegel, Andrea ; Limani, Perparim ; Müllhaupt, Beat

BACKGROUNDSolid tumors, such as hepato-pancreato-biliary cancer, develop tumor hypoxia with tumor growth. Despite advances in surgery, a majority of these patients are in an unresectable condition. At this stage standard cytotoxic chemotherapy regimens are applied with limited success. Novel biological treatment options based on an antiangiogenic mechanism of action neglect other hypoxia mediated mechanisms (e.g. epithelial-mesenchymal transition, Warburg effect, and immunological response) leading to an increased invasiveness with a poor outcome. The novel antihypoxic molecule myo-inositoltrispyrophosphate (ITPP, OXY111A) acts as an allosteric effector of hemoglobin and promotes normoxia in hypoxic tumors. In preclinical studies, tumor growth was reduced and survival prolonged. Additionally, a beneficial side effect profile was observed.METHODSIn this first Ib/IIa clinical trial we will assess safety and tolerability of OXY111A as well as a proof of concept regarding efficacy in patients with non-resectable primary and secondary tumors of the liver, pancreas, and biliary tract. The study design is exploratory, prospective, open-labelled and mono-centric. The study is divided in a dose escalation part with a maximum of 48 subjects and an extension part, in which 21 subjects will be included.DISCUSSIONThe novel antihypoxic compound OXY111A has been tested in several cancer animal models showing beneficial effects for both survival and low side effect profiles. This first in patient application of OXY111A will reveal potential beneficial outcomes if anti-hypoxic therapy is added to standard cytotoxic treatment in patients with primary and secondary hepatopancreatobiliary tumors.TRIAL REGISTRATIONInstitution Ethical Board Approval ID: KEK-ZH-Nr. 2014-0374; Swiss regulatory authority Swissmedic (2015DR1009); ClinicalTrials.gov Identifier: NCT02528526 , prospectively registered on November 11^th, 2014.

100 项与 Myoinositol Trispyrophosphate 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	Myoinositol Trispyrophosphate	-	-

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
不孕	临床3期	-	Biosearch SA	2016-02-01
多囊卵巢综合征	临床3期	-	Biosearch SA	2016-02-01
胆管上皮癌	临床3期	瑞士	University of Zurich	2014-02-01
结直肠癌	临床3期	瑞士	University of Zurich	2014-02-01
胰腺癌	临床3期	瑞士	University of Zurich	2014-02-01
心脏衰竭	临床3期	-	University of Zurich	-
肥胖	临床3期	-	University of Zurich	-
肝细胞癌	临床2期	瑞士	University of Zurich	2014-02-01
肿瘤	临床2期	瑞士	-	-
心脏衰竭	药物发现	美国	NormOxys, Inc.	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02528526 (Pubmed \| Nat Commun) 人工标引	临床1期	肿瘤	28	Myo-inositol trispyrophosphate	(網醖構廠範簾夢醖襯獵) = 32 treatment-related toxicities (mostly hypercalcemia) 鏇願醖鬱獵膚選衊鬱顧 (蓋廠選餘鏇願網網鹹窪 )	积极	2021-06-21