This randomized phase II trial studies how well combination chemotherapy and bevacizumab with or without CBP/beta-catenin antagonist PRI-724 (PRI-724) works in treating patients with newly diagnosed colorectal cancer that has spread to other places in the body. Drugs used in chemotherapy, such as leucovorin calcium, oxaliplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. PRI-724 may help stop the growth of cancer cells by blocking the specific signaling pathway that cancer cells need to grow and spread. It is not yet known whether combination chemotherapy and bevacizumab works better with or without PRI-724 in treating patients with metastatic colorectal cancer.

开始日期2015-11-01

申办/合作机构

University of Southern California

[+2]

NCT02432027 / Completed临床1/2期

A Single-Center, Randomized, Observer Blind, Vehicle- and Comparator-controlled Trial to Evaluate the Antipsoriatic Efficacy and Safety of Topical Formulations of C-82 in a Psoriasis Plaque Test

Evaluate the effects of topical C-82 in a psoriasis plaque test.

开始日期2015-06-01

申办/合作机构

PRISM Pharma Co., Ltd.

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项与 PRISM Pharma Co., Ltd. 相关的文献（医药）

2017-07-01·Cancer Research

Abstract 5172: E7386, an orally active CBP/beta-catenin modulator, induces T cells infiltration into tumor and enhances antitumor activity of anti-PD-1 mAb in Wnt1 tumor syngeneic mice model

作者: Ozawa, Yoichi ; Kato, Yu ; Kouji, Hiroyuki ; Matsui, Junji ; Odagami, Takenao ; Nomoto, Kenichi ; Matsushima, Tomohiro ; Hori, Yusaku ; Yamada, Kazuhiko ; Owa, Takashi

AbstractRecently, immunotherapeutic approaches have come to forefront in melanoma, non-small cell lung cancer, bladder cancer, and so on. However, sufficient benefits from these treatments have been limited. T cell infiltrating into tumor tissues is reported as one of the response biomarker candidates for the immune checkpoint inhibitors. Recent studies have shown that the activation of the Wnt/beta-catenin signaling pathway results in T cell exclusion and resistance to immune checkpoint inhibitor in melanoma patients. We established the Wnt1 tumor syngeneic mice model (Wnt1 model) by implantation of mammary adenocarcinomas isolated from MMTV-Wnt1 transgenic mice. Here we demonstrate whether E7386, a first-in-class orally active CBP/beta-catenin modulator, affects the recruitment of T cells into tumor tissues, leading to the enhancement of anti-PD-1 mAb in Wnt/beta-catenin signaling pathway activating tumor model. The mice were treated with E7386 (50 mg/kg, orally, BID) and/or anti-mouse PD-1 mAb (10 mg/kg, intraperitoneal, twice a week) for three weeks. Tumor diameters are measured with digital calipers, and the tumor volume in mm3 is calculated. Immunohistochemical (IHC) analysis was evaluated for tumor-infiltrating T cells. E7386 showed significant antitumor activity in Wnt1 model, but anti-PD-1 mAb did not. In contrast, E7386 with anti-PD-1 mAb indicated prominent antitumor activity compared to each single treatment. Enhancement of body weight loss in combination group was not observed. In IHC analysis, infiltration of T cells was limited in vehicle control group, in contrast T cell infiltration into tumors was clearly observed in both E7386 treatment group and combination group. As a result, antitumor activity of immune checkpoint inhibitor was limited in Wnt-driven tumor model and E7386 as a novel CBP/beta-catenin modulator enhanced the antitumor activity of anti-PD-1 mAb via induction of tumor-infiltrating T cells.Citation Format: Yusaku Hori, Kazuhiko Yamada, Yu Kato, Yoichi Ozawa, Takenao Odagami, Junji Matsui, Tomohiro Matsushima, Kenichi Nomoto, Hiroyuki Kouji, Takashi Owa. E7386, an orally active CBP/beta-catenin modulator, induces T cells infiltration into tumor and enhances antitumor activity of anti-PD-1 mAb in Wnt1 tumor syngeneic mice model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5172. doi:10.1158/1538-7445.AM2017-5172

2017-07-01·Cancer Research

Abstract 5177: E7386 : First-in-class orally active CBP/beta-catenin modulator as an anticancer agent

作者: Matsukura, Masayuki ; Yokoi, Akira ; Tsuruoka, Akihiko ; Hori, Yusaku ; Uenaka, Toshimitsu ; Matsushima, Tomohiro ; Yamaguchi, Atsumi ; Takemura, Atsushi ; Matsui, Junji ; Yamada, Kazuhiko ; Ozawa, Yoichi ; Harada, Hitoshi ; Matsuki, Masahiro ; Nomoto, Kenich ; Owa, Takashi ; Semba, Taro ; Inoue, Satoshi ; Nakamoto, Kazutaka ; Yoneda, Naoki ; Yamamoto, Yuji ; Odagami, Takenao ; Kouji, Hiroyuki ; Iso, Kentaro ; Tsukamoto, Shuntaro ; Iwata, Masao ; Kubara, Kenji

AbstractCarcinogenesis is often accelerated by the aberrant activation of components molecules of Wnt signaling pathway, especially, APC and beta-catenin are frequently reported to be mutated in various cancers. Therefore, Wnt signal pathway is thought to be one of the attractive therapeutic targets. PRI-724 generated by PRISM Pharma is a small molecule inhibitor of beta-catenin and its transcriptional coactivator CREB binding protein (CBP) thereby specific modulating Wnt/beta-catenin signaling pathway by intravenous continuous infusion. Here we firstly generated orally active small molecular inhibitor, E7386. E7386 disrupted the interaction between beta-catenin and CBP in co-immunoprecipitation assay. E7386 inhibited canonical Wnt signaling pathway /TCF reporter gene activity in LiCl-stimulated HEK-293 and MDA-MB-231 in a dose dependent manner with IC50 values of 55 nmol/L and 73 nmol/L, respectively. E7386 modulated the expression of Wnt signaling pathway related genes including AXIN2 and other genes, which were down-regulated by artificial knockdown of beta-catenin. These results indicate that E7386 controls the expression of Wnt target genes through modulation of beta-catenin/CBP interaction. Next we investigated anti-polyposis effect in ApcMin/+ mice as an in vivo proof of mechanism model. ApcMin/+ mice develops polyps in the intestinal tract caused by the aberrant activation of Wnt/beta-catenin signaling pathway. Oral administration of E7386 significantly suppressed the number of polyposis in a dose dependent manner at the dose range from 8.5 to 50 mg/kg. In addition, E7386 significantly changed the expressions of Wnt related genes in whisker follicle of ApcMin/+mice model. Finally, we investigated anti-tumor activity of E7386 in vitro tumor proliferation panel against 28 human tumor cell lines. E7386 showed relatively potent anti-proliferative activity against cancer cell lines harboring exclusively mutated Wnt signaling pathway molecules such as APC or beta-catenin. E7386 also showed significant antitumor activity in a dose dependent manner on human tumor cell line xenograft harboring APC mutation. Taken together, E7386 is a first in class orally active CBP/beta-catenin modulator and showed potent inhibitory activity against aberrant activation of Wnt/beta-catenin signaling pathway.Citation Format: Kazuhiko Yamada, Yusaku Hori, Atsumi Yamaguchi, Masahiro Matsuki, Shuntaro Tsukamoto, Akira Yokoi, Taro Semba, Yoichi Ozawa, Satoshi Inoue, Yuji Yamamoto, Kentaro Iso, Kazutaka Nakamoto, Hitoshi Harada, Naoki Yoneda, Atsushi Takemura, Masayuki Matsukura,, Kenji Kubara, Takenao Odagami, Masao Iwata, Akihiko Tsuruoka, Toshimitsu Uenaka, Junji Matsui, Tomohiro Matsushima, Kenich Nomoto, Hiroyuki Kouji, Takashi Owa. E7386 : First-in-class orally active CBP/beta-catenin modulator as an anticancer agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5177. doi:10.1158/1538-7445.AM2017-5177

2016-05-20·Journal of Clinical Oncology

Final results of a phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-line therapy after FOLFIRINOX or FOLFOX.

作者: Kwak, Eunice Lee ; McWilliams, Robert R. ; Chiorean, E. Gabriela ; Inada, Tetsuhi ; Ko, Andrew H. ; Nadler, Paul I. ; Wood, Debra L. ; Fujimori, Masamoto ; Lenz, Heinz-Josef ; Kouji, Hiroyuki

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