AMSTERDAM and GENEVA, Oct. 19, 2023 /PRNewswire/ -- iOnctura, a clinical-stage biotech developing selective cancer therapies against targets that play critical roles in multiple tumor survival pathways, today announces publication of new research data in the peer-reviewed journal Cancer Research, that supports a strategy of combining autotaxin inhibitor IOA-289 with TGF-β pathway inhibitor IOA-359..

阿姆斯特丹和日内瓦，2023年10月19日/PRNewswire/--iOnctura，一家临床阶段生物技术公司，针对在多种肿瘤生存途径中起关键作用的靶标开发选择性癌症疗法，今天宣布在同行评审的期刊cancer research，支持将自分泌运动因子抑制剂IOA-289与TGF-β途径抑制剂IOA-359结合的策略。。

The research, generated in collaboration with the lab of Professor Davide Melisi, Associate Professor of Medical Oncology at the Department of Medicine, University of Verona, uncovers a central role for autotaxin in resistance to TGF–β pathway inhibition. The TGF-β pathway plays a critical role in promoting tumor aggressiveness, immune escape and resistance to therapy, which has made it an attractive target for cancer therapy.

这项研究是与维罗纳大学医学系医学肿瘤学副教授Davide Melisi教授的实验室合作产生的，揭示了自分泌运动因子在抵抗TGF-β途径抑制中的核心作用。TGF-β途径在促进肿瘤侵袭性，免疫逃逸和对治疗的抗性中起关键作用，这使其成为癌症治疗的有吸引力的靶标。

Previous attempts to interrupt TGF-β pathway signaling in cancer have been thwarted by activation of alternative resistance pathways by the tumor. By characterising these resistance mechanisms, iOnctura is designing novel, safe combination treatments that promise to override resistance..

先前中断癌症中TGF-β途径信号传导的尝试已被肿瘤激活替代抗性途径所阻碍。通过表征这些阻力机制，iOnctura正在设计新颖，安全的组合治疗方法，有望超越阻力。。

Professor Davide Melisi said: 'We have uncovered a new mechanism of action for autotaxin in resistance to TGF–β pathway inhibition. Data generated by our laboratory across in vitro and in vivo models and from human clinical samples support this important finding. These findings pave the way for clinical studies combining autotaxin inhibitors with TGF-β pathway inhibitors, addressing the fibrotic barrier that protects tumors and reversing immunosuppressive mechanisms encouraging the immune system to mount an attack against cancer cells.' .

Davide Melisi教授说：“我们发现了自分泌运动因子抵抗TGF-β途径抑制的新作用机制。我们实验室在体外和体内模型以及人类临床样本中生成的数据支持了这一重要发现。这些发现为将自分泌运动因子抑制剂与TGF-β途径抑制剂相结合的临床研究铺平了道路，解决了保护肿瘤的纤维化屏障和逆转免疫抑制机制，促使免疫系统对癌细胞发起攻击 .

Catherine Pickering, Chief Executive Officer of iOnctura, said: 'These data support the clinical development of autotaxin inhibitors in combination with TGF-β inhibitors and standard of care for the treatment of pancreatic cancer. This validates our strategy of combining IOA-289, iOnctura's clinical stage autotaxin inhibitor, with IOA-359, our TGF–β inhibitor that we are preparing for clinical development.'.

iOnctura首席执行官Catherine Pickering说：“这些数据支持autotaxin抑制剂联合TGF-β抑制剂和治疗胰腺癌的标准治疗的临床开发。这验证了我们将IOA-289（iOnctura的临床阶段自分泌运动因子抑制剂）与IOA-359（我们正在为临床开发做准备的TGF-β抑制剂）相结合的策略。

The published research showed that blocking the TGF–β pathway in vivo or in in vitro co-culture models increased the number of autotaxin-producing inflammatory cancer associated fibroblasts (iCAFs). The autotaxin enzyme in turn increased lysophosphatidic acid (LPA) NF- κB signaling in tumor cells which triggered treatment resistance.

已发表的研究表明，在体内或体外共培养模型中阻断TGF-β途径会增加产生自分泌运动因子的炎性癌相关成纤维细胞（iCAF）的数量。自分泌运动因子反过来增加肿瘤细胞中的溶血磷脂酸（LPA）NF-κB信号传导，从而引发治疗抵抗。

Specifically, NF-kB promoted CXCL1 expression and recruitment of myeloid suppressive cells (MDSCs), that limited CD8 T-cell infiltration. Adding the autotaxin inhibitor IOA-289 to TGF-β pathway inhibitor galunisertib and standard of care in PDAC-bearing mice, suppressed NF-κB signaling, reduced MDSC and increased CD8 T-cell infiltration, resulting in prolonged overall survival and curing 40% of the mice..

具体而言，NF-kB促进CXCL1表达和骨髓抑制细胞（MDSC）的募集，这限制了CD8T细胞浸润。将autotaxin抑制剂IOA-289添加到TGF-β途径抑制剂galunisertib和PDAC携带小鼠的标准治疗中，抑制NF-κB信号传导，减少MDSC和增加CD8 T细胞浸润，导致总体存活延长并治愈40%的老鼠。。

Most importantly, pancreatic ductal adenocarcinoma (PDAC) patients treated with galunisertib from the H9H-MC-JBAJ trial, had significantly elevated levels of autotaxin compared to patients in the control arm. Median progression free survival was shorter for those with higher autotaxin levels compared to those with lower..

最重要的是，与对照组患者相比，用H9H-MC-JBAJ试验中的galunisertib治疗的胰腺导管腺癌（PDAC）患者具有显着升高的自分泌运动因子水平。自分泌运动因子水平较高的患者的中位无进展生存期较低。。

About iOnctura

关于Ionctura

iOnctura is a clinical-stage biotech developing selective cancer therapies against targets that play critical roles in multiple tumor survival pathways such as cellular proliferation; escape from immune detection; and drug resistance. iOnctura's pioneering approach to drug development is expected to offer significant clinical benefits over the traditional approach of targeting a single pathway alone.

iOnctura是一家临床阶段生物技术公司，开发针对在多种肿瘤存活途径（如细胞增殖）中发挥关键作用的靶点的选择性癌症治疗；逃避免疫检测；和耐药性。预计iOnctura开创性的药物开发方法将比单独针对单一途径的传统方法提供显着的临床益处。

iOnctura has progressed two therapeutic candidates into mid-stage clinical development: Roginolisib (IOA-244), a first-in-class allosteric modulator of PI3Kδ; and IOA-289, a highly-selective, non-competitive autotaxin (ATX) inhibitor. IOA-359, a TGF–β pathway inhibitor is also undergoing an extensive pre-clinical program in preparation for first-in-human studies.

iOnctura已将两种治疗候选药物发展为中期临床开发：Roginolisib（IOA-244），PI3Kδ的一流变构调节剂；和IOA-289，一种高选择性，非竞争性自分泌运动因子（ATX）抑制剂。IOA-359是一种TGF-β途径抑制剂，也正在接受广泛的临床前计划，以准备首次人体研究。

iOnctura is backed by specialist institutional investors including M Ventures, Inkef Capital, VI Partners, Schroders Capital, and 3B Future Health Fund. iOnctura BV is headquartered in Amsterdam, The Netherlands with its wholly owned Swiss subsidiary, iOnctura SA, located in Geneva, Switzerland..

iOnctura得到专业机构投资者的支持，包括M Ventures，Inkef Capital，VI Partners，Schroders Capital和3B Future Health Fund。iOnctura BV总部设在荷兰阿姆斯特丹，其合资瑞士子公司iOnctura SA位于瑞士日内瓦。。

About IOA-289

关于IOA-289

IOA-289 is an orally dosed molecule that has shown preclinically to inhibit the growth and proliferation of cancer cells, stimulate immune cell infiltration into tumours and inhibit the development of fibrosis. IOA-289 is being developed as a first-in-class therapy for highly fibrotic cancer indications that overexpress ATX including pancreatic, liver, colorectal, ovarian and breast cancers.

A Phase 1b study of IOA-289 in combination with chemotherapy in metastatic pancreatic cancer started in Q4 2022 (NCT05586516)..

IOA-289联合化疗治疗转移性胰腺癌的1b期研究始于2022年第4季度（NCT05586516）。。

About IOA-359

关于IOA-359

IOA–359 is a novel oral TGF–β pathway inhibitor that will be evaluated in solid tumors. Activation of the TGF-β signaling pathway in tumors correlates with tumor aggressiveness, immune escape and resistance to therapy, making it an attractive target for cancer therapy. The inhibition of TGF-β signaling with IOA-359 is expected to attenuate cancer progression through direct effects on cancer, immune and stromal cells.

IOA-359是一种新型的口服TGF-β途径抑制剂，将在实体瘤中进行评估。肿瘤中TGF-β信号传导途径的激活与肿瘤侵袭性，免疫逃逸和对治疗的抗性相关，使其成为癌症治疗的有吸引力的靶标。预期用IOA-359抑制TGF-β信号传导可通过直接作用于癌症，免疫和基质细胞来减弱癌症进展。

By characterising the resistance mechanisms that typically arise when targeting the TGF-β pathway alone, iOnctura's data-driven precision oncology methods are being used to design novel combination treatments that promise to override tumor survival pathways..

通过表征单独靶向TGF-β途径时通常出现的耐药机制，iOnctura的数据驱动精确肿瘤学方法被用于设计有望超越肿瘤存活途径的新型联合治疗。。

SOURCE iOnctura

来源：Ionctura