Galunisertib

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. 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. 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. 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." 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." 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. 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. 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. About 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 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 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. About 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). About 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. 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. SOURCE iOnctura

结直肠癌(CRC)是全球第三大常见癌症，具有很高的转移风险。男性的结直肠癌发病率和死亡率高于女性，可能是由于女性性激素的保护作用。绝经后妇女的激素替代治疗与发生CRC的风险较低相关。更好地了解结直肠癌 结直肠癌(CRC)是全球第三大常见癌症，具有很高的转移风险。男性的结直肠癌发病率和死亡率高于女性，可能是由于女性性激素的保护作用。绝经后妇女的激素替代治疗与发生CRC的风险较低相关。更好地了解结直肠癌雌激素相关过程的潜在机制对于开发新的治疗方法和改善患者的预后是必要的。 雌激素通过雌激素受体(ER-α和ER-β)发挥生物学功能。E-R-α和ER-β相互拮抗，以相反的方式调节肿瘤的进展。ERα主要在乳腺癌组织中表达，并促进雌激素相关的肿瘤转移，而ERβ在结直肠癌组织中高表达，并被发现与抑制结直肠癌进展有关。 图片来源：https://doi.org/10.1038/s41419-023-05956-0 近日，来自北京大学肿瘤医院与研究所的研究人员在Cell Death and Disease杂志上发表了题为“WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer”的文章，该研究揭示了WFDC3通过促进ERβ介导的TGFBR1转录抑制抑制结直肠癌的肿瘤转移。 雌激素在结直肠癌中起保护作用，主要通过雌激素受体β(ER-β)发挥作用。然而，与ERβ相关的结直肠癌治疗的临床策略仍在研究中。研究者发现证实WFDC3是一种肿瘤抑制因子，通过ERβ/TGFBR1信号轴促进雌激素诱导的肿瘤转移抑制。 WFDC3与ERβ相互作用，通过抑制其蛋白酶体依赖的降解来增加其蛋白质的稳定性。WFDC3通过ERβ介导的转录抑制TGFBR1mRNA的表达。在临床试验中使用针对β的药物Galunisertib阻断转化生长因子受体1信号转导，可削弱WFDC3缺失诱导的结直肠癌细胞的迁移。 此外，WFDC3在结直肠癌中的表达具有临床意义，肿瘤细胞中WFDC3高表达的结直肠癌患者预后良好。因此，本研究提示WFDC3可作为结直肠癌患者雌激素/ERβ通路靶向治疗的指标。 WFDC3促进ERβ介导的对TGFBR1转录的抑制 图片来源：https://doi.org/10.1038/s41419-023-05956-0 总体而言，这项研究确认WFDC3是一种肿瘤抑制因子，通过ERβ依赖的转化生长因子β信号抑制结直肠癌的转移。WFDC3在ERβ/TGFBR1轴中的作用表明WFDC3可能成为结直肠癌患者ERβ特异性治疗的潜在靶点。（生物谷 Bioon.com） 参考文献 Tianqi Liu et al. WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer. Cell Death Dis. 2023 Jul 13;14(7):425. doi: 10.1038/s41419-023-05956-0.