Li Ka Hou C, Gulia Ashish, Duffaud Florence, Jones Robin L
Sarcoma Unit, Royal Marsden and Institute of Cancer Research, London, UK.
Department of Oncology, Oxford University, Oxford, UK.
Oncol Ther. 2025 Mar;13(1):1-9. doi: 10.1007/s40487-024-00317-z. Epub 2024 Dec 9.
The systemic treatment landscape for advanced and metastatic chondrosarcoma, a malignancy with limited responsiveness to conventional therapies, has always been notoriously challenging. While standard chemotherapy offers minimal benefits, certain subtypes, such as mesenchymal and dedifferentiated chondrosarcomas, have shown some response to systemic therapies initially developed for other sarcomas. Investigational strategies are focusing on molecular targets, including mutations in the isocitrate dehydrogenase gene (IDH), signaling pathways, such as hedgehog and death receptor 5 (DR5) and immune modulation. IDH mutations, notably found in conventional and dedifferentiated chondrosarcomas, have prompted the evaluation of IDH inhibitors, which have demonstrated promising efficacy in preclinical and early clinical trials, despite limited data in chondrosarcoma. Additionally, the hedgehog pathway, implicated in chondrosarcoma progression, has been targeted with inhibitors, although clinical translation has shown mixed results. Immunotherapy, including programmed cell death 1 (PD-1) checkpoint inhibitors and chimeric antigen receptor-T (CAR-T) cells, is also being investigated but faces challenges due to the immunosuppressive tumour microenvironment. Among new approaches, DR5 agonists such as INBRX-109 have shown single-agent efficacy, with minimal toxicity, opening possibilities for use in combination therapies to improve outcomes. Given the heterogenous and treatment-resistant nature of chondrosarcoma, we highlight the need for multi-omics and genetic profiling to guide personalized, combination therapies that target multiple carcinogenic pathways. The integration of multi-targeted approaches could enhance efficacy, address tumour heterogeneity, and overcome resistance, presenting a hopeful direction for systemic therapy in this challenging cancer. The investigation of combination regimens with IDH inhibitors, immunotherapy and DR5 agonists hold promise for transforming the management of advanced chondrosarcoma.
晚期和转移性软骨肉瘤是一种对传统疗法反应有限的恶性肿瘤，其全身治疗领域一直极具挑战性。虽然标准化疗的益处微乎其微，但某些亚型，如间充质和去分化软骨肉瘤，对最初为其他肉瘤开发的全身治疗显示出一定反应。研究策略集中在分子靶点上，包括异柠檬酸脱氢酶基因（IDH）突变、信号通路，如刺猬信号通路和死亡受体5（DR5）以及免疫调节。IDH突变在传统型和去分化软骨肉瘤中尤为常见，这促使人们对IDH抑制剂进行评估，尽管软骨肉瘤方面的数据有限，但IDH抑制剂在临床前和早期临床试验中已显示出有前景的疗效。此外，刺猬信号通路与软骨肉瘤进展有关，已成为抑制剂的作用靶点，不过临床转化结果喜忧参半。免疫疗法，包括程序性细胞死亡蛋白1（PD-1）检查点抑制剂和嵌合抗原受体T细胞（CAR-T），也在研究中，但由于免疫抑制性肿瘤微环境而面临挑战。在新方法中，诸如INBRX-109等DR5激动剂已显示出单药疗效，且毒性极小，为联合疗法改善治疗效果带来了可能性。鉴于软骨肉瘤的异质性和治疗抵抗性，我们强调需要进行多组学和基因分析，以指导针对多种致癌途径的个性化联合疗法。多靶点方法的整合可以提高疗效、解决肿瘤异质性并克服耐药性，为这种具有挑战性的癌症的全身治疗提供了一个充满希望的方向。对IDH抑制剂、免疫疗法和DR5激动剂联合方案的研究有望改变晚期软骨肉瘤的治疗方式。
