Advancing Systemic Therapy in Chondrosarcoma: New Horizons
Abstract 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 dedifferen...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Adis, Springer Healthcare
2024-12-01
|
| Series: | Oncology and Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s40487-024-00317-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761633660829696 |
|---|---|
| author | Ka Hou C. Li Ashish Gulia Florence Duffaud Robin L. Jones |
| author_facet | Ka Hou C. Li Ashish Gulia Florence Duffaud Robin L. Jones |
| author_sort | Ka Hou C. Li |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-c5fef2e201e746158fdf1e0781bce763 |
| institution | DOAJ |
| issn | 2366-1070 2366-1089 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Adis, Springer Healthcare |
| record_format | Article |
| series | Oncology and Therapy |
| spelling | doaj-art-c5fef2e201e746158fdf1e0781bce7632025-08-20T03:05:57ZengAdis, Springer HealthcareOncology and Therapy2366-10702366-10892024-12-011311910.1007/s40487-024-00317-zAdvancing Systemic Therapy in Chondrosarcoma: New HorizonsKa Hou C. Li0Ashish Gulia1Florence Duffaud2Robin L. Jones3Sarcoma Unit, Royal Marsden and Institute of Cancer ResearchDepartment of Surgical Oncology, Homi Bhabha Cancer Hospital & Research Centre, Tata Memorial CentreOncology Unit, La Timone University Hospital–Aix-Marseille UniversitySarcoma Unit, Royal Marsden and Institute of Cancer ResearchAbstract 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.https://doi.org/10.1007/s40487-024-00317-zAdvanced/metastatic chondrosarcomaSystemic therapyIDH inhibitorsDR5 agonistImmunotherapy |
| spellingShingle | Ka Hou C. Li Ashish Gulia Florence Duffaud Robin L. Jones Advancing Systemic Therapy in Chondrosarcoma: New Horizons Oncology and Therapy Advanced/metastatic chondrosarcoma Systemic therapy IDH inhibitors DR5 agonist Immunotherapy |
| title | Advancing Systemic Therapy in Chondrosarcoma: New Horizons |
| title_full | Advancing Systemic Therapy in Chondrosarcoma: New Horizons |
| title_fullStr | Advancing Systemic Therapy in Chondrosarcoma: New Horizons |
| title_full_unstemmed | Advancing Systemic Therapy in Chondrosarcoma: New Horizons |
| title_short | Advancing Systemic Therapy in Chondrosarcoma: New Horizons |
| title_sort | advancing systemic therapy in chondrosarcoma new horizons |
| topic | Advanced/metastatic chondrosarcoma Systemic therapy IDH inhibitors DR5 agonist Immunotherapy |
| url | https://doi.org/10.1007/s40487-024-00317-z |
| work_keys_str_mv | AT kahoucli advancingsystemictherapyinchondrosarcomanewhorizons AT ashishgulia advancingsystemictherapyinchondrosarcomanewhorizons AT florenceduffaud advancingsystemictherapyinchondrosarcomanewhorizons AT robinljones advancingsystemictherapyinchondrosarcomanewhorizons |