New targeted treatments for advanced sarcomas.

Abstract

PURPOSE OF REVIEW:

The purpose of this review is to provide the rationale and results behind recent clinical trials regarding molecular-targeted agents for advanced sarcomas.

RECENT FINDINGS:

Tazemetostat, a first-in-class EZH2 inhibitor, was approved to treat advanced epithelioid sarcoma. In synovial sarcoma, the interaction between pathognomonic SS18-SSX fusion protein and the BAF complex has brought insight in using BRD9 inhibitors as a treatment based on synthetic lethality. MDM2 overexpression is an important mechanism to suppress p53 function, and MDM2 gene amplification is pathognomonic in well differentiated and dedifferentiated liposarcoma. Two MDM2 inhibitors, milademetan and BI907828, have both reached the optimal dosing and have shown promising efficacy in MDM2-amplified liposarcoma. Late-stage pivotal studies are ongoing for both of these MDM2 inhibitors. The co-amplification of CDK4 and MDM2 in liposarcoma also provided a rationale for CDK4/6 inhibitors as a potential therapy. Selinexor, an exportin-1 inhibitor, has shown single-agent activity in dedifferentiated liposarcoma and action in gastrointestinal stromal tumour in combination with imatinib. Lastly, a new formulation of mTOR inhibitor, nab-sirolimus, was recently approved for perivascular epithelioid cell tumour (PEComa).

SUMMARY:

Molecular-guided precision medicine holds a bright future in bringing more active treatments for advanced sarcoma patients.

• Authors: Chia-Chen Li, Tom Wei-Wu Chen
• Journal: Current opinion in oncology (Curr Opin Oncol) Vol. 35 Issue 4 Pg. 309-314 (07 01 2023) ISSN: 1531-703X [Electronic] United States
• PMID: 37222206 (Publication Type: Review, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• Proto-Oncogene Proteins c-mdm2
• Antineoplastic Agents
• BRD9 protein, human
• Transcription Factors

Topics

• Humans
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism, therapeutic use)
• Sarcoma (drug therapy, genetics)
• Liposarcoma (drug therapy, genetics, pathology)
• Cell Differentiation
• Antineoplastic Agents (therapeutic use)
• Transcription Factors (therapeutic use)