The Landscape of Drug Sensitivity and Resistance in Sarcoma

Biochemistry Basic Medical Sciences Life Sciences Immunology Oncology Pharmacy Medicine Cell Biology
drug sensitivity sarcoma functional precision medicine patient-derived tumor organoids clinical correlation

Background Introduction

This study explores the landscape of individual drug sensitivity and resistance in sarcoma patients. Sarcomas are a diverse group of tumors originating from mesenchymal tissue, including types such as osteosarcoma and soft tissue sarcoma, mostly affecting young people. Although the annual incidence of sarcomas is relatively low, their mortality rate is high. For example, osteosarcoma ranks third as a cause of cancer-related death in young patients. Current treatment methods include surgical resection, chemotherapy, targeted therapy, and radiotherapy, but these approaches often do not cure the disease, and many patients have a low five-year survival rate. Due to the heterogeneity of sarcomas and the diversity of their subtypes, effective treatment options are difficult to determine, highlighting the urgent need for novel personalized treatment strategies.

In recent years, precision medicine technologies have gradually become important tools for identifying feasible characteristics and improving patient treatment outcomes. Common methods include next-generation sequencing (NGS) and immunohistochemistry (IHC), used to identify molecular changes and potential drug targets. However, the complexity of genetic variations and the limited effectiveness of chemotherapy and targeted therapies often lead to unsatisfactory outcomes when selecting drugs based on genomic precision medicine. To address this issue, researchers have developed functional testing methods based on patient-derived tumor organoids (PDTOS) to complement genetic testing. This approach not only has the advantage of processing and predicting treatment responses but also provides actionable treatment information for each patient in a short time.

Source of Study

This paper was authored by Ahmad Al Shihabi and collaborators, published in the journal “Cell Stem Cell” on October 3, 2024. The research team, mainly from institutions such as the University of California, Los Angeles (UCLA), utilized patient-derived organoids cultured from over 110 sarcoma samples to study the drug sensitivity and resistance of different sarcoma types.

Research Procedure

This paper is a resource-based study analyzing patient and subtype-specific responses across 21 types of sarcomas. A total of 194 samples from 126 patients were collected, covering 24 sarcoma subtypes. The sample collection and processing were as follows:

  1. Sample Collection and Preparation: Samples were obtained from the biopsies or surgical resections of sarcoma tissues at the UCLA Health Center. After collection, the tissues underwent digestion, and tumor cells were cultured in a three-dimensional matrix to generate organoids.
  2. Histological and Molecular Characterization: Histopathological analysis was conducted on the organoids and parental tumors to confirm the presence of tumor cells and ensure retention of primary characteristics in vitro. Additionally, RNA sequencing was performed to analyze the molecular features of the tumors and organoids.
  3. High-Throughput Drug Sensitivity Screening: A high-throughput screening platform was used to test drug sensitivity on the organoids, including single drugs and drug combinations, with results available within a week following surgery. Drug sensitivity was correlated with clinical characteristics such as tumor subtype, treatment history, and disease progression.

The organoids used in the study retained the histological and molecular characteristics of sarcoma subtypes, validated through various molecular and phenotypic indicators. These organoids demonstrated diverse in vitro growth dynamics, indicating that under standardized culture conditions, they could preserve the sarcoma phenotype specific to subtypes and individual patients.

Main Research Findings

Drug Sensitivity of Organoids

  • Drug Sensitivity Analysis: Among the 92 screened samples, over 80% exhibited significant sensitivity to more than one drug, while approximately 19.6% showed no significant response to any drug. Regarding specific drug sensitivity differences, certain samples demonstrated unique sensitivity and resistance patterns, such as high sensitivity to the MEK inhibitor trametinib while being more resistant to other drugs.
  • Effects of Combination Therapy: Some samples showed strong sensitivity to drug combinations such as gemcitabine-docetaxel. The results indicate that drug combinations can enhance therapeutic efficacy, contributing to the development of personalized treatment strategies.

Influence of Clinical Characteristics on Drug Response

The study also explored the association between clinical characteristics (e.g., patient age, lesion type, treatment history) and drug response. For instance, tumors that had undergone systemic treatment showed higher sensitivity to mTOR inhibitors and multi-targeted tyrosine kinase inhibitors (such as lenvatinib and cediranib). The relationship between age and drug response revealed that organoids derived from adult patients were more resistant to cediranib, while those from younger patients were more sensitive to it.

Research Conclusions

Using the high-throughput screening platform of PDTOS, the research team successfully depicted a panoramic view of drug sensitivity and resistance in sarcomas, revealing unique sensitivity and resistance patterns among different sarcoma subtypes and individual patients. The findings validate the potential of organoids in functional precision medicine, especially in sarcomas characterized by high heterogeneity and limited effectiveness of traditional treatment strategies.

  • The Value of Functional Precision Medicine: Through the rapid detection system of organoids, actionable treatment recommendations can be generated in a short time. In the study, about 59% of samples showed a significant response to at least one FDA-approved or NCCN-recommended treatment regimen.
  • Heterogeneity and Personalized Treatment: Drug sensitivity testing also revealed numerous subtype-specific and patient-specific sensitivities and resistances, supporting the development of personalized treatment plans for patients.
  • Potential Applications: The organoid screening platform has broad application potential, aiding in the identification of ineffective treatment cases, avoiding unnecessary treatments, and improving treatment outcomes. Additionally, it can help discover new indications and suitable drug combinations.

Research Highlights

  1. Rapid Generation of Organoids: The platform can complete drug sensitivity testing within a week post-surgery, providing immediate support for clinical decision-making.
  2. Highly Individualized Sensitivity Testing: Organoid testing revealed specific drug responses in different sarcoma subtypes, such as differential sensitivity to mTOR and MEK inhibitors.
  3. Precision Drug Selection: Effective regimens from at least one FDA-approved or NCCN-recommended treatment were identified in 59% of samples, showcasing the application prospects of the organoid platform in precision medicine.
  4. Heterogeneity and Individualized Precision Medicine: Repeated testing of different samples from the same patient demonstrated variations in drug responses among different tumor sites in vivo, emphasizing the importance of personalized treatment in highly heterogeneous tumors like sarcomas.

Significance and Value

The study demonstrated the potential application of PDTOS in drug screening for sarcoma patients. It can quickly generate individualized treatment plans to optimize patient outcomes. Meanwhile, the organoid screening platform can also be used to explore different drug indications and combinations, providing important references for clinical treatment. This functional precision medicine approach can complement genetic testing, further promoting personalized treatment for sarcomas and other cancers.