Dedifferentiated Liposarcoma (DDL) constitutes a unique and particularly virulent variation of liposarcoma, a cancer that arises from adipocytic (fat) tissue cells. Protheragen provides complete diagnostic and therapeutic development services for DDL, utilizing advanced technologies in molecular biology, pharmacology, and bioinformatics to expedite therapeutic discovery.
Overview of Dedifferentiated Liposarcoma (DDL)
Dedifferentiated Liposarcoma (DDL) is one of the rarest and most aggressive forms of liposarcoma. It develops from the progression of well-differentiated liposarcoma (WDL) or atypical lipomatous tumors (ALT) into a non-lipogenic sarcoma. This progression is marked by the presence of supernumerary ring and giant marker chromosomes, which contain amplified sequences of the 12q13-15 chromosomal region. This region harbors critical oncogenes like MDM2 and CDK4, which underlie the malignant transformation and aggressive nature of DDL. It is most common in the retroperitoneum and deep soft tissues of the limbs, with peak incidence in middle-aged and older adults. It is characterized by a high rate of local recurrence (about 40%), metastasis in 15-30%, and overall mortality of 28%. The anatomical site, particularly the retroperitoneum, is a major prognostic factor, with extremity sites generally having a better overall prognosis.
Fig.1 Oversized marker chromosome present in dedifferentiated liposarcoma. (Nishio J.,
et al., 2021)
Diagnostics Development for Dedifferentiated Liposarcoma (DDL)
Histopathological Analysis
DDL is diagnostically histological DDL as exhibiting biphasic features of WDL/ALT and a non-lipogenic sarcoma transition. The WDL/ALT features mature adipocytes blended with atypical stromal spindle cells. Dedifferentiated areas display marked morphological diversity ranging from undifferentiated pleomorphic sarcoma to high-grade myxofibrosarcoma. Diagnosis requires immunohistochemistry MDM2 and CDK4 both showing consistent nuclear reactivity in the dedifferentiated areas.
Molecular Diagnostics
Molecular diagnostics help in recognizing particular genetic changes for DDL. FISH-based detection of MDM2 and CDK4 amplifications is a standard diagnostic procedure with a high sensitivity and specificity. In addition, NGS (Next-Generation Sequencing) is capable of identifying fusion genes (for example, CTDSP1/2-DNM3OS) along with other co-amplified regions, thus furnishing a detailed genetic blueprint for tailoring therapeutics.
Therapeutics Development for Dedifferentiated Liposarcoma (DDL)
- Targeted Therapies
Since MDM2 and CDK4 are DDL pathogenesis core components, therapies focusing on these molecular culprits are being investigated and developed. Inhibitors of MDM2, such as RG7112 and SAR405838, are designed to disrupt the MDM2-p53 binding, with the goal of reactivating the tumor-suppressing activities of p53. Initial clinical trials for these therapies have been conducted and shown safety and DDL amplification, and MDM2 preliminary effectiveness.
- Immunotherapies
Immunotherapy utilizing immune checkpoint inhibitors that target PD-1/PD-L1 is emerging as a potential therapy for advanced DDL. Some clinical trials with PD-1 inhibitors, for example, pembrolizumab and nivolumab, have shown a response in some DDL patients. These therapies function by preventing the interaction between PD-1 and PD-L1, hence facilitating a better immune response against tumor cells.
Table 1. Therapeutics of Dedifferentiated Liposarcoma (DDL). (Nishio J., et al., 2021)
| Therapeutics |
Drug Name |
Mechanism |
Description |
Stage |
| Chemotherapy |
Anthracycline-based regimen (e.g., Doxorubicin) |
Inhibits DNA replication by intercalating between DNA strands and inhibiting topoisomerase II |
Standard first-line therapy for advanced DDL |
Approved |
| Microtubule Dynamics Inhibitors |
Eribulin |
Inhibits microtubule dynamics, preventing mitosis |
Approved for advanced liposarcoma after prior anthracycline-based therapy |
Phase III |
| DNA Binding Agent |
Trabectedin |
Binds DNA in the minor groove, disrupting transcription and inducing apoptosis |
Approved for advanced liposarcoma after prior chemotherapy |
Phase III |
| Combination Therapy |
Gemcitabine and Docetaxel |
Gemcitabine inhibits DNA synthesis; Docetaxel inhibits microtubule disassembly |
Active in advanced STS, but less effective in DDL |
Phase III |
| CDK4 Inhibitors |
Palbociclib, Ribociclib, Abemaciclib |
Inhibits CDK4/6, blocking cell cycle progression |
Effective in CDK4-amplified DDL |
Phase II |
| XPO1 Inhibitors |
Selinexor |
Inhibits the export of tumor suppressor proteins, leading to tumor cell death |
Demonstrated efficacy in preclinical studies, with some clinical activity |
Phase II |
| PD-1 Inhibitors |
Pembrolizumab, Nivolumab |
PD-1 inhibitors that enhance T-cell-mediated immune responses |
Promising results in DDL with PD-L1 expression |
Phase II |
| Tyrosine Kinase Inhibitors (TKIs) |
Pazopanib |
Inhibits multiple receptor tyrosine kinases, disrupting angiogenesis and tumor growth |
Used in advanced STS, with some efficacy in DDL |
Phase II/III |
| MDM2 Inhibitors |
RG7112, SAR405838 |
Inhibits the MDM2-p53 interaction, allowing tumor suppression by p53 |
Potential therapy for MDM2-amplified DDL |
Phase I/II |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers comprehensive preclinical research services for the development of diagnostics and therapeutics targeting Dedifferentiated Liposarcoma (DDL). Our services encompass a wide range of capabilities, from molecular diagnostics and histopathological analysis to advanced imaging techniques and therapeutic development.
Disease Models
- CDX (Lipo246, Lipo224, Lipo863, IB115, or SW872 Cell lines ) Models
- Akt2 Overexpression Models
- Notch1 Overexpression Models
- IL-22 Overexpression Models
- Atgl/Hsl Double Knockout Models
Protheragen's advantage lies in our integrated approach to DDL diagnostics and therapeutics development. By combining advanced molecular diagnostics with comprehensive preclinical research services, we offer a seamless transition from discovery to development. Our experienced team of scientists ensures that each project is executed with the highest standards of quality and innovation. If you are interested in our services, please feel free to contact us.
Reference
- Nishio, Jun, et al. "Biology and management of dedifferentiated liposarcoma: state of the art and perspectives." Journal of Clinical Medicine 10.15 (2021): 3230.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
