Atypical Lipomatous Tumors (ALT) are a subclass of liposarcomas because of their well-differentiated form and ability to recur locally or metastasize distantly. Atypical Lipomatous Tumors (ALT) diagnostics and therapeutics, highly specialized services from Protheragen. Starting from target discovery and validation all the way to preclinical development, we focus on providing comprehensive services to radically reduce time-to-market for novel therapies devoted to ALT.
Overview of Atypical Lipomatous Tumors (ALT)
Atypical Lipomatous Tumors (ALT) or well-differentiated liposarcomas (WDL) are uncommon cancers that develop from adipose (fat) tissue. They are mostly found in the deep soft tissues of the body, such as the retroperitoneum, limbs, and trunk. ALT/WDL are locally recurrent and usually do not spread to distant parts of the body. Early diagnosis is often difficult because of the overlap in histological features with benign lipomas. Although classed as low-grade malignancies because of the well-differentiated appearance, ALT/WDL can dedifferentiate to more aggressive and aggressive variants. Such transitions are often accompanied by genetic changes, mostly involving the MDM2 and CDK4 genes, which are important in the tumor's pathology and evolution.
Fig.1 Fluorescence in situ hybridization (FISH) for MDM2. MDM2 is seen as an orange signal; CEP12 as a green signal. (Sugiyama K.,
et al., 2022)
Diagnostics Development for Atypical Lipomatous Tumors (ALT)
Imaging Techniques
The ALTs can be diagnosed and monitored non-invasively through imaging. MRIs are especially useful as ALTs are usually low intensity on T1-weighted images and high intensity on T2-weighted images with accompanying septal structures. Metabolic insights can be gathered from 18F-FDG PET/CT scans as well—with more aggressive tumors showing higher SUVmax. Greater diagnostic accuracy and tailored therapeutic approaches are achieved through combining these imaging methods and histological and molecular analyses.
Histological and Molecular Diagnostics
The diagnosis of ALT lesions is still best given through histological analysis, where the presence of atypical spindle cells, pleomorphic stromal cells, and multivacuolated lipoblasts distinguishes them from lipomas. Immunohistochemical staining for MDM2, CDK4, and other proteins seems to be of high value for the diagnosis, given the specificity and sensitivity offered. The MDM2 amplification is best detected by fluorescence in situ hybridization (FISH), focusing on the area 12q13-15.
Therapeutics Development for Atypical Lipomatous Tumors (ALT)
- Targeted Therapies
Using inhibitors of crucial molecular mechanisms of tumor growth as directed therapeutics for ALTs is more effective. Tumor suppressor activity is restored by MDM2 inhibitors SAR405838 and MK-8242, which target MDM2's interactions with p53. Cell cycle progression is inhibited by CDK 4/6 inhibitors palbociclib and ribociclib through the inhibition of retinoblastoma (RB) protein phosphorylation. Clinically, some PPARy agonists, which aid in adipocytic differentiation, have shown activity in myxoid liposarcomas.
- Immunotherapy
Immunotherapeutic strategies, especially those directed against the PD1/PD-L1 pathways, are being investigated as possible therapies for ALTs. Inhibitors of PD1, like Pembrolizumab, have been shown to work well in some advanced liposarcoma patients. Other newer approaches, for instance, the use of some immunotherapy combined with oncolytic viruses like GLV-1h68, are being developed to bolster the anti-tumor immune responses and the effectiveness of the therapeutics.
- Chemotherapy and Other Agents
Traditional chemotherapeutic agents, such as anthracyclines and eribulin, remain mainstays in the therapeutic of advanced ALTs. Eribulin, a microtubule inhibitor, has shown improved overall survival in randomized phase 3 trials. Pazopanib, a multitarget tyrosine kinase inhibitor, has demonstrated efficacy in controlling tumor progression, with significant progression-free survival rates observed in clinical studies.
Table 1. Therapeutics of Atypical Lipomatous Tumors (ALT). (Mashima E., et al., 2021)
| Therapeutics |
Drug Name |
Mechanism |
Description |
Stage |
| Anthracycline-Based Therapy |
Doxorubicin |
Inhibits DNA synthesis by intercalating into DNA |
First-line therapy for advanced or metastatic disease. Often used alone or in combination with ifosfamide. |
Approved |
| Anthracycline-Based Therapy |
Ifosfamide |
Alkylates DNA, causing cross-linking and preventing DNA replication |
Used in combination with doxorubicin to improve progression-free survival, but has no significant impact on overall survival. |
Approved |
| Antitumor Antibiotic |
Trabectedin |
Binds to DNA minor groove, disrupting transcription and causing cell death |
Effective in advanced liposarcoma, showing progression-free survival rates. |
Approved |
| Microtubule Inhibitor |
Eribulin |
Interferes with microtubule dynamics, causing cell cycle arrest and apoptosis |
Improved overall survival compared to dacarbazine in phase 3 trials. |
Phase III |
| Multitarget Tyrosine Kinase Inhibitor |
Pazopanib |
Inhibits angiogenesis and tumor growth by targeting VEGF receptors |
Demonstrated progression-free survival rates in phase 2 studies. |
Phase II |
| PD1/PD-L1 Inhibitor |
Pembrolizumab |
Blocks PD1/PD-L1 interaction, enhancing immune response |
Favorable responses in dedifferentiated liposarcoma. |
Phase II |
| MDM2 Inhibitor |
SAR405838 |
Blocks interaction between MDM2 and p53, restoring tumor suppressor function |
Phase 1 trial showed stable disease in 65% of patients. |
Phase I |
| MDM2 Inhibitor |
MK-8242 |
Inhibits MDM2, allowing p53 to function normally |
Partial responses in 7% of liposarcoma patients. |
Phase I |
| CDK4/6 Inhibitor |
Ribociclib |
Inhibits CDK4/6, leading to cell cycle arrest |
No objective responses but stable disease in 15% of patients for 6 months. |
Phase I |
| Exportin 1 Inhibitor |
Selinexor |
Inhibits nuclear export of proteins, leading to tumor cell apoptosis |
No objective responses but stable disease in 47% of patients for 4 months. |
Phase I |
| PPARγ Agonist |
Pioglitazone |
Enhances adipocytic differentiation |
Sustained partial response observed in myxoid liposarcoma. |
Phase I |
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 provides a comprehensive suite of services dedicated to advancing the preclinical development of diagnostics and therapeutics for ALT. Our expertise spans the entire drug discovery pipeline, from initial target identification and validation to lead compound optimization and preclinical efficacy studies.
Disease Models
- 3D Organoid Culture
- Patient-Derived Xenograft (PDX) Models
- Akt2 Overexpression in Zebrafish
- Epistatic Gene Interaction Models
- IL-22 Overexpression in Mice
At Protheragen, we offer a robust platform for preclinical research in ALT. Our services include the development and utilization of various in vitro and in vivo models. We can establish and characterize patient-derived xenograft (PDX) models, which closely mimic the genetic and phenotypic features of human tumors. If you are interested in our services, please feel free to contact us.
References
- Sugiyama, Kana, et al. "Differential diagnosis of lipoma and atypical lipomatous tumor/well-differentiated liposarcoma by cytological analysis." Diagnostic Cytopathology 50.3 (2022): 112-122.
- Mashima, Emi, Yu Sawada, and Motonobu Nakamura. "Recent advancement in atypical lipomatous tumor research." International journal of molecular sciences 22.3 (2021): 994.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
