Abstract 108P
Background
Liposarcomas (LPS) are rare soft tissue tumors of mesenchymal origin. The two main histological subtypes are well-differentiated (WD) and dedifferentiated (DD) LPS. Aggressive surgery is the only curative treatment to date and local recurrences remain frequent. Surgeons need new tools to maximize benefit from surgery. The aim of this project was the development and validation of antibodies (Ab) for fluorescence guided surgery.
Methods
The systematic amplification of MDM2 in this subgroup of tumors results in a metabolic signature related to serine metabolism. We showed that MDM2 is recruited to chromatin to regulate a transcriptional program involving amino acid metabolism and particularly to the 3 enzymes of the serine synthesis pathway and its transmembrane transporter (SLC)-1A4.
Results
We confirmed that the serine carrier SLC1A4 is overexpressed in LPS cell lines and on fresh patient’s tumors in LPS-WD and LPS-DD. Using Phage display technology, we developed six antibodies against the extra membrane loop domain of the SLC. We validated four Antibodies in western blot, QPCR, FACS and immunofluorescence microscopy using cell lines with or without expression of SLC1A4 and LPS cell lines with Sh-SLC1A4. We confirmed the same tropism in immunohistochemistry on human kidney, testicular and skin samples as the commercial antibody targeting the intracellular part of the transporter. We started testing them for diagnosis on several LPS and other sarcomas with promising results. We also confirmed their specificity on mice tissue samples, that allow us to test human form of the antibodies in PDX LPS models. In a collaborative study with the expert company SurgiMab, we managed to show intense fluorescent signal in the tumor since 12 hours after peritoneal injection until more than five days with no secondary effect on mice.
Conclusions
In conclusion, the use of these new biomarkers for histopathological diagnosis in LPS-WD and LPS-DD appears feasible with further development. In vitro and in vivo experiments are very encouraging for “fluorescence guided surgery” and have to be tested on human in a clinical trial after conducting a study on the pharmacodynamics, pharmacokinetics and toxicity.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Inserm.
Funding
Institut National du Cancer.
Disclosure
All authors have declared no conflicts of interest.