Advances in the treatment of dedifferentiated liposarcoma

Contrary to carcinomas, sarcomas are a rare form of cancer and grow in connective tissue. They arise in blood vessels, bones, cartilages, fat, muscles, nerves, and tendons. They are mostly found in arms and legs but can occur in other parts of the body. More than fifty types of sarcoma can be distinguished and grouped into two main kinds: osteosarcoma and soft tissue sarcoma. They often can be treated by having surgery to eradicate the tumor. Radiotherapy can be used to shrink the tumor before surgery or kill the cancer cells remaining after surgery. Finally, chemotherapy can constitute the first line of treatment when the cancer has spread. Surgery alone can lead to patient recovery, especially if the tumor is low-grade. High grade sarcomas are, however, more difficult to eliminate successfully. In 2016 in the US, close to 16,000 new cases will be diagnosed by biopsy (FISH, IHC, and RT-PCR) and imaging (CT and MRI scans) and 6,500 patients will be expected to die.

What is dedifferentiated liposarcoma?

Liposarcoma is a malignancy of fat cells and represents the most common form of soft tissue sarcoma. It accounts for approximately 5% of all sarcomas. The prognosis varies depending on tumor site, size, grade, and histologic subtype. The World Health Organization recognizes five subtypes of liposarcoma: well-differentiated, dedifferentiated, myxoid, round cell, and pleomorphic. Patients with a low grade and well differentiated sarcoma have a relatively good prognosis with a five-year survival rate of 85%. Conversely, patients with a high grade tumor (e.g. dedifferentiated sarcoma) have a poor prognosis with a five-year survival rate of 18-21%. Dedifferentiated liposarcoma (DDLPS) occurs when a low grade tumor changes and newer cells with higher grade arise in the tumor. Dedifferentiated liposarcoma is frequently found in the retroperitoneum and the extremities (arms and legs). The etiology and the exact mechanism of dedifferentiation remains unknown. It is, however, thought to occur spontaneously due to certain chromosomal abnormalities.

Genomic characterization of dedifferentiated liposarcoma

Very little is known about DDLPS. A deeper understanding of the mechanisms driving these tumors is, therefore, required to identify new therapeutic targets and develop new treatments options. Dr. Hanes and colleagues from the Institute of Cancer Research in Oslo performed both exome and transcriptome sequencing as well as DNA copy number analysis on three metastatic tumors and a NRH-LS1 cell line generated from a patient-derived xenograft. Genes located in 12p12-22 and known to be amplified in liposarcoma such as CDK4, HMGA2, and MDM2 were found to be amplified and overexpressed in DDLPS. After closer examination of the pathways that can be potentially targeted, the authors identified KITL and FRS2. The KITL gene codes for the ligand of a tyrosine kinase receptor called c-KIT. The targeting of c-KIT with the kinase inhibitor Imatinib had, unfortunately, no effect on the proliferation of NRH-LS1 cells. FRS2 is co-amplified alongside MDM2 and encodes an adaptor protein linking the fibroblast growth factor receptor (FGFR) with downstream signaling pathways. FRS2 is situated downstream of FGFR. Although there is no known inhibitor of FRS2, signaling might still very much depend on the kinase activity of FGFR and the latter might constitute a valid target for the treatment of DDLPS.

Therapeutic potential of FGF receptor inhibition

NVP-BGJ398, a pan-FGFR inhibitor, was shown to have a dose-dependent effect on the proliferation of DDLPS cells in vitro. Combining a caspase-3/-7 assay with Enzo’s NUCLEAR-ID® Red DNA stain, the authors determined that apoptotic cells only represented a small percentage of the total cell population and that apoptosis alone could not explain the effect this inhibitor had on proliferation. Almost 50% of the cell population were found to be in G0 phase, either quiescent or senescent. Using Enzo’s Cellular senescence live cell analysis assay, only 6.3% of cells treated with NVP-BGJ398 and 2.8% of untreated cells were positive for senescence-associated β-galactosidase (SA-β-Gal) activity. These results led to the conclusion that the drop of proliferation of DDLPS cells following treatment with NVP-BGJ398 was, in fact, associated with the cells entering a quiescent state rather than a senescent phase. Regrettably, this cell cycle arrest was found to be temporary as proliferation of NRH-LS1 cells recovered quickly after withdrawal from FGFR inhibition. Analogous experiments were conducted with two DDPLS having similar FRS2 expression profile. Only one in two cell lines responded similarly. Altogether, the results of this study are encouraging, with the discovery of a new therapeutic target in patients with otherwise limited treatment options. Further work will be required to identify new ways of inhibiting FGFR signaling in an efficient and sustainable manner.

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