PPP2R1B in Dedifferentiated Liposarcoma
Abstract
Liposarcomas (LPS) are cancers that arise from fat tissue. Approximately 2000 new cases of liposarcoma are diagnosed in the United States each year. While there are several different types of liposarcoma, almost half are defined as well-differentiated (WDLPS) or dedifferentiated (DDLPS) liposarcomas. Both WDLPS and DDLPS share a genetic abnormality whereby a portion of chromosome 12 is duplicated many times in the cancer cell. This results in the overexpression of genes located on chromosome 12, most notably MDM2 and CDK4, which is thought to cause these cells to become cancerous. While WDLPS and DDLPS share this chromosomal duplication they differ in many important ways. WDLPS retains many of the qualities of normal fat and patients with WDLPS have an encouraging prognosis with a five-year survival rate of over 90%. DDLPS, on the other hand, is much more aggressive. Only 30% of patients with this type of LPS are expected to live beyond five years. These patients tend to be middle-aged, and both men (59% of cases) and women (41% of cases) are affected. Remarkably, the way DDLPS is treated has not changed significantly in the last fifty years primarily because of our limited knowledge of the molecular mechanisms of this disease. Our project began by comparing WDLPS to DDLPS to search for additional molecular changes in DDLPS which might account for its poor prognosis. Through these studies, we discovered that a protein called PPP2R1B is lost in DDLPS compared to WDLPS. PPP2R1B is part of the protein phosphatase 2A (PP2A) complex which is an important off-switch for cellular signaling pathways. When PPP2R1B is lost, the activity of these pathways goes unchecked which may lead to aggressive forms of cancer. PPP2R1B s role in the PP2A complex is only very poorly understood and, in most tissues, PPP2R1B does not appear to be important. However, our preliminary findings suggest that PPP2R1B plays a previously unrecognized essential role in fat tissue and its loss is a disease-defining event in DDLPS. This proposal will test the hypothesis that loss of PPP2R1B is a key molecular cause of DDLPS and that pathways regulated by PPP2R1B-containing complexes represent novel and actionable targets for new targeted treatment strategies. Our proposal will target all three of the Fiscal Year 2022 Rare Cancer Research Program Focus Areas. Specific Aims 1 and 2 will identify PPP2R1B and the downstream signaling pathways regulated by PPP2R1B-complexes as disease-defining molecular pathways of DDLPS. Specific Aim 2 will develop a new genetically engineered mouse model of DDLPS to support clinical trial readiness. Specific Aim 1 will identify the signaling pathways dysregulated when PPP2R1B is lost with emphasis on those which may be targeted by existing therapies to immediately, upon completion of this work, provide novel therapeutic strategies for the treatment of this rare cancer. If our hypothesis is borne out, this proposal will have a significant and immediate impact on advancing DDLPS research and treatment by increasing our understanding of the molecular basis of the disease, providing new treatment strategies, and developing a new model of the disease. Successful completion of this proposal will establish an essential role for PPP2R1B-containing complexes during the genesis of DDLPS. We have already identified one likely key target of PPP2R1B which may drive the development of DDLPS and is targetable with approved therapies. We will assess this pathway as a therapeutic target and uncover additional targets as part of our studies. In addition, the novel genetically engineered mouse model generated in this proposal will create a superior model of DDLPS that can be used to pre-clinically validate the therapeutic targets we identify in this project and will be useful for other groups to test their therapeutic strategies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310969
Entities
People
- Steven T Sizemore
Organizations
- Ohio State University
- United States Army