Targeting at MAN2A1-FER Fusion Gene Product
Abstract
The clinical outcomes of prostate cancer are highly variable. Over 80% of prostate cancer patients will not develop metastasis or suffer from prostate cancer-related death. A small proportion of prostate cancer patients developed life-threatening metastasis, clinical relapse, and actually died from prostate cancer. The current treatment modalities of prostate cancer include radical prostatectomy, radiation therapy, hormonal therapy, or watchful waiting. Relatively young and healthy patients generally choose to undergo prostatectomy, while older patients choose radiation therapy. When prostate cancer proves relapsing or metastatic, additional anti-androgen treatment or chemotherapy will be used to combat the cancer. Recently, we found that prostate cancer cells create a new set of fusion genes that are not present in normal individual. When any of these fusion genes are positive, patients have a less than 10% chance to survive 5 years without prostate cancer coming back to other organs, even after thorough surgical resection of the cancer was done. One of these fusion genes is between mannosidase class 2A member 1 (MAN2A1) and FER. The former is enzyme adding sugar residue to protein so that the protein can be recognized by ligand when it sticks out of cell surface. The latter is a tyrosine kinase that adds phosphate to proteins so that proteins can be activated to stimulate cell growth. Normally, FER is inactive and dormant because there is an inhibitory domain to block the enzyme. However, in the fusion protein between MAN2A1 and FER, the inhibitory domain of FER is lost. FER is active all the time. MAN2A1 drags FER to a room where sugar was added to the protein. Since MAN2A1 also loses a critical domain such that it does not add sugar to proteins anymore. Instead, it adds phosphate to proteins. This leads to activation all the proteins in the room. The cells go crazy to proliferate and to invade. In this study, we will try to find out which protein in the room was added to a phosphate group and how the addition of phosphate activates the protein and leads to cancerous changes. Second, we will develop two new treatments for prostate cancer positive for this fusion gene. One of treatment targets at the unique DNA sequence that was created by DNA rearrangement. Based on our preliminary data, the treatment is highly effective and has minimal side effects on mice and cultured cells. Another treatment is targeting the function of the fusion protein such that it blocks the fusion protein from adding phosphate to other proteins and thus stops its bad behavior.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610364
Entities
People
- Jianhua Luo
Organizations
- United States Army
- University of Pittsburgh