Therapeutic Targeting of the ATAD2 Oncogene in Ovarian Cancer
Abstract
Ovarian cancer is the fifth leading cause of cancer deaths in women and the most deadly gynecological disease. Most ovarian cancers are not detected until they have metastasized. Standard treatment measures include surgical debulking and chemotherapy, including carboplatin and paclitaxel, while recurrent ovarian cancer is often treated with doxorubicin. Both carboplatin and doxorubicin are DNA-damaging agents, while paclitaxel inhibits cell division. The development of resistance to standard chemotherapy in women with recurrent disease significantly increases patient mortality. Increased expression of proteins involved in DNA repair mechanisms in recurrent tumors helps to lead to enhanced drug resistance of tumors. The need for novel therapies that target important genes and proteins involved in ovarian cancer development, metastasis and drug resistance is paramount in finding new ways to treat ovarian cancer in a more effective, less toxic manner. Oncogene X (identified within the application) is a driver of ovarian cancer development, progression and, likely, drug resistance. Oncogene X is expressed at low levels in most normal tissues, except for the testis and embryonic stem cells, but is overexpressed in cancer tissue. Oncogene X is overexpressed in 43% of serous ovarian cancers and its overexpression is associated with decreased patient survival as well as increased tumor stage, metastasis to the omentum, increased ascites formation and increased CA-125 levels. Oncogene X also has a potential role in ovarian cancer drug resistance. It has been shown in breast cancer cells that Oncogene X protein levels were increased after treatment with carboplatin or doxorubicin, and was responsible for increased DNA repair due to enhanced expression of BRCA1. Furthermore, Oncogene X knockdown enhanced sensitivity to these chemotherapeutic agents. In a gastric cancer model, Oncogene X was identified as one of four genes upregulated during the development of paclitaxel resistance. This suggests two things: that Oncogene X expression is increased during ovarian cancer patient treatment and that Oncogene X is involved in the acquisition of drug resistance. While Oncogene X is recognized as a driver of ovarian cancer, it is not as druggable a target as other proteins in its class due to a less well-defined enzymatic domain and there are no approved therapies that target Oncogene X. We have discovered that Oncogene X protein is naturally targeted for degradation in cells by a protein called UBR5. UBR5 is involved in ovarian cancer progression, but has been shown to play both tumor-promoting and tumor-inhibiting functions. We propose to develop a new drug, called a PROTAC (PROteolysis TArgeting Chimera), that will get inside the ovarian tumor cells and enhance the interaction between UBR5 and Oncogene X, leading to the enhanced destruction of Oncogene X. PROTACs are a new type of drug that have had success in clinical trials targeting other proteins in other diseases. Our PROTAC is a peptide that contains a small part of each protein where they bind to each other, linked together, thereby attracting the two proteins together with the PROTAC in the middle. We have identified how the two proteins interact and used molecular modeling to identify which amino acids are involved in the interaction. We have also done molecular modeling to the whole PROTAC that will allow the two protein parts to keep in their native structure so that they can be recognized in cells. We have also added cell-penetration sequences to allow the peptides to get into cells and tumors. We have candidate PROTACs designed and ready to be synthesized and tested. We will first test them in cells in culture for their ability to get into cancer cells and bring about Oncogene X destruction and inhibition of its functions. We will then test them in tumors generated in mice to determine whether they can inhibit tumor growth and enhance chemotherapy
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210843
Entities
People
- Scott Eblen
Organizations
- Medical University of South Carolina
- United States Army