Dissecting the Biology and Therapeutic Vulnerabilities of RB1-Mutant Osteosarcoma Using RB iPSCs
Abstract
The Principal Investigator plans to take advantage of the financial stability and support from this Horizon Award to pursue a highly promising project in defining RB1 mutation-derived oncogenic signature in osteosarcoma and develop a directed therapeutic strategy targeting RB1-mutant osteosarcoma. Through this Horizon Award, I expect to develop into an independent cancer researcher by the training from my mentor through this project. Since I joined Dr. Dung-Fang Lee’s lab in March 2017, I have acquired the necessary skills of induced pluripotent stem cell (iPSC) reprogramming and culture, osteoblast differentiation, and CRISPR/Cas9 technologies. I am very skilled in molecular biology techniques such as flow cytometry, western blotting, co-immunoprecipitation (Co-IP), immunofluorescent staining, and molecular cloning. Currently I have expanded my research skills with next-generation sequencing technologies (e.g., RNA-seq and ChIP-seq) and their related mapping and analyses. Those techniques are essential to my proposed project. Cancer starts when cells in the body begin to grow out of control. Cells in nearly any part of the body can become cancer, and then spread to other areas of the body. Osteosarcoma (also called osteogenic sarcoma) is the most common type of cancer that forms in the bones. Osteosarcoma comprises almost 60% of the common subtypes of bone sarcoma. RB1 missense mutations and deletions are found in more than 30% of clinical osteosarcoma specimens, highlighting the crucial role of RB1 in preventing bone malignancy. Patients with hereditary retinoblastoma (RB), an inherited autosomal dominant cancer disorder, have more than 400-fold increased incidence of osteosarcoma, suggesting a strong mechanistic link between RB1 loss and osteosarcomagenesis. Although mice offer many advantages when conducting cancer research, unlike humans, Rb1 knockout mice do not develop OS, suggesting the urgent requirement for alternative disease models to understand how RB1 mutation leads to osteosarcomagenesis. Taking advantage of state-of-the-art induced pluripotent stem cells (iPSCs) and genome editing technologies such as CRISPR/Cas9 methodologies, we generated human RB iPSCs. iPSCs are stem cells derived from skin cells that can be made into any cell in the body. We plan to apply these RB iPSCs to elucidate the pathological mechanisms of osteosarcomagenesis caused by RB1 mutation. Meanwhile, we will evaluate the therapeutic potential of inhibitor (Thiostrepton) to treat RB1-mutant osteosarcoma. This primary exploration in the lab is the first step to explore the potential of these inhibitors for clinical trials in the future. We fully expect that the project will be completed in the 2-year award period. We expect these studies will allow us to gain a more in-depth understanding of how RB1 mutations contribute to osteosarcomagenesis. RB1 mutations have been identified in a spectrum of human cancers. We expect our research outcomes will not only benefit osteosarcoma patients, but also other cancer patients, such as those with breast cancer, bladder cancer, and small cell lung cancer. Since osteosarcoma occurs not only in the children, but also young adults and older adults, our research will definitely benefit all active duty military Service members, their families, Veterans, and other military beneficiaries and will improve qualities of life for patients and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010389
Entities
People
- Dandan Zhu
Organizations
- United States Army
- University of Texas Health Science Center at Houston