Identifying Novel Compounds for Treatment of pdChordoma and Other SMARCB1-Deficient Rare Tumors
Abstract
This proposal focuses on a group of extremely rare tumors with a common driver of tumor growth - loss of the SMARCB1 gene, also known as INI1. These tumors include poorly differentiated chordoma, atypical teratoid/rhabdoid tumor, epithelioid sarcoma, epithelioid malignant nerve sheath tumor, epithelioid schwannoma, extrarenal and renal rhabdoid tumors, extraskeletal myxoid chondrosarcoma, myoepithelial carcinoma, ossifying fibromyxoid tumor, and renal medullary carcinoma. These tumors are very rare, occurring in no more than 1 in 1 million people each year, many occur in young children, and most have very poor survival. None have effective medical therapies available. Our National Cancer Institute group runs a natural history study at the National Institutes of Health Clinical Center for very rare solid tumors in children, teens, and adults. This study follows patients with different rare tumors to see what their challenges are and how they respond to the treatments they receive. We also collect tumor tissue to look at what genes are mutated in tumors and to make new research tools. Through a partnership with the Chordoma Foundation, a chordoma advocacy group, we are learning about patients with poorly differentiated chordoma as well as conventional chordoma that doesn’t lose SMARCB1. By interacting with participants in our study, we are gaining expertise in theses diseases. We have opened a treatment trial for patients with mutations in the SMARCB1 gene that can test drugs in the different tumor types with SMARC1 loss listed above. In this proposal, we are testing our hypothesis that there are drugs that will treat tumors with SMARCB1 loss even if the tumors are different types. Oregon Health Sciences University has technology to test thousands of drugs on tumor cells. Through a collaboration between the National Cancer Institute and Oregon Health Sciences University, we will address all three of the Focus Areas for the Rare Cancer Research Program. First, we will make new research models by putting a fluorescent gene into chordoma cells. By making the cell nucleus glow, we can more easily count cells using machines to measure fluorescent light. This can make our drug screens more exact and lets us look at whether drugs stop cells from dividing or kills them. We will also make chordoma cells that either turn SMARCB1 on or off in tumor cells that still have it. These cells can be used by researchers interested in studying SMARCB1 function. Because these cells can be used for many different types of experiments, we will share them with researchers through the Chordoma Foundation biobank. Secondly, we will use the chordoma cells that turn on or off SMARCB1 to learn how loss of SMARCB1 leads to tumor formation. SMARCB1 is part of a protein complex that sits on DNA and changes which genes are expressed. We will look at how changing SMARCB1 expression changes the DNA and which genes are turned on or off. There is also evidence that when SMARCB1 is lost, there are changes in genes that control how cells get nutrients they need to grow (called nutrient transporters). If we can understand this process, we may be able to starve tumor cells so they can’t grow. Because the biology of poorly differentiated chordoma hasn t been studied, what we learn about how loss of SMARCB1 changes molecular pathways will help us develop new ideas for treating poorly differentiated chordoma. Finally, we will use our new cell lines to test which drugs can block cell growth or cause cell death. The team at Oregon Health Sciences University will test both U.S. Food and Drug Administration (FDA)-approved drugs for potential drug repurposing as well as compounds that have not yet been developed into drugs but may have specific activity against tumors that have lost SMARCB1. We will take drugs and other compounds that inhibit chordoma cells with SMARCB1 loss and test them in mouse models of chordoma, as well as other type o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310796
Entities
People
- Sanjay Malhotra
Organizations
- Oregon Health & Science University
- United States Army