Partnering with Patients to Create a Rare Soft Tissue Sarcoma Functional Genomics Platform as a Community Resource
Abstract
For decades, clinicians have treated most cancers with highly toxic therapies, with the hope that these would kill rapidly dividing tumor cells and spare normal ones. Unfortunately, few such therapies produced durable benefits. Many cancers were not affected at all, and most of these drugs led to serious side effects, since these drugs also killed rapidly dividing normal cells in the body. At the time, we simply did not understand what the key vulnerabilities, or dependencies, of each type of cancer were. If this were known, drug companies could develop smarter drugs that targeted these distinct dependencies. After the sequencing of the human genome in 2001, scientists began analyzing the genomes of many types of cancer in the hope that the genetic changes that caused cancer would lead to the straightforward enumeration of these dependencies. For certain common cancers, such as lung cancer and skin cancer, this hypothesis was accurate. New drugs, including both targeted therapies that hit the cancer cells or immunotherapies that re-activate the immune system, have been developed that have led to profound, and in some cases long-lasting, responses for specific patient populations whose tumors harbor specific molecular features, such as a key mutation. However, for the vast majority of rare cancers, including the rare types of sarcomas that we are proposing to study in this proposal, this hypothesis did not fully bear fruit. Thanks to the genomic revolution, we now have a reasonably good understanding of the biological basis of which genes and cellular pathways get disrupted to cause each type of rare cancer. However, these insights have only helped less than 5% of patients with rare tumors. We need to understand how these genetic changes lead to dependencies, so we can generate drugs that hit them and keep them at bay. In this project, we are proposing to do just this by creating a community resource that scientists everywhere can benefit from. We will grow cells from rare tumors, such as rare soft tissue sarcomas, in the laboratory, and by creating a type of model of each tumor called a cell line, or an organoid. Once these models grow, we can test candidate therapies against them and also use a new technology called CRISPR, which can knockout each gene, one at a time, to tell us which targets lead to cell death. This will help point drug companies in the right direction. To begin, we will invite patients anywhere in the United States or Canada who have recently been diagnosed with one of three types of cancer (desmoid tumor, clear cell sarcoma, or leiomyosarcoma) to provide consent for participation in our project via an online interface. This will enable us to send a sample kit to their clinician that can be returned via overnight shipping, so we can obtain the living tumor sample in our laboratory at the Broad Institute. We will grow many samples in our laboratory and use these to systematically find their dependencies. Finally, we will share all of our cell models and dependency data freely with the international scientific community pre-publication, without restriction. If we are able to succeed for these three rare cancers, we believe we can expand this research program to eventually include nearly every type of rare cancer in the decade ahead, so many future patients will stand to benefit.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110934
Entities
People
- Jesse S Boehm
Organizations
- Massachusetts Institute of Technology
- United States Army