Systematic Approaches to Dissect Driver Pathways in Small Cell Carcinoma of the Ovary, Hypercalcemic Type
Abstract
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but often deadly form of ovarian cancer. Despite its rarity, it is important to study SCCOHT because it affects young women (the average age at diagnosis is 24 years) and even some infants, but current treatments often fail to cure the patient. Usually, SCCOHT gives no warning signs and has a poor outcome; at best, only about a third of those diagnosed survive the condition. It was first identified in the 1970s, but it was not until 2014 that the underlying genetic basis of this cancer was discovered. Remarkably, it appears that almost all cases of SCCOHT share one genetic problem: the tumor cells lack a protein called SMARCA4. SMARCA4 regulates expression of many important cellular genes and is necessary to the normal function of human cells. The SMARCA4 mutations found in SCCOHT result in a complete absence of SMARCA4 protein in tumor cells. What is even more remarkable is that apart from SMARCA4 mutations, these tumors seem to contain virtually no other genetic alterations. This is in complete contrast to most types of ovarian cancer, which often contain hundreds of different mutations and many structural rearrangements of chromosomes, which makes it very difficult to know which mutations or rearrangements may be the cause of that particular cancer. Since mutations in SMARCA4 appear to be the only consistent genetic change in SCCOHT tumors, it is reasonable to assume they cause the development of the disease. Now that we have a genetic cause for these aggressive tumors, the next step is to use that information to find a better way to treat the young women and girls who develop SCCOHT. The goal of our proposal is to identify drugs that will only kill SCCOHT cancer cells, which have no SMARCA4 protein, but spare the normal cells that still have SMARCA4 present. We know from advances in treatment for other cancer types that tumors with very specific genetic lesions are very susceptible to this approach, so we are confident this should work for SCCOHT as well. The challenge is, How do we identify the right specific drugs? We could use different criteria to choose drugs to test individually, but the most efficient way to succeed is to approach this systematically. Using genetic engineering technology that allows us to turn off specific genes in cells, we will look for the ones that, when turned off, kill only the SCCOHT tumor cells. Once such genes are identified, we will use large collections of chemical compounds specifically designed for such screening tests (these contain drugs already employed in the clinic as well as other chemical compounds) to see if we can turn these genes off by chemical treatment and prevent the cancer cells from growing. We will initially focus on genes that already have treatments attached to them (i.e., where the drug is already being sold and is known to be safe to use for treatment) because these candidates will have the highest chance to translate into clinical studies to treat SCCOHT patients. To confirm our findings, we will use model systems, including cell culture, mouse models of cancer and, very importantly, tumor samples from SCCOHT patients. Thus far, we have available to us all the known SCCOHT tumor cell lines, as well as the largest collection of SCCOHT tumor samples in the world. We are still collecting these rare but essential reagents to improve our chances to find effective treatments for this aggressive disease. Importantly, our findings may also be extended to other cancer types, such as the rare childhood brain cancer known as atypical teratoid/rhabdoid tumor (AT/RT), because our preliminary work suggests that AT/RTs are similar to SCCOHT tumors. Not only do SCCOHT resemble AT/RTs when looking down the microscope, but in addition they share mutations in similar genes, the SMARC family of genes. Our very exciting preliminary data suggest that the same sets of genes are turned of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510497
Entities
People
- William David Foulkes
Organizations
- Jewish General Hospital
- United States Army