Past Research is Limited

Uterine and ovarian carcinosarcomas, also known as malignant mixed Müllerian tumors (MMMT) or sarcomatoid carcinoma, are a rare type of gynecologic malignancy which represent 1-2% of ovarian cancers and 3-4% of uterine cancers.1 Because it is so rare, minimal research has been performed to determine how the tumor develops, what causes the tumor to grow, and how it can best be treated. To better understand the disease, researchers and clinicians must acquire basic knowledge about the changes in the genetic code of the tumor. Some initial work has been performed to find the genetics changes that occurred in a small group of patients.2 These researchers found mutations in genes commonly found in cancer but also uncovered mutations that have not previously been described, highlighting the need for more research to fully understand this complex disease.

 

The GCS Project’s Research Goals

A major goal of the current research funded by the GCS Project is to further expand on the genetic characterization of carcinosarcoma to uncover new targets for therapy and learn about the genetic changes that underlie the disease. This will be accomplished using gene sequencing technology. As a first step, whole exome sequencing (WES) will be used to find mutations in the portion of tumor genes that translate into protein (the exome), which often drive tumor formation and growth. More information on whole exome sequencing can be found here and here. With this information, mutations in the tumor genome can be found, leading to the discovery of actionable molecular events. These are changes in the genome that result in mutated proteins capable of being specifically targeted by drugs. This concept is often described as “precision medicine,” which is nicely discussed here.

 

Another important aspect of a cancer to learn about are the epigenetic changes that occur to contribute for its formation, evolution, and response to therapies. Epigenetics is a new and rapidly developing field, concerned with the science by which our genetic code is regulated to influence almost every aspect of how a cell functions in the body and how its dysregulation can lead to disease. A good explanation of epigenetics and its relation with diseases like cancer can be found here. This will be initially explored through studies of the DNA methylation pattern of tumors. This technique highlights which genes are turned on and off in a cancer, giving a fingerprint of its gene expression.

 

Carcinosarcoma patients often have metastases, or spread of tumor to other parts of the body, which contribute significantly to disease burden and a patient’s prognosis. For that reason, we are also focusing on identifying the genetic changes that occur in the metastases to find more targets for therapies. Obtaining whole exome sequencing in both the primary tumor site (the location where the tumor started) and in the metastases will give a more complete picture of the disease and potential for therapies.

 

Immunotherapy is an emerging area of cancer care that utilizes the body’s immune system to fight cancer. You can find a good summary of the topic here. Currently, it is unclear whether immunotherapy can play a role in the treatment of carcinosarcoma, but our research will help to shed light on its potential application to the disease. We are supporting research to identify and characterize the immune cells that are present in tumors to see if they can be reprogrammed to fight the tumor. Also, the genetic studies we are supporting will also highlight if this cancer may be susceptible to certain immunotherapies.

 

The Research So Far

We have been very fortunate to partner with Dr. Michael Birrer, MD, PhD, director of cancer care at the University of Alabama and world expert on carcinosarcoma, to lead much of our research efforts. Our focus thus far has been on characterizing the genetic landscape of carcinosarcoma primary tumors and metastases. This has been done in collaboration with Dr. Priscilla Brastianos, MD of Massachusetts General Hospital, an expert on research regarding the genetics of metastases, and the Broad Institute, a world leader in cutting-edge genomics research. A large batch of tumor samples have been submitted and analyzed for:

 

  • Whole exome sequencing
  • DNA methylation
  • Tumor lymphocyte infiltrates

 

When combined, this data will provide the most comprehensive view of carcinosarcoma to date and help to compile critical knowledge on the development and evolution of this disease. Importantly, this work will also help clinicians to design and implement clinical trials to test available or new drugs for patients with carcinosarcoma.

 

References

  1. Pacaut C., Bourmaud A., Rivoirard R., . . . Merrouche, Y. (2015). Uterine and ovary carcinosarcomas: Outcome, prognosis factors, and adjuvant therapy. Am J Clin Oncol38(3), 272-277. doi:10.1097/COC.0b013e3182979b27.
  2. Zhao S., Bellone S., Lopez S., . . . Santin, A. D. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition. (2016). Proc Natl Acad Sci U S A, 113(43), 12238-12243. doi:10.1073/pnas.1614120113.