Nita Ahuja, M.D., Sarcoma Program, Director and Surgical Oncologist
Sarcomas are rare tumors with 50 different subtypes. To understand sarcomas better, we have been developing unique patient-derived tumors that can help us understand these tumors and develop better therapies. Our laboratory has been at the forefront in the understanding of epigenetic changes in cancers. Epigenetic modifications represent changes to the folding of the genes without affecting its DNA code so that the gene function is lost. Epigenetic modifications are commonly used by cancers to become invasive and then develop resistance to standard therapies. These epigenetic modifications are reversible, representing exciting potential to treat cancers without chemotherapy. Our laboratory has been studying the utility of epigenetic therapy in the treatment of sarcomas.
Primary Investigator:Nita Ahuja (Surgical Oncology) Title:Understanding the role of radiation therapy in treatment of liposarcomas, including intraoperative radiation therapy
Liposarcomas are one of the most common tumors seen in the retroperitoneum. Unfortunately, these tumors are often quite large (20-50cm) by the time they are discovered. Surgical removal of these tumors can be difficult since they often involve major blood vessels, nerves and digestive organs. Moreover, these tumors often recur (or come back) locally from where they were originally removed. We are studying our institutional experience in treatment of retroperitoneal sarcomas including role of intraoperative radiation therapy using well annotated databases.
Primary Investigators:Laura M. Fayad (MRI) and Rathan Subramanium (PET) Co-investigator: Elizabeth Montgomery (Pathology) Title: Multiparametric quantitative imaging of neoadjuvant therapy response in malignant soft tissue sarcomas
Soft tissue sarcomas are often treated with a combination of radiation and chemotherapy before surgery is performed to remove the tumor, with the goal of shrinking the tumor, killing the tumor cells and making the surgical removal easier. Ideally, we would like to know how a soft tissue sarcoma responds to radiation or chemotherapy before surgery: If we are able to determine that the chemotherapy is not working adequately to kill the tumor cells, we can change the treatment regimen before the patient goes on to have the tumor removed. Unfortunately, at the present time, we do not have good methods of determining treatment response before surgery; we most accurately determine whether a tumor responded to treatment by the amount of dead tissue that is identified after the tumor is taken out completely, thereby missing an opportunity to change the chemotherapy before surgery.
Through this research project, we will use advanced metabolic imaging techniques with MRI and PET scanning to determine the degree of response to therapy before surgery is performed to remove the sarcoma. We have found, through our preliminary research findings, that a specific metabolic marker picked up by MRI and PET (namely, Choline) can show important metabolic changes in a sarcoma after its cells are successfully treated by chemotherapy. We believe that metabolic imaging with MRI and PET will prove accurate for the prediction of response to therapy and provide valuable information for planning treatment and determining prognosis. These cutting edge imaging techniques have been developed and optimized at Johns Hopkins by members of the Department of Radiology and the Hopkins Sarcoma Program.
Dr. Loeb has active laboratory and clinical research efforts. In the laboratory, Dr. Loeb studies a gene called WT1. High levels of WT1 convey a poor prognosis for patients with osteosarcoma and soft tissue sarcomas. Dr. Loeb's laboratory has shown that WT1 expression is regulated, in part, by the amount of oxygen in a tumor, and that low oxygen levels lead to higher WT1 expression, which in turn leads to an increase in the ability of tumor cells to cause new blood vessels to form. The laboratory is studying both the mechanism by which oxygen levels control WT1 expression and the way WT1 regulates blood vessel growth. In a related project, Dr. Loeb’s laboratory is working to identify, characterize, and therapeutically target Ewing sarcoma stem cells. Cancer stem cells are thought to be inherently resistant to chemotherapy and are thought to cause most cases of refractory or relapsed disease. In collaboration with the laboratory of Dr. Jonathan Powell, Dr. Loeb has identified one pathway, called the mTOR signaling pathway, that may be important for sarcoma stem cells to resist chemotherapy. This finding prompted the initiation of a clinical trial, led by Dr. Loeb, to test the combination of Doxil, a standard chemotherapy drug, and Temsirolimus, an inhibitor of the mTOR signaling pathway, in patients with high risk sarcomas. Future clinical trials, already being planned, will test additional means by which the inherent chemoresistance of these key cells can be overcome, hopefully leading to significant improvements in the survival of patients with recurrent or refractory sarcomas.
Dr. Frassica is a radiation oncologist at Central Maryland Radiation Oncology, a joint collaboration between Johns Hopkins and the University of Maryland Medical Center located in Columbia, Md. Her primary interests are musculoskeletal, breast and colorectal cancers. The center participates in clinical trials under the auspices of the Radiation Therapy Oncology Group, the Eastern Cooperative Oncology Group, the American College of Surgeons Oncology Group, and The Johns Hopkins University.
Dr. Meyer’s research focuses on investigating food pathways that drive sarcomas to grow and divide. Sarcomas use nutrition from common sources such as sugars and proteins to fuel their growth. These common energy sources feed into pathways inside cells that can be blocked with various drugs. He uses both mouse models and cell lines in collaboration with Drs. Loeb and Jonathan Powell to test these drugs and attack these pathways.
One set of drugs targets the mTOR pathway, which drives much of the basic cell nutrition pathways. Research in Dr. Powell’s lab identified a promising combination of mTOR blockade for pancreatic cancer that is now being tested in mouse sarcomas. Given the multiple types of sarcomas, attacking these basic pathways might provide a successful strategy to increase treatment responses in a number of types of them. They are working to bring these combinations from the laboratory to clinical trials.
Dr. Terezakis' research is focused on improving the treatment of children with cancer of several specific types including, rhabdomyosarcoma, other soft tissue sarcomas, Hodgkin lymphoma, and pediatric CNS tumors. Her specific aims are to study how to most effectively utilize radiation therapy in the management of pediatric tumors with regard to the specific issues of indications, timing, sequence with chemotherapy, treatment volume, and dose intensity. Dr. Terezakis also has a specific research interest in assessing the late effects of cranial radiotherapy in brain tumor patients and using novel radiation techniques to treat radioresistant sarcomas.