Neuroblastoma is the third most common childhood cancer. Unfortunately, despite intensive treatment, two-thirds of children with advanced neuroblastoma succumb to their disease. New treatment options must be developed to improve outcomes in this devastating disease. This requires a better understanding of how neuroblastoma cells survive in the face of these intensive therapies. N-Myc is a member of a family of proto-oncogenes (genes capable of leading to cancer development) implicated as a cause of several cancers. N-Myc plays a central role in the aggressiveness of neuroblastoma tumors. Children whose neuroblastoma tumors have extra copies of the N-Myc gene (N-Myc amplification) fare worse than children whose tumors have the normal number of N-Myc genes. However, it is unknown why extra N-Myc leads to poor outcomes. Mxi1 is a protein related to the Myc family, however, it counteracts the ability of N-Myc to cause cell growth. Mxi0 is a similar protein, but it does not inhibit N-Myc like Mxi1. In this proposal, we will test the hypothesis that the balance of Mxi1 and Mxi0 expression is important for maintaining normal growth, and that N-Myc alters this balance, leading to treatment resistance. To accomplish this, we developed a new kind of mouse which has its Mxi1 or Mxi0 genes removed. In this project, we will examine the impact of decreasing Mxi1 or Mxi0 expression on neuroblastoma tumor formation and response to treatment, with the overall goal of finding a mechanism to bypass the effects of N-Myc and improve the outcomes of children with neuroblastoma.
Rhabdomyosarcoma is a connective tissue cancer with features of skeletal muscle, and the most common soft tissue cancer of childhood and adolescence. While most children with the embryonal variant of rhabdomyosarcoma are cured, there is a sub-group of children with high-risk features, making their chance of survival less than one in three. One hypothesis underlying these high-risk features is that there are rhabdomyosarcoma stem cells that can persist in the body despite current standard therapy. A goal of our research laboratory is to identify the cellular pathways that contribute to this persistence of rhabdomyosarcoma stem cells. Over the past several years we have observed that some cellular pathways active during normal skeletal muscle development have been hijacked by embryonal rhabdomyosarcoma cells. We even think that these development pathways communicate with one another to support and reinforce rhabdomyosarcoma stem cells. Our aim in this project is to understand how these cellular pathways communicate with one another, whether they can be inhibited by gene manipulations or pharmacologic agents, then test combinations of these treatments in rhabdomyosarcoma cells in culture and in laboratory mice. We hope to someday translate these findings to clinical trials, opening the door to new treatments for children with this disease.
Pancreatic cancer is a very aggressive disease. It is the 4th leading cause of cancer deaths in the USA. Only 6% of patients who can undergo surgery will survive past five years. Late diagnosis and lack of good treatment options are some of the reasons for this outcome. Recent progress in cancer immune therapy showed effect in cancers such as relapsed leukemia and metastatic melanoma. Unfortunately, immune therapy was not effective in patients with pancreatic cancer. One explanation for this result is that pancreatic cancer blocks immune responses against cancer. Thus, understanding how cancer promotes immune suppression is vital to our ability to treat this deadly disease. Our initial work has revealed that B cells promote growth of pancreatic cancer. However, it is not clear how B cells promote cancer growth, and how targeting these cells can benefit patients. We propose to understand how B cells function in pancreatic cancer. The goal of this research project is to find new targets that can block immune suppression in pancreatic cancer. Using both mouse models of pancreatic cancer and patient samples, we hope to identify B cell based targets in pancreatic cancer. We ultimately hope to translate our findings into effective therapies that may also work with existing immune therapy treatments.
Funded by the Stuart Scott Memorial Cancer Research Fund
The human gut contains trillions of bacteria. In fact, there are more bacteria in the gut than there are cells of the human body. To protect the body from gut bacteria, immune cells constantly battle with gut bacteria. This battle occurs inside every person but in some, this battle can cause tumors to grow. Tumors often grow in the colon and this type of cancer, called colorectal cancer, is the location where most gut bacteria dwell. How can the battle with gut bacteria cause colon tumors to grow? To answer this question we must first find out which immune cells control and design the battle plan. We think that the battle plan against gut bacteria is designed by a special immune cell, the dendritic cell. There are many different types of dendritic cells and we found that each has a different battle plan. We want to find out which dendritic cells enter colon tumors, which dendritic cell’s battle plan cause tumors to grow, and which battle plan may help fight the tumor. When colon tumors grow we think that gut bacteria force the dendritic cell to make proteins that shield the tumor from attack and help the tumor to grow. We are testing these ideas by changing how dendritic cells respond to gut bacteria, to find out how this changes the battle plan, and to discover how this impacts colon cancer.
Following surgery and treatment, breast cancer patients live with a high risk of developing a relapse. When tumors do recur, especially at distant sites, they are often incurable. Therefore, it is important to develop new approaches for preventing breast cancer relapse. The period between treatment of the primary tumor and the formation of a recurrent tumor is called dormancy. During this stage there are cancer cells somewhere in the patient’s body that are dormant, or not actively growing. These dormant cells are the source from which recurrences must arise. Understanding how these cells survive for long periods and designing ways to kill them is important for preventing recurrences.
Dormant tumors cannot be detected by current imaging methods, and so studying these cells in patients is difficult. We have developed mouse models that allow us to study dormancy and recurrence. Using these models, we have found that dormant tumors have a unique type of metabolism. In order to translate this finding to a potential therapy it is important to know more about this metabolism works, and whether dormant cells can be killed by targeting this metabolism. In this proposal we will use the mouse models we developed to address these questions. Once we understand more about dormant cell metabolism, we may be able to design drugs that can kill dormant cells and prevent breast cancer relapse.
