Langerhans Cell Histiocytosis (LCH) is a rare disease of white blood cells in which an overabundance of abnormal dendritic cells causes damage to the skin, bone and other organs. The disease affects both children and adults, with peak incidence occurring in children between 5 and 10 years old. The incidence in children is approximately five per million, and in adults, approximately half that.
Because LCH is rare, few physicians have experience in evaluating and treating it; patients and their families must often see physicians who do not give timely or proper evaluations and treatment.
For those affected by it, LCH is an exceptionally frightening and sometimes disabling experience. It can manifest in an alarming variety of ways: as a scaly rash that does not respond to treatment; as bone pain, headaches and severe leg pain; as severe gastrointestinal pain, vomiting, diarrhea, bleeding from the esophagus, weight loss and failure to thrive; as swelling and inflammation in the mouth, face, ears, scalp and lymph nodes; and even as mental deterioration. Although most patients with bone, skin or lymph node involvement survive, they can suffer multiple recurrences and face long-term disability.
The Research Challenge
Unlike other rare white blood cell disorders, such as acute myelogenous leukemia or lymphoma, the cell of origin and causes of LCH remain unknown. Despite clinical trials conducted by the Histiocyte Society, many fundamental questions remain unanswered regarding the biology and treatment of LCH. Few significant scientific studies have even attempted to identify basic biologic characteristics of LCH. Most importantly, there have been no systematic studies of LCH that provide the fundamental knowledge essential to developing effective targeted therapies. Additionally, we lack the knowledge necessary to identify patients who, at the time of diagnosis, might require more intensive treatments.
One of the most important challenges we face is identifying those genes responsible for the development, growth and dissemination of LCH. Over the past 20 years, only a limited number of genes have been studied for their role in LCH. Most of these studies used techniques that, in retrospect, could not have yielded accurate results.
Now, using newly available, advanced technologies, we have the capability of assessing gene expression in LCH in a highly sophisticated and comprehensive manner. Data, obtained over the past two years from ongoing studies of cell-specific expression of more than 45,000 genes, have significantly changed our view of the biology of LCH. We have identified new genes important to the pathogenesis of LCH that regulate lymphocyte movement and other molecular pathways not previously associated with LCH. We are poised to use this data to further understand the genetic abnormalities that cause LCH and thus to better identify effective targets for treatment.
Advances in our understanding of LCH will help us understand the biology and treatment of the other histiocytic diseases.
The Histocytosis Research Program
Despite decades of research, the origin of LCH remains speculative, and survival of patients with severe disease remains poor. The overall goal of the LCH Research Program at Texas Children’s Cancer Center is to comprehensively identify essential genes critical to the growth and development of LCH. By knowing the genes, we can understand the key proteins that regulate cell function and the pathways they control. This knowledge will lead to a complete understanding of how LCH lesions are formed and how they progress and, ultimately, to better treatments and a cure for this disease.
Our LCH Research Program has four main areas of endeavor:
- Comprehensive Analysis of Cell-Specific Gene Expression in LCH Tumors
This project is the core of our research program. It is based on the idea that we cannot improve treatment of patients with LCH until we understand the fundamental nature of the cells that comprise LCH lesions. These lesions can arise in almost any organ system, and their severity can range from a rash to systemic disease that obstinately resists chemotherapy.
Data from our cell-specific microarray experiments do not support the current concept that LCH arises from clonal proliferation of activated-immature Langerhans’ cells (LCs) from the skin. We propose an alternative hypothesis that LCH tumors arise from pathologic myeloid dendritic cells that affect lymphocyte activation, migration and accumulation.
- Developing a Comprehensive Genomic Database
We also plan to develop a comprehensive genomic database for LCH, JXG, RDD, ECD, and malignant histiocytosis that will be used by Texas Children’s investigators and also by collaborators from various institutions in the United States and around the world. This genomic database will help identify novel therapeutic targets based on the genetic changes unique to histiocytic diseases.
As the largest LCH clinic in the world, and as the tumor bank for a consortium of LCH clinics performing basic biologic studies in the histiocytic diseases, Texas Children’s Cancer Center is the logical choice to lead this project. We intend to recruit an additional investigator to help us more rapidly achieve our research goals.
- Developing Unique Models for Preclinical Drug Screening
A significant obstacle in developing novel therapies for LCH has been the lack of a preclinical model that accurately mimics LCH in humans to predict clinical response. The large number of samples acquired by our laboratory now makes it possible to attempt development cell culture and animal models that may be used to study disease progression and test therapies.
- Implementing High Throughout Therapeutic Drug Validation Strategies
Once we have identified potential drug targets using the gene profiling studies described above, we will perform high-throughput studies to validate these possible targets. For this crucial step, we have the special advantage of being able to use highly sophisticated technologies now available to us through the recent establishment of the John S. Dunn Gulf Coast Consortium for Chemical Genomics. Using this state-of-the-art facility, we propose to use siRNA approaches to independently validate the function of the candidate genes and pathways by either targeted inactivation or by using whole genome siRNA libraries.
We will also use the chemical genomics approach as part of the target validation process. The compounds identified at this stage could be used both as chemical probes to further dissect the pathways and as potential lead compounds in the subsequent drug development phase of the project.