# Functional Genomics and Precision Therapy Testing for Langerhans Cell Histiocytosis

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2020 · $45,520

## Abstract

The long-term goal of this project is to define the mechanisms that underlie pathogenesis of 
Langerhans cell histiocytosis (LCH). Specifically, I will investigate the role of genomic 
alterations and cell(s)-of-origin so that future therapies can be precisely tailored to molecular 
disease targets in each patient. Historically, the cellular and molecular causes of LCH have 
remained enigmatic, with diverse clinical presentations ranging from simple, self-resolving 
 skin lesions to disseminated multi-organ involvement that is potentially fatal. Thus, 
treatment for the disease has remained empiric, based on clinical risk assessment—from resection of 
single skin lesions to systemic chemotherapy. More than half of patients remain 
unresponsive to front-line vinblastine/prednisone chemotherapy and often acquire permanent 
disease morbidities, such as diabetes insipidus. The first breakthrough in molecular 
disease pathogenesis, and a potential molecular target for therapy, (BRAF-V600E) was 
reported in 2010. Subsequent studies have provided more genomic, cellular and molecular evidence to 
support the hypothesis that LCH pathogenesis is the result of altered MAPK pathway activation at 
various stages of differentiation along the myeloid dendritic cell lineage. In additional to BRAF- 
V600E, alternatie mutually exclusive mutations have been discovered in BRAF and MAP2K1, accounting 
for
~90% of all LCH cases. This research is intended to define the pathogenesis of LCH at the genomic, 
cellular and molecular levels in order to promote design of therapies that are precisely directed 
at molecular targets, in effort to improve patient clinical outcomes over current 
front-line chemotherapeutics. We hypothesize that varied genomic alterations in LCH lesions 
activate MAPK pathway signaling in myeloid lineage origin cells to drive disease pathogenesis, and 
targeted therapy can block this signaling in pre-clinical LCH models. In Specific Aim 1, we plan to 
utilize an integrated genomic and transcriptomic approach to identify the genomic alterations in 
each LCH lesion, as well as the relative frequencies of such alterations. We will use clinical 
information to determine any statistically significant associations with LCH genomic 
alterations. Additionally, we will determine the hematopoietic lineages in which 
non-BRAF-V600E genome alterations occur. In Specific Aim 2, we will evaluate the impact of LCH 
genomic alterations on MAPK pathway activation, their sensitivity to varied MAPK pathway inhibitors 
and the gene expression profiles associated with specific alterations.

## Key facts

- **NIH application ID:** 9925217
- **Project number:** 5F31CA228360-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Thomas M. Burke
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-05-03 → 2021-05-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925217

## Citation

> US National Institutes of Health, RePORTER application 9925217, Functional Genomics and Precision Therapy Testing for Langerhans Cell Histiocytosis (5F31CA228360-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9925217. Licensed CC0.

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