Project title: Molecular Events Underlying Development and Progression of DIPNECH
Dan Merrick, MD University of Colorado Anschutz Medical Campus
- Status: Active
- Year(s): 2021
- Grant Type: Investigator
- Research Type: Translational
- Primary Tumor Site: Lung
- Area of Inquiry: Carcinoid tumors of the lung
Using DNA sequencing, Merrick and his team will search for the underlying mechanism responsible for the development of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, or DIPNECH. The team will also assess invasive carcinoid tumors to identify those factors that drive NET development in DIPNECH.
What question will the researchers try to answer?
Dr. Merrick will assess the mutational status of premalignant and invasive neuroendocrine lung lesions to identify a potential driver mutation that underlies the development of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). DIPNECH is characterized by the formation of numerous premalignant neuroendocrine cell hyperplastic lesions throughout the airways of affected patients. These lesions can lead to clinically incapacitating airway obstruction and are almost always accompanied by a progression to invasive carcinoid tumors at one or more sites of the premalignant lesions. Given the characteristic presentation and similar pathogenesis underlying progression of other airway-related premalignant lesions to invasive cancer, they are investigating whether DIPNECH results from a somatic (non-hereditary) mutation that affects pulmonary neuroendocrine cells and leads to the proliferation and wide dispersal within the bronchial epithelium. He and his team will micro-dissect premalignant and invasive neuroendocrine lesional tissue from patients who have DIPNECH and use whole-exome sequencing to search for underlying driver mutations that may cause this disease.
Why is this important?
DIPNECH is associated with significant morbidity and mortality, with the latter related to both malignancy and airway obstruction-related complications. While carcinoid tumors are a nearly ubiquitous complication of DIPNECH, they also occur as sporadic lung tumors in patients without DIPNECH. Identifying an underlying driver mutation in DIPNECH would provide a key diagnostic tool that could be used to guide surveillance and care in patients who have DIPNECH. Additionally, driver mutations in neoplastic disease provide targets for personalized therapy. Such agents for the prevention of carcinoid tumor development and treatment of invasive carcinoid tumors could significantly impact morbidity and mortality of patients who have DIPNECH. These therapies may also prevent the development of life-threatening respiratory failure that can only be treated by drastic measures such as lung transplant, which is successful in less than half of cases.
What will researchers do?
At the University of Colorado, Dr. Merrick has documented nearly 60 cases of patients who have been diagnosed with or have features that point to DIPNECH. His team will review these cases to identify premalignant and invasive neuroendocrine lesions for analysis as well as to catalog the presence of characteristic clinical and radiologic features of the disease so they can separate and compare sporadic and DIPNECH-associated lesions. They will then micro-dissect and extract the DNA from pre-malignant neuroendocrine lesions and associated invasive carcinoid tumors. they will use the DNA to perform whole-exome sequencing, providing a comprehensive assessment of all protein-coding DNA to discover an underlying mutational driver event(s) in patients who have DIPNECH.
How might this improve the treatment of NETs?
Identifying a driver mutation for DIPNECH would point to the key biological alterations that lead to the development of this disease. A driver gene itself may likely be the key mediator of the neoplastic changes and provide a focus for developing targeted therapies. Uncovering the biological pathways that promote the development of DIPNECH may also suggest additional targets for treating this disease.
What is the next step?
Dr. Merrick has collected a robust number of cases to study and has developed specialized protocols to generate comprehensive whole-exome sequencing data from these relatively small, pre-malignant lesions. They will obtain purified lesional tissue via microdissection and extract DNA to perform whole-exome sequencing. Their bioinformatics team will catalog any genomic alterations and correlate these with the diagnosis of DIPNECH. If a characteristic mutational alteration is identified, they will pursue additional support to develop diagnostic testing for DIPNECH and to develop effective preventive and therapeutic agents for this disease.
- City: Aurora
- State: Colorado
- Country: USA
- Grant Duration: 2 years
NETRF funds laboratory research to understand the development of neuroendocrine tumors and translational research to explore new concepts in treatment. Research grant descriptions and research updates from NETRF are not intended to serve as medical advice. It can take years for research discoveries to be fully validated and approved for patient care. Always consult your health care providers about your treatment options.