Degron Disruption in Small Cell Lung Cancer

Background: Most proteins in our cells are constantly broken down and recycled. Degrons are a sequence of amino acids within a protein that are recognized by cells to be labeled for degradation. In cancer cells, many degrons are mutated or missing. When degrons are missing, the rest of the protein is not broken down and recycled normally. Accumulation of oncogenic proteins without degrons can drive certain cancers like non-small cell lung cancers with MET exon 14 skipping. In this proposal, we will analyze the effects of degron disruption in small cell lung cancer.

Areas of Emphasis: Our proposal is relevant to the LCRP Areas of Emphasis: (1) Understand the molecular mechanisms of initiation and progression to lung cancer and (2) Identify innovative strategies for the treatment of lung cancer.

The ultimate impact of our work might identify new treatments for patients with lung cancer. More specifically, we will analyze one of the largest datasets of genomic data from patients with small cell lung cancer. We will analyze these data with a new bioinformatics pipeline that our team developed. We expect to identify whether degrons are commonly mutated in small cell lung cancer and which genes are most commonly affected.

If any of these genes have FDA-approved therapies associated with them for other indications, we anticipate that we could rapidly develop novel clinical trials to test their use in this patient population. If these genes do not have any FDA-approved therapies associated with them, we will then rank the most frequently altered degrons and prioritize those for validation using models in our laboratory to then identify novel therapeutics. Although the timeline for the proposed project is 1 year, the translation of our findings could be as short as 1 year to trial or many years later following additional laboratory work.

Small cell lung cancer predominantly results from tobacco use, which is more prevalent in active duty military personnel and Veterans than the civilian population. Since small cell lung cancer is most frequently diagnosed in the elderly, we suspect that the successful completion of our aims would be more relevant to the Veteran population than active duty military personnel and their families. To our knowledge, there is no military or Veteran-specific genomic dataset for small cell lung cancer. For this reason, we have decided to compile the main publicly available genomic datasets of small cell lung cancer to create one of the largest repositories for our analysis.