Rationale: Up to 50% of non-small cell lung cancer (NSCLC) patients will develop brain metastasis (BM). BM usually portends a poor prognosis and can leave patients severely disabled. Despite this, we currently have no way of predicting which patients will develop BM, and little is known about the biology that permits cancer cells to spread to and survive in the brain. Our group has found distinct molecular differences in the primary lung (PL) tumors of those patients who ultimately develop BM. We believe the cancer cells that go on to seed BM (BMSC) are present in the PL tumor at initial diagnosis.

Areas of Emphasis:

1. Identify strategies for prompt detection and/or characterization of progressive disease (Detection).

2. Develop or optimize biomarkers to assist with therapeutic decision-making (Treatment and prognosis).

3. Enhance the treatment and understanding of brain metastases in lung cancer (Treatment and prognosis).

Objectives:

1. To define molecular features in PL tissues that could identify lung cancer patients at the highest risk of developing BM.

2. To better understand the biology of BMSCs present in PL specimens when patients are initially diagnosed with NSCLC.

3. To characterize the interactions between BMSCs and the other cells and tissues in PL tumors.

Approach: In this project, we will use modern genomics methods such as bulk and single-cell DNA and RNA sequencing to identify and characterize BMSCs in the tumor microenvironment of a cohort of NSCLC patients. These insights may help us predict which patients are likely to develop BM and identify novel targets for therapy. We have already obtained funding to conduct bulk DNA and RNA sequencing on 345 specimens, and this work is underway. The funding from the proposed grant will enable the analysis of that data and more complex experiments referred to in the second and third objectives above.

Applicability: More than 235,000 Americans are diagnosed with lung cancer annually, and Veterans are 75% more likely to be diagnosed with lung cancer. This work is poised to save thousands of military lives through risk stratification, early identification, and treatment of NSCLC BM. If successful, this study will dramatically improve our fundamental understanding of the biology of NSCLC BM. Furthermore, the learnings from this work may enable us to successfully identify the patients with NSCLC at the highest risk of developing BM later in their disease course. That understanding would allow us to screen these patients more regularly and catch BM before they cause serious harm (for example, with MRI brain) or to treat patients with drugs that we know have activity in the brain. This grant team also hopes to fundamentally understand the cellular interactions between BMSCs and the surrounding tissues early in a patient’s disease course. This knowledge would enable drug discovery projects to produce agents that prevent lung cancer cells from spreading to the brain or to treat them better if that has already occurred.