Notch Pathway Activation Promotes the Adaptation of Metastatic Lung Cancer Cells to the Brain Microenvironment

Areas of Emphasis: (1) Identify innovative strategies for the treatment of lung cancer; (2) understand mechanisms of resistance to treatment (primary and secondary).

Rationale, Objective, and Aims: Brain metastasis, the spread of cancer to the brain, is a leading cause of death in non-small cell lung cancer patients. Despite the application of multiple treatment modalities, lung cancer brain metastasis (LCBM) has an extremely grim prognosis with overall survival ranges from only 3 to 6 months. Importantly, more and more lung cancer patients are diagnosed and die from brain metastasis due to improved survival from newly developed treatments. Despite ongoing research efforts, the factors that drive resistance in

LCBM to therapies are not fully understood. Growing evidence suggests that neuronal activity significantly promotes the growth of cancer cells. With gene expression analysis, we found that brain-metastatic lung cancer cells acquire neuron-like features that facilitate their adaptation to the brain with subsequent communication with the surrounding cells. One of the crucial signaling pathways in neural development and function is the Notch pathway. Increased Notch pathway activity also correlates with tumor growth and metastasis. We therefore propose to determine the role of the Notch pathway to drive brain metastasis from lung cancer. We will achieve this objective through pursuing the Aim that will determine the role of the Notch pathway to regulate the adaptation of lung cancer cells to the brain microenvironment.

Applicability of the Research: The treatment of lung cancer brain metastases remains an unmet clinical need. Despite significant advances in the treatment of primary lung cancer, there is a remarkable lack of chemotherapeutic options against brain metastases. Given its increasing incidence and grim prognosis, new therapeutic strategies for the treatment of LCBM are urgently needed. Our proposed studies would discover a novel mechanism for the Notch pathway to promote the establishment and growth of LCBM. Several clinically applicable Notch inhibitors have been developed and tested against other cancers. Notch inhibitors are highly brain-penetrant and well tolerated, with minimal side effects. Therefore, our findings could help develop new therapeutic strategies for the treatment of brain metastasis that can eventually be brought to the clinic. Altogether, these studies could eventually reduce lung cancer-related morbidity and mortality in Service Members, Veterans, their families, and civilians and also improve their quality of life.