Lung cancer is the deadliest cancer in the world and 2-3% of non-small cell lung cancers (NSCLC) are caused by mutations in the BRAF kinase. These activating BRAFV600E mutations are found in many cancer types and have been the target of much investigation. Many BRAFV600E inhibitors have been developed, including vemurafenib and dabrafenib, however, their success has been limited due to either lack of initial response (even in BRAFV600E positive cancers) or the emergence of drug-resistant disease. While efforts to target the BRAFV600E oncoprotein directly have had mixed results, another line of investigation has emerged. It has become apparent that tumor cells may be supported by the surrounding tumor microenvironment, providing a new source of tumor promoting cells and signals to be targeted for therapy. One of the main component of the microenvironment are the tumor associated macrophages (TAMs), and these cells have been shown to promote tumorigenesis in multiple cancer types. The presence of tumor infiltrating TAMs is a negative predicator of survival in NSCLC patients, suggesting these cells also play a role in lung cancer. While correlative data suggests a role for TAMs in NSCLC, no mechanisms by which they promote lung tumorigenesis has yet been identified. This project uses sophisticated genetically engineered mouse models of BRAFV600E induced lung tumorigenesis to probe the role of TAMs in NSCLC.
Aim 1 focuses on the role of TAMs in promoting BRAFV600E induced lung tumor initiation. Using pharmacologic depletion of macrophages, I will determine if TAMs are required for BRAFV600E tumor initiation. Recent work from the sponsor's lab has demonstrated that BRAFV600E induced lung tumors require an intact WNT/-catenin/c-MYC signaling axis to form. Thus, a sub aim of aim 1 seeks to determine if TAMs are the source of these WNT ligands. This will be achieved using another mouse model which harbors a constitutively active -catenin protein in addition to expression of BRAFV600E. Results from aim 1 will delineate both: (1) the necessity of TAMs in BRAFV600E induced lung tumor formation and (2) if TAMs are the source of WNT ligands necessary for BRAFV600E tumor initiation.
While aim 1 focuses on tumor initiation, aim 2 focuses on the more clinically important question of TAMs requirement for tumor maintenance and/or progression. The first sub aim of aim 2 will test, whether macrophage depletion in established BRAFV600E induced lung tumors can lead to tumor stasis and/or regression. The second sub aim of aim 2 seeks to determine if macrophage depletion can synergize with BRAF inhibition to lead to increased tumor regression compared to BRAF inhibition alone. Together the questions addressed in aim 2 have the potential to lead to the development of macrophage depletion as therapy for NSCLC patients. Together the experiments proposed here have the potential to elucidate molecular mechanisms by which TAMs support NSCLC and directly impact the development of therapies for patients with few other therapeutic options currently available.
Lung cancer is the leading cause of cancer deaths worldwide, and while some therapies have increased patient survival, most patients eventually develop recurrent and lethal drug resistant disease. The tumor microenvironment is a potential source of tumor-promoting or suppressing signals that may be exploited in combination with existing therapies, to increase patient survival and combat the evolution of drug resistant disease. The experiments proposed here seek to elucidate the role of one microenvironment component, the tumor associated macrophage, in lung cancer initiation and progression to guide the development of macrophage targeted agents for the treatment of this most deadly cancer.
| van Veen, J Edward; Pringle, Daphne R; McMahon, Martin (2016) P2A-Fluorophore Tagging of BRAF Tightly Links Expression to Fluorescence In Vivo. PLoS One 11:e0157661 |
