Targeting amyloid beta for myeloid reprogramming in brain metastasis

PROJECT SUMMARY/ABSTRACT Many patients with advanced-stage cancer will develop metastatic disease in the brain. Most patients who develop brain metastasis (BM) will succumb to the disease. Despite such poor outcomes, BM-specific therapies are currently lacking. Recent clinical trials have demonstrated that BM may respond to immune

checkpoint inhibitors. However, responses in BM tend to be less durable than those seen in extracranial metastases, warranting further investigation into how immunotherapies can be better leveraged against BM. Recent findings from our group have suggested that amyloid beta (Aβ), a protein well-established for its role in

Alzheimer’s disease pathogenesis, facilitates immunosuppression within the BM microenvironment and inhibits cancer cell phagocytosis by macrophages, permitting for tumor outgrowth. Likewise, one study in glioblastoma found that the use of BACE inhibitors (BACEi), which stall the β-secretase enzymes involved in Aβ production,

decreases tumor burden by increasing cancer cell phagocytosis and inflammatory signaling by macrophages. We hypothesize that Aβ drives immunosuppression in BM in a macrophage-dependent manner, and that targeting Aβ will lead to the reprogramming of macrophages, promoting anti-tumor immunity in the BM

microenvironment. In Aim 1, we will perform a novel characterization of Aβ in the BM microenvironment using immunocompetent mouse models. Following this characterization, we will determine if treatment with BACEi, alone or in combination with anti-PD1, inhibits the outgrowth or even induces the regression of BM. Aim 2 will

unpack the mechanisms by which Aβ interacts with macrophages to inhibit cancer cell phagocytosis and facilitate their immunosuppressive characteristics. We will also study how this Aβ-macrophage interaction influences downstream T cell phenotypes. Collectively, this work will establish Aβ as a potential therapeutic target in BM

and uncover novel myeloid-based molecular candidates for next-generation immunotherapies. The training plan for this fellowship will span 2.5-years, during which 1.5-years will be dedicated to research and 1-year will be dedicated to clinical training. The research detailed above will allow me to establish

mastery in the fields of cancer biology and immunology, positioning me well to achieve my goals of becoming a professor and establishing my own tumor immunology laboratory. In addition to investigating the immunologic functions of Aβ in BM, I will attend and present at a multitude of internal seminars and international meetings.

To develop my mentorship skills, I will engage in several opportunities to mentor high school and undergraduate students. Additionally, I will continue my involvement with NYU’s Clinical and Translational Science Institute to foster my development as a translational scientist. Lastly, I will support my clinical training by attending Oncology

Tumor Boards and Hematology/Oncology grand rounds, shadowing a heavily research-focused oncologist, and completing my medical school core clerkship curriculum.