DELINEATE THE TUMOR IMMUNE MICROENVIRONMENT FOR BETTER UNDERSTANDING IMMUNOTHERAPY RESPONSE

Project Summary Monoclonal gammopathy of undetermined significance (MGUS) is a precancerous condition in which a person has moderately elevated levels of an abnormal immunoglobulin (Ig) protein (called M protein) in the blood. MGUS patients have a cancer risk ~6.5 times as high as the control population. MGUS may progress to

multiple myeloma (MM), Waldenström macroglobulinemia (WM), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), amyloid light-chain (AL) amyloidosis, or plasmacytoma. MM, WM, a large portion of NHL, and AL amyloidosis are incurable diseases. CLL and plasmacytoma are rarely cured. The significance

of MGUS calls for a cancer prevention-interception U54 Specialized Center dedicated to this precancerous condition  MGUS affects ~1% of the population, MGUS progresses to cancer or other associated blood disorders persistently at a rate of ~1% per year, and ~90% cancer/disorder that progressed from MGUS are

incurable. All patients with MGUS are potential candidates for cancer prevention and interception. We hypothesize that cancer-driving molecules and the bone marrow microenvironment promoting MGUS progression are suitable targets for precision cancer prevention and interception. We propose to establish the

Cancer Prevention-Interception against MGUS Progression to Cancer (CAP-MGUS) Center as an agile and effective network infrastructure dedicated to preventing MGUS progression. This Center will undertake collaborative research focusing on immunologically and chemically targeted agents that prevent or intercept

the oncogenic process in patients with MGUS or smoldering diseases. We propose three aims to achieve the CAP-MGUS Center’s overarching goal. In Aim 1, we will functionally validate several oncotargets in tumor initiation and progression to invasive cancer and ascertain their suitability for targeted intervention strategies.

In Aim 2, we will discover innovative immuno- and chemo-prevention and interception agents through in vitro and in vivo efficacy evaluation. In Aim 3, we will develop new projects by identifying novel targets for cancer- preventive or interceptive interventions against MGUS progression. Collectively, we expect to obtain

chemoprevention and immunoprevention agents for further development or earlier phase clinical trials.