Targeting acetyl-CoA synthetase 2 to remodel obesity-evoked inflammatory microenvironment in myeloma
Jing Yang
PhDHouston Methodist Research Institute
Project Term: July 1, 2023 - June 30, 2026
Our proposal aims to develop a novel strategy to improve therapeutic efficacy for patients with multiple myeloma by remodeling obesity-induced inflammatory microenvironment. We hypothesize that acetyl-CoA synthetase 2, which is stimulated by obesity, enhances inflammatory cytokine production from myeloma cells, leading to an inflammatory niche where anti-tumor function of CD8+ T cells is dampened, and tumor growth is promoted. Our study will be the first to explore a novel insight for how obesity impacts the interaction between myeloma cells and microenvironment. In preparation of using the inhibitor of acetyl-CoA synthetase 2 in the clinical setting, we will establish its potential as a single agent or in combination of other chemo- or immuno- drugs to treat myeloma.
Multiple myeloma (MM) is the second most common blood cancer in the US. Despite of advancement in medicine, most patients will relapse, and MM remains incurable. Obesity increases the chance of transformation from benign to cancer state as well as occurrence and death rates for MM patients. Yet, the exact mechanisms of how obesity affects MM treatment is not clear. One hallmark of obesity is activation of inflammation; the tumor microenvironment (TME) is usually inflammatory in nature. Tumor cells interact with neighboring non-cancer cells to suppress host anti-tumor immunity and promotes their own growth. Thus, inhibition of obesity-induced inflammation is a novel valid strategy to maximize the efficacy of drugs to treat MM.
We previously found that obesity promotes MM growth through acetyl-CoA synthetase 2 (ACSS2), which is a protein expressed in MM cells and essential for acetyl-CoA synthesis. In MM patients with obesity, the amount of ACSS2 expression in MM cells is much higher; its high level is strongly correlated with poorer outcomes. Here, we identify a link between ACSS2 and obesity-induced inflammation. Tumor cells can secrete IL1β and IL18, two key proteins to initiate the inflammatory process. We found higher levels of IL1β and IL18 in obese MM patients and in diet-induced obesity (DIO) mice, whereas reduction of ACSS2 expression in MM cells reduced such effects. The anti-tumor activity of CD8+ T cells within bone marrow was also impaired in MM-bearing DIO mice. These results suggest the importance of ACSS2 in obesity-induced inflammation within TME. An ACSS2 inhibitor is well tolerated in Phase I clinical trial to treat advanced solid tumors. We found that treatment of ACSS2 inhibitor significantly reduced tumor growth, IL1β and IL18 levels in MM DIO mice, indicating that targeting ACSS2 is a rational strategy for MM treatment.
Our proposal aims to develop a novel strategy to improve efficacy of MM treatment. Our hypothesis is that ACSS2, stimulated during obesity, triggers assembly of inflammasome in MM cells, enhances IL1β and IL18 production from MM cells, leads to an inflammatory TME where CD8+ T cell anti-tumor function is dampened, tumorigenesis is promoted; and ACSS2 inhibitor can be used as a novel therapeutic agent to reduce inflammatory TME and improve anti-MM efficacy. We will use cultures, DIO mouse models, and obese MM patient samples to determine how ACSS2 enhances IL1β and IL18 secretion from MM cells and how ACSS2 induces inflammatory microenvironment to suppress immunity and promote tumor growth (Aim 1); and to explore the potential of ACSS2 inhibitor alone or with other drugs to treat MM with the goal of translating the most promising ones to the clinic (Aim 2). Our study is the first to provide a novel insight for MM-TME interaction in the context of obesity. Our strategy and reagent (e.g. ACSS2 inhibitor) are highly translational to clinical applications.