Role of KDM4A as an Epigenetic Regulator with Oncogenic and Immunosuppressive Features in Malignant Pleural Mesothelioma
Abstract
Malignant pleural mesothelioma (MPM), as a Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) FY21 PRCRP Topic Area, is an infrequent but devastating cancer with the vast majority of case linked to previous asbestos exposure. Asbestos was long used for fire and heat protection in buildings, ships, brake-pads, and other industries, many related to the military. Despite discontinued new use of asbestos in the United States, its use continues unabated in large parts of the world, causing exposure and MPM risks in U.S. military personnel. Standard therapy is limited to very few therapeutic options. The overall prognosis is dismal and there is a significant need for effective long-term treatments. The genomic landscape in MPM has been defined through whole exome sequencing, revealing predominantly recurrent loss-of-function mutations in tumor suppressors, and there is an apparent lack of obvious vulnerabilities. To overcome this challenge, there is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In MPM, a substantial number of genetic abnormalities in factors involved in chromatin remodeling have been identified, such as the SET domain containing 2 (SETD2) histone methyltransferase. We found that KDM4A, a histone lysine demethylase that counteract the activity of SETD2, is overexpressed in MPM tumors compared to normal tissue. While the role of KDM4A is not fully understood, particularly in MPM, it is suggested to be important in cancer development and to regulate apoptosis, DNA repair, splicing, self-renewal, and other biological effects. Experimental inhibitors of KDM4A activity have emerged that suggest a beneficial effect in some cancer models with KDM4A alterations. Our preliminary data suggest that KDM4A is uniquely elevated in MPM, and its functional expression is required for growth and viability in vitro and in vivo, therefore representing a novel potential therapeutic vulnerability. Tumor cells can evade immunosurveillance by activating immune checkpoint pathways that suppress antitumor immune responses. Emerging evidence suggests that KDM4A acts as a negative regulator of immune cell function and promotes an immune suppressive environment. These findings hint at additional combinatorial therapeutic opportunity in MPM patients, and novel therapeutic approaches that work in combination with immunotherapy and have the potential to prolong overall survival are sought. This study is to analyze gene expression in response to KDM4A targeting in relation to genome-wide chromatin accessibility. It is designed to specifically investigate changes presented in MPM cells and is thus expected to have little impact on normal cells. Chromatin marks related to KDM4A activity will be identified and compared to KDM4A chromatin binding by chromatin immunoprecipitation sequencing. We will thereby define the key role of KDM4A as an essential epigenetic regulator that activates oncogenic and immunosuppressive pathways in MPM. We will further proceed with functional characterization of the changes in preclinical models, including 3D spheroid assays and in vivo mouse experiments including immune checkpoint inhibitors and KDM4A pathway-targeted targeted therapies. By doing so, this application will also address the FY21 PRCRP Overarching Challenge: transform cancer treatment through the identification of new targets; improve immunotherapy and identify and understand the mechanisms behind cancer epigenetics. There is great impetus to determine the molecular and cellular abnormalities in transformation to satisfy the need to drive therapeutic advances in MPM that may lead to future clinical trials that would benefit the entire patient population. MPM is intrinsically related to the FY21 PRCRP Military Health Focus Area, Environmental exposure risk factors associated with cancer, as exposure to asbestos has been linked to manifestation of MPM after lo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210962
Entities
People
- Srinivas Vinod Saladi
Organizations
- Massachusetts Eye and Ear Infirmary
- United States Army