CAP-IT MGUS has two projects.
1. Prevention of MGUS Progression to MM by Modulating the Bone Marrow Microenvironment (UAMS)
2. Prevent IgM MGUS Progression by Targeting the Driver Mutation (BCM & Duke)
Research involving MGUS mouse models and primary human samples from MGUS patients has demonstrated that bone marrow cellular senescence related to aging, iron metabolism, and increased DKK1 in MGUS plasma cells are linked to MGUS progression. The hypothesis is that alterations in the bone marrow microenvironment (ME) alter gene expression of MGUS plasma cells and induce both bone destruction and immunosuppression, resulting in MGUS plasma cell proliferation and disease escape from effective immune surveillance.
To test this hypothesis, three specific aims are set:
1. Determine the role of cellular senescence of ME in MGUS progression.
2. Determine the role of DKK1 in promoting MGUS progression in adoptive transgenic mice.
3. Determine cellular and molecular mechanisms of MGUS progression.
The long-term objective of this work is to determine the functional role of the bone marrow microenvironment in regulating the plasma cell growth of MGUS, using multiple MGUS mouse models to define reliable biomarkers. The results are expected to lay the groundwork for developing new treatment strategies to prevent the progression of MGUS to multiple myeloma (MM).(For additional information, please visit NIH RePORTER)
This project investigates IgM MGUS, a precursor to various hematologic cancers, focusing on the MYD88 L265P mutation, prevalent in about 90% of Waldenström macroglobulinemia (WM) cases and a significant number of other related cancers. This mutation's uniqueness in both precancerous and cancerous stages makes it an ideal target for cancer prevention. Research has identified that the RNF138 protein specifically modifies MYD88 L265P, a process crucial for its cancer-promoting activity. Leveraging deep learning AI, millions of compounds have been screened, leading to the identification of several compounds that inhibit MYD88 L265P. One of these compounds has shown efficacy in reducing lymphoma growth in models with the MYD88 L265P mutation. Additionally, it was found that RNF138 deletion in mice does not majorly impact physiological functions but significantly reduces cancer development in cells with the MYD88 L265P mutation. This supports our hypothesis that interrupting the MYD88 L265P-RNF138 interaction could prevent IgM MGUS progression.
The project proposes two specific aims:
1. Use an AI-developed MYD88 L265P-targeting compound to prevent IgM MGUS progression
2. Employ DNA vaccines against RNF138 to prevent IgM MGUS progression.
The goal is to develop effective agents for cancer prevention against IgM MGUS progression without significant toxicities. (For more details, please visit NIH RePORTER)
