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)
By studying MGUS mouse models and primary human samples from MGUS patients, we have demonstrated that bone marrow cellular senescence related to aging, iron metabolism, and increased DKK1 in MGUS plasma cells are linked to MGUS progression. We hypothesize that changes 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.
We propose three specific aims to prove this hypothesis:
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. Our findings should form the basis for designing novel treatment approaches to prevent MGUS progression 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. Our research found that the RNF138 protein specifically modifies MYD88 L265P, a process crucial for its cancer-promoting activity. Leveraging deep learning AI, we screened millions of compounds and identified several that inhibit MYD88 L265P. One compound, in particular, proved effective in reducing lymphoma growth in models with the MYD88 L265P mutation. Further, we discovered 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.
Two aims are proposed:
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)
Despite the critical need, there are no approved treatments to prevent MGUS from progressing to MM. This is due to two major challenges: the lack of effective methods to identify high-risk MGUS patients and the absence of effective preventive interventions. This application proposes to address these two challenges by leveraging computational approaches to integrate diverse genomic and transcriptomic data from previous studies.
First, a Cell-of-Origin gene signature consisting of 20 genes (PBM20) will be applied to select MGUS patients with a high risk of progression. By integrating the PBM20 signature with traditional clinical factors, machine learning and statistical methods will be used to build classification and survival regression models, optimizing the accuracy of predicting MGUS progression to MM.
Second, systematic drug repurposing analysis will be performed to identify new candidate drugs to prevent MGUS progression from existing drugs approved by the FDA for treating other indications.
The goal is to develop effective agents for cancer prevention against IgM MGUS progression without significant toxicities. (For more details, please visit NIH RePORTER)
