# Effects of PPAR agonists on response to immunomodulatory agents in patients with multiple myeloma

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $175,088

## Abstract

PROJECT SUMMARY
Multiple myeloma (MM) is the second most common hematological malignancy in the United States and is
a disease of older adults. Many of myeloma patients have co-existing medical problems including diabetes
and dyslipidemia. Peroxisome proliferator-activated receptor (PPAR) agonists including PPARa agonists
(the fibrates) and PPARg agonists (the thiazolidinediones) are FDA-approved drugs for the treatment of
dyslipidemia and type 2 diabetes and are commonly used in myeloma patients with those conditions. There
is a fundamental gap in understanding how PPAR agonists affect the treatment response and outcomes in
patients with MM. We have recently demonstrated that PPAR agonists down-regulate the expression of
cereblon, an E3 ligase and the direct target of immunomodulatory agents (IMiDs), in myeloma cells. We
have further found that co-administration of fenofibrate attenuated the anti-myeloma activity of lenalidomide
in vitro and in vivo in myeloma xenograft mouse model. Moreover, myeloma patients treated with IMiDs in
the presence of PPAR agonists appeared to have lower very good partial response rate and worse overall
survival compared to myeloma patients with similar characteristics but not taking PPAR agonists. Our long-
term goal is to improve the care and outcome of patients with MM. The overall objectives in this application
are to determine the molecular mechanism through which PPAR agonists regulate cereblon expression and
to characterize the effects of concurrent PPAR agonists on IMiD based chemotherapy in myeloma patients.
The central hypothesis is that co-administration of PPAR agonists in conjunction with IMiDs has worse
outcomes including decreased response, and decreased progression free and overall survival in myeloma
patients compared to patients receiving IMiDs without PPAR agonists. The rationale for the proposed study
is that the results have the potential to change our practice in treating myeloma patients who also have
diabetes and/or dyslipidemia. Our hypothesis will be tested by pursuing two specific aims: Aim 1 is to
determine the molecular mechanisms through which PPAR agonists negatively regulate cereblon
expression. Chromatin immunoprecipitation assay, luciferase reporter gene assay, and promoter point
mutation will be performed. Aim 2 is to determine if PPAR agonists alter the treatment response and
outcomes of myeloma patients treated with IMiDs. A retrospective study with immunohistochemical staining
of archived bone marrow biopsy samples will be performed. The study is innovative, because it focuses on
the novel interaction between PPAR agonists and IMiDs. The research is significant, because it is expected
to vertically advance and expand the knowledge of how we treat multiple myeloma patients with diabetes
and dyslipidemia, medical conditions commonly co-existing in older demographic.

## Key facts

- **NIH application ID:** 9838733
- **Project number:** 5R21CA234701-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Yubin Kang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $175,088
- **Award type:** 5
- **Project period:** 2019-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838733

## Citation

> US National Institutes of Health, RePORTER application 9838733, Effects of PPAR agonists on response to immunomodulatory agents in patients with multiple myeloma (5R21CA234701-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838733. Licensed CC0.

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