# Regulation and Function of Very Long Chain Fatty Acid Biosynthesis in Multiple Myeloma

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $384,326

## Abstract

Multiple Myeloma (MM) is a plasma cell disorder that accounts for ~10% of all hematologic malignancies.
Due to high production of IgG in endoplasmic reticulum (ER), MM cells continuously undergo ER stress which is
considered an “Achille’s heel” of the disease. This feature makes MM susceptible to the agents that exacerbate
ER stress, such as proteasome inhibitor bortezomib. Yet, currently MM is incurable for most patients due to
rapidly emerging resistance to proteasome inhibitors. Therefore, identification of novel anti-MM drugs and
targets is of high importance.
 Conversely, an increase in protein export from ER is a part of the adaptive response to ER stress. In the
current application, we propose a novel clinically relevant pathway controlling ER homeostasis and resistance
to bortezomib in MM via modulation of sphingolipid composition of the ER membrane. Our preliminary data
suggest that such modulation affects ER-to-Golgi transport, ER homeostasis and ultimately MM cell viability.
Furthermore, we identified 3-hydroxyacyl-CoA dehydratases (HACD3), an enzyme involved in the biosynthesis
of very long fatty acids (VLCFA), as an important regulator of ER-to-Golgi export and ER homeostasis.
Importantly, HACD3 mRNA levels were increased during MM progression and in MM cells from MM patients
refractory to bortezomib-containing therapy.
 Therefore, in Specific Aim 1, we will functionally characterize mechanisms underlying VLCFA-dependent
regulation of ER homeostasis and characterize enzymes upstream and downstream of HACD3 responsible for
such regulation. In Specific Aim 2, we will identify mechanisms regulating HACD3 mRNA expression in MM cells.
In Specific Aim 3, we will evaluate the efficacy of pharmacological suppression of VLCFAs in MM mouse models.

## Key facts

- **NIH application ID:** 10317554
- **Project number:** 1R01CA264984-01
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Mikhail Nikiforov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,326
- **Award type:** 1
- **Project period:** 2021-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317554

## Citation

> US National Institutes of Health, RePORTER application 10317554, Regulation and Function of Very Long Chain Fatty Acid Biosynthesis in Multiple Myeloma (1R01CA264984-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10317554. Licensed CC0.

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