# Sequestration and deactivation of anthracycline by adipocytes in the leukemia microenvironment

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $380,446

## Abstract

Obesity increases both the incidence and mortality of numerous types of cancer. Children and adults who
are obese at the time of diagnosis of high-risk acute lymphoblastic leukemia (ALL) have a 50% increased risk
of relapse compared to their lean counterparts. Using mouse and tissue culture models, we showed that
obesity directly impacts the progression and treatment outcome of ALL. We discovered that adipocytes protect
ALL cells from a number of chemotherapies, including the anthracycline daunorubicin (DNR). We have found
that fat cells break down DNR to an inactive form, which depletes local levels and protects nearby ALL cells
from this chemotherapy.
 In the present grant, we will further elucidate this mechanism, using a combination of cell culture, mouse
experiments, and clinical studies. We will first investigate which enzymes in adipocytes contribute to their
ability to breakdown anthracyclines like DNR, and explore strategies to block these enzymes. We will use
mouse models to determine how adipocytes in vivo alter systemic DNR availability, as well as that in the bone
marrow and other ALL microenvironments. We will also explore how clinical variables such as age and gender
alter these effects. Finally, we will perform a limited sampling PK study in lean and obese children, to estimate
DNR and DNR-ol plasma and intracellular exposure during ALL therapy. These studies will increase our
understanding of how the leukemia microenvironment can contribute to treatment failure, particularly in the
obese state. Findings could lead to improved strategies for anthracycline dosing and monitoring in children and
adults. These results, along with our previous studies on how adipocytes affect vincristine and L-asparaginase
PK and PD, will lay the groundwork for a personalized dosing study of Induction chemotherapies in children
with ALL.

## Key facts

- **NIH application ID:** 9999324
- **Project number:** 5R01CA213129-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Stan Gee Louie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,446
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999324

## Citation

> US National Institutes of Health, RePORTER application 9999324, Sequestration and deactivation of anthracycline by adipocytes in the leukemia microenvironment (5R01CA213129-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999324. Licensed CC0.

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