# Targeting obesity to improve survival from childhood acute lymphoblastic leukemia

> **NIH NIH R37** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2022 · $690,162

## Abstract

Obesity is a worldwide health challenge that increases the risk of developing and dying from multiple types of
cancer. B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Despite improved
cure rates, children with obesity at diagnosis are more than twice as likely as their lean peers to respond poorly
to induction therapy, and eventually to relapse and die from their disease. Thus, survival for children with obesity
has not improved in lockstep with the broader B-ALL population. Chemotherapy for B-ALL induces many of the
same physiologic changes in non-obese children as those found in the obese, thereby placing even lean children
at risk for chemotherapy resistance. In a series of clinical and laboratory models, chemoresistance in ALL due
to obese physiology was found to be potentially reversible. A recent Phase I trial demonstrated proof-of-principle
that a combination of calorie, fat, and glucose restriction (CFGR), achieved through diet and physical activity,
could reverse obesity-induced chemoresistance. The trial showed that CFGR could be integrated into pediatric
B-ALL induction regimens, and most importantly, that CFGR reduced by ~71% the rate of minimal residual
disease at the end of induction (EOI MRD); EOI MRD is one of the most significant predictors of relapse in B-
ALL. In investigating the mechanisms underlying the efficacy of CFGR, insulin was discovered to be a likely key
initiator of chemoresistance, and adiponectin, an underappreciated hormone countering insulin effects in B-ALL.
The central hypothesis of this proposal is that CFGR will reduce MRD in B-ALL through improving
chemosensitivity by lowering circulating insulin and increasing adiponectin, together reducing signaling
in ALL pro-survival/anti-apoptotic pathways. The long-term goal of this research is to reverse obesity-induced
chemoresistance to improve survival from B-ALL. In this proposal, CFGR efficacy will be evaluated in a
randomized, multicenter Phase II trial conducted through a pediatric leukemia consortium. Lean and obese
enrolled patients with high-risk B-ALL will receive induction chemotherapy with or without CFGR for four weeks.
In Aim 1, patients randomized into strata by obesity status and starting leukemia burden (white blood cell count)
will receive either one-time nutrition and exercise education (control arm) or education plus CFGR (intervention
arm). Primary endpoints will be reductions in MRD and change in fat mass. Secondary endpoints will assess
adherence, fitness, motor function, toxicity, and quality of life. In Aim 2, the contribution of circulating insulin and
adiponectin to obese chemoresistance and CFGR efficacy will be explored. Changes in obese physiology by
CFGR will be assessed via hormones, cytokines, and metabolomics. The opposing effects of obese physiology
and CFGR on intracellular activation of AKT, mTOR, and Raf/Ras chemoresistance pathways will be measured
using mass cytometry. Results from this trial w...

## Key facts

- **NIH application ID:** 10488577
- **Project number:** 5R37CA252236-02
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Etan Orgel
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $690,162
- **Award type:** 5
- **Project period:** 2021-09-14 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488577

## Citation

> US National Institutes of Health, RePORTER application 10488577, Targeting obesity to improve survival from childhood acute lymphoblastic leukemia (5R37CA252236-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10488577. Licensed CC0.

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