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.

Public Health Relevance

Overweight children who get leukemia have a 50% higher chance of having the cancer come back after treatment. We have found that fat cells accumulate and break down an important chemotherapy, daunorubicin, and are investigating with cells, mice, and clinical samples, how this might affect the ability of the drug to kill leukemia cells and how we can stop this.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA213129-02
Application #
9544889
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
2017-08-15
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Tucci, Jonathan; Alhushki, Waseem; Chen, Ting et al. (2018) Switch to low-fat diet improves outcome of acute lymphoblastic leukemia in obese mice. Cancer Metab 6:15
Sheng, Xia; Parmentier, Jean-Hugues; Tucci, Jonathan et al. (2017) Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin. Mol Cancer Res 15:1704-1713