Abstract
Obesity is a major contributor to cancer mortality, and is responsible for ~90,000 cancer deaths per year in the U.S. Part of this association can be attributed to the effect of obesity to increase cancer incidence, while obesity has been shown to worsen the outcome from a number of types of cancer. Retrospective studies have shown that obese children diagnosed with the high-risk form of the most common childhood cancer, acute lymphoblastic leukemia (HR-ALL) have a substantially higher risk of relapse than lean children.
We have investigated these associations, generating laboratory models to investigate how obesity might impact ALL progression and treatment. Using two mouse models, we found that obesity accelerates the appearance of spontaneous leukemia. We have further discovered that obese mice implanted with leukemia had poorer survival after treatment with either vincristine or L-asparaginase. We have identified several effects of adipocytes which appear to contribute to this worse outcome. Adipocytes attract ALL cells to migrate into adipose tissue via secretion of the chemokine CXCL12, protect ALL cells from a number of chemotherapies, absorb chemotherapy leading to unfavorable pharmacokinetics, and secrete glutamine and possibly other fuels to support leukemia cell proliferation. In all, adipocytes have a number of effects which likely contribute to the worse prognosis in obese patients with ALL.
These effects are particularly concerning given the high prevalence of overweight and obesity in leukemia patients. Two-thirds of adults and one-third of children in the U.S. are either overweight or obese. Almost half of new patients with HR-ALL in our institution are overweight and obese. Furthermore, we have observed that the body fat of these patients increases by ~20% during the first month of treatment, and even further by several months into therapy. HR-ALL patients therefore have a large and increasing burden of adipose tissue which may directly impair leukemia treatment and worsen prognosis.
We now have evidence that the effect of obesity might be reversible. A retrospective analysis of HR-ALL patients showed that those who were obese at diagnosis, but lost weight and became non-obese for more than half of their treatment, had an improved outcome, similar to patients who were never overweight or obese. Experiments in our laboratory demonstrated that switching obese mice to a low-fat diet at start of ALL treatment substantially improves outcome from vincristine treatment, compared to those continued on the high fat-diet (92% vs. 17% survival, p<0.001). In fact, this dietary intervention led to a better survival than even control mice raised on the same low-fat diet.
These bench and clinical findings set the stage for an obesity-targeted intervention in children with ALL. We hypothesize that targeting obesity during leukemia treatment will reduce body fat gain, improve quality of life, and potentially improve outcome.
Citation Format: Steven D. Mittelman. Childhood obesity and leukemia: Opportunities for intervention. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN10-03.
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