Dr. Steven Mittelman is an Associate Professor of Pediatrics and Physiology & Biophysics in the Center for Endocrinology, Diabetes & Metabolism at the Keck School of Medicine, University of Southern California.
He received his MD and PhD degrees from the Keck School of Medicine, where he worked on elucidating the physiological mechanisms by which insulin regulates blood sugar. Further work examined how pancreatic beta-cells compensate for obesity-induced insulin resistance, and how appetite regulating hormones work in obese adolescents. Steven completed his residency in pediatrics and fellowship in pediatric endocrinology at Children's Hospital Los Angeles.
During his subspecialty training, Steven learned of an important finding by researchers in the Children's Center for Cancer and Blood Diseases: children who are obese when they are diagnosed with high-risk leukemia have a 50% higher chance of relapsing than those who are lean. In fact, obesity increases the risk of dying from many different types of cancer, such as breast, colon, and prostate, and may be responsible for up to 15-20% of cancer deaths in the U.S. Dr. Mittelman turned his expertise in obesity into work exploring the relationships between obesity and leukemia relapse, in collaboration with Drs. Nora Heisterkamp and Anna Butturini. His laboratory is currently investigating how obesity and cancer interact, using both mouse models and tissue cultures. He has found evidence that fat tissue may absorb some chemotherapies, so that these drugs are not available to kill the cancer cells. He also found that fat cells play an active role in the cancer microenvironment, participating in a two-way communication with cancer cells, and producing metabolic fuels and survival factors which protect cancer cells from chemotherapies. These findings have led to multiple publications which have been well-received in both the scientific and lay press.
Dr. Mittelman is currently investigating strategies to block some of these effects of adipocytes, in the hopes that this will lead to improvements in cancer survival in both thin and overweight people.
University of Southern California Keck School of Medicine
Children's Hospital Los Angeles; Pediatrics
Children's Hospital Los Angeles; Pediatrics
Children's Hospital Los Angeles; Pediatric Endocrinology
Pediatrics; American Board of Pediatrics
American Diabetes Association, American Association of Cancer Research
Childrens Hospital Los Angeles Associates and Affiliates Award 2003
EA Ehsanipour, X Sheng, JW Behan, X Wang, A Butturini, VI Avramis, SD Mittelman: Adipocytes Cause Leukemia Cell Resistance to L-Asparaginase via Release of Glutamine Cancer Research, In Press
JW Behan, EA Ehsanipour, R Pramanik, X Sheng, Y-M Kim, Y-T Hsieh, SD Mittelman: Activation of Adipose Tissue Macrophages in Obese Mice does not Require Lymphocytes Obesity, In Press (DOI: 10.1002/oby.20159)
R Pramanik1, X Sheng1, B Ichihara, N Heisterkamp, SD Mittelman: Adipose tissue attracts and protects acute lymphoblastic leukemia cells from chemotherapy Leukemia Research, 37:503-9, 20131co-first authors
DJ Lesser, R. Bhatia, WH Tran, F. Oliveira, R Ortega, TG Keens, SD Mittelman, MCK Khoo, SL Davidson Ward: Sleep Fragmentation and Intermittent Hypoxemia Associated with Decreased Insulin Sensitivity in Obese Adolescent Latino Males, Pediatric Research, 72:293-8, 2012
R Antony, X Sheng, EA Ehsanipour, E Ng, R Pramanik, L Klemm, B Ichihara, SD Mittelman: Vitamin D Protects Acute Lymphoblastic Leukemia Cells from Dexamethasone Leukemia Research, 36:591-93, 2012
LJ Noetzli, A Panigrahy, SD Mittelman, A Hyderi, A Dongelyan, TD Coates, JC Wood: Pituitary iron and volume predict hypogonadism in transfusional iron overload, American Journal Of Hematology, 87:167-71, 2012
LJ Noetzli, SD Mittelman, RM Watanabe, TD Coates, JC Wood: Pancreatic iron and glucose dysregulation in thalassemia major, American Journal Of Hematology, 87:155-60, 2012
CM Southern Reh, SD Mittelman, C-P Wee, AC Shah, FR Kaufman, JR Wood: A Longitudinal Assessment of Lipids in Youth with Type 1 Diabetes,
Pediatric Diabetes, 12:365-71, 2011
SA Chung, F Dorey, SD Mittelman, V Gilsanz: Effect of Gender on Intra-abdominal Fat in Teenagers and Young Adults, Pediatric Radiology, 41:469-75, 2011
Books, Chapters, Articles
SD Mittelman and A Butturini. Mechanisms Linking Obesity and Leukemia Prognosis. In: SD Mittelman and NA Berger (Eds.) Energy Balance and Hematologic Malignancies (pp. 47-69), New York, NY, Springer Science and Business Media, LLC, 2012
SD Mittelman and NA Berger (Eds.) Energy Balance and Hematologic Malignancies, New York, NY: Springer Science and Business Media, LLC, 2012
Obesity and cancer in children
Adipose tissue inflammation
Obesity can cause a number of negative health effects. One of these effects is that being obese increases the risk of cancer and makes cancer harder to cure. We are trying to figure out the mechanisms responsible for obesity interacting with cancer.
Leukemia is the most common type of cancer in children. Researchers in The Saban Research Institute at Children’s Hospital Los Angeles discovered that children who were obese at the time they were diagnosed with the most common type of childhood leukemia have about a 50% higher chance of their disease coming back after treatment than patients who were lean. In our laboratory, we are looking into ways in which fat tissue might interact with leukemia cells, making the disease harder to cure. We are investigating how fat tissue:
- Attracts leukemia cells to migrate closer to fat cells.
- Absorbs some chemotherapy drugs, making them unable to reach the leukemia cells.
- Produces fuels such as amino acids and fatty acids that help leukemia cells survive.
- Secretes substances that signal the leukemia cells, making them more able to resist chemotherapy.
We are also studying how body weight, and other nutritional factors like vitamin D, might impact patients with leukemia both before and after treatment.
As obesity develops, immune cells infiltrate fat tissue, causing inflammation. This inflammation may be partly responsible for the development of diabetes, heart disease and cancer. We are looking into the communications between adipocytes, lymphocytes and macrophages, and how this might lead to insulin resistance and diabetes.
- We were the first to demonstrate that fat cells protect leukemia cells from a variety of chemotherapies.
- We demonstrated, in two different models, that obesity directly accelerates leukemia progression.
- We have found that macrophage infiltration of adipose tissue in obesity does not require lymphocytes.
- To unravel the mechanisms responsible for obesity both increasing the chance of getting leukemia and decreasing the chance of surviving leukemia.
- To develop strategies to block these effects of obesity on cancer.
- To use our understanding of body weight regulation to improve the lives of patients with leukemia and other cancers.
- Fellowship Director for the Center for Endocrinology, Diabetes & Metabolism since 2006.
- Director of the Donnell Society for Pediatric Scientists, which is dedicated to improving the health of children by training pediatric scientists to perform innovative and high-quality research
- NIH/NCI R01: Investigating the Role of Adipocytes on Leukemia Relapse (PI: Mittelman)
This grant supports our investigations into how obesity can affect the dosing of chemotherapy drugs such as vincristine and dexamethasone. It also supports our work to understand how fat cells can directly protect leukemia cells from chemotherapy.
- Gabrielle’s Angel Foundation: Overcoming L-Asparaginase-Resistance Caused by Adipocyte Production of Glutamine (PI: Mittelman).
This grant supports our studies on how fat cells produce amino acids which fuel leukemia cells and allow them to survive the chemotherapy, L-Asparaginase.
- Leukemia & Lymphoma Society Translational Research Project: Vitamin D, Fat, and Development of Bone Abnormalities in ALL (PI: Mittelman)
This grant funds a double-blind, placebo-controlled study of vitamin D and calcium supplementation in children with acute lymphoblastic leukemia.
The V Foundation Translational Grant: Improving treatment outcome in leukemia by disruption of bone marrow-leukemia interactions relevant to minimal residual disease (PI: Heisterkamp).
The purpose of this grant is to inhibit molecular pathways leading to leukemia migration into and adhesion within the bone marrow, to test whether this will improve leukemia outcome.
The Saban Research Institute 2nd R01 Pilot Award: The Role of Lymphocytes in Obesity-Induced Adipose Tissue Inflammation and Diabetes (PI: Mittelman).
The aim of this grant is to investigate the role of lymphocyte subsets in the accumulation and activation of adipose tissue macrophages, using novel immunodeficient mouse models.
- In addition to the above awards, our laboratory is grateful for the funding we receive from: The Bogart Cancer Research Program, the T.J. Martell Foundation and The Saban Research Institute.