MedicalResearch.com Interview with:
Chengcheng (Alec) Zhang, Ph.D.
Hortense L. and Morton H. Sanger Professorship in Oncology
Michael L. Rosenberg Scholar for Medical Research
Department of Physiology
UT Southwestern Medical Center
MedicalResearch.com: What is the background for this study?
Response: New therapeutic targets and approaches are needed to effectively treat leukemia. Acute myeloid leukemia (AML) is the most common form of adult acute leukemia whereas acute lymphoblastic leukemia (ALL) is the most common form of cancer in children; ALL also occurs in adults. Although treatment of pediatric ALL is highly effective, a sizeable number of patients are non-responders who succumb to this disease. The outcome of ALL in adults is significantly worse than for pediatric ALL. Additionally, some types of ALL have a much poorer prognosis than others.
Dietary restriction, including fasting, delays aging and has prolonged effects in a wide range of organisms and has been considered for cancer prevention. In certain types of solid tumor,_ENREF_1 dietary restriction regimens are able to promote T cell-mediated tumor cytotoxicity and enhance anticancer immunosurveillance, and coordinate with chemotherapy to promote the anti-cancer effects. However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown. Furthermore, whether dietary restriction alone can inhibit cancer development is not clear.
MedicalResearch.com: What are the main findings?
1: Using mouse tumor models, we found that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B-cell and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), but not acute myeloid leukemia (AML).
2: Mechanistically, in the mouse models, we found that attenuated leptin receptor (LepR) expression is essential for the development and maintenance of ALL, and that fasting promotes ALL cell differentiation and inhibits ALL development by upregulation of LepR and its downstream signaling through the protein Prdm1.
3: Moreover, expression of LepR signaling-related genes correlated well with the prognosis of pediatric pre-B-ALL patients, and fasting effectively inhibited B-ALL growth in a human xenograft model.
MedicalResearch.com: What should readers take away from your report?
1: Our results indicate that the effects of fasting on tumor growth are cancer-type dependent.
2: _ENREF_4This study suggests new avenues for the development of treatment strategies for ALL leukemia. The therapeutic strategy of forcing malignant cells to terminally differentiate was proposed several decades ago. however, differentiation therapy has so far been successfully used only in acute promyelocytic leukemia (APL). Our study suggests the potential of fasting for differentiation therapy in both de novo and relapsed ALL patients.
3: Our results also provide a mechanism explanation for the link between obesity and ALL patients. In most human populations, there is a strong association between obesity and ALL leukemia but the underlying mechanism remains poorly understood. Our study suggests that adipocytes can provide a niche-like environment with high leptin levels to suppress LepR expression and thereby inhibit ALL cell differentiation.
4: Besides of LepR signaling, other systemic and leukemic cell effects will undoubtedly be involved in fasting-induced ALL inhibition. Our study provides an effective platform to identify novel targets for ALL treatment.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
- We are expanding the fasting treatment to more leukemia models driven by different oncogenes, to test whether fasting has a universal inhibition effect on other ALL leukemia, and also to figure out which one between the cells of origin and the oncogene drivers contributes to the different responses of ALL and AML to fasting.
- We look forward to collaborating with the clinicians to move the fasting or fasting mimicking strategies forward into clinical translation.
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