In a study published this week in Nature entitled “IAPP-driven metabolic reprogramming induces regression of p53-deficient tumors in vivo,” a team of researchers led by Dr. Elsa Flores, associate professor of molecular and cellular oncology at MD Anderson Cancer Center, showed that the gene IAPP could potentially be used as therapeutics for tumors deficient in p53.
The p53 is a transcription factor with a key role in the maintenance of genetic stability, therefore preventing cancer formation. Studies have found p53 reactivation in mice to be tumor suppressive. However, this preposition has been difficult to apply for therapeutic purposes. This transcription factor belongs to a family of genes composed of p53, p63, and p73, with researchers hypothesizing that by manipulating two of the p53 family genes, p63 and p73 (isoforms lacking acid transactivation domain), they could find an alternative therapeutic-oriented strategy.
Results from this study revealed that deletion of p63 and p73 metabolic reprogrammed and regressed p53-deficient tumors through upregulation of IAPP (an amylin encoding gene related to the use of insulin).
Moreover, results indicated that IAPP is involved in tumor regression, since amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis. With regard to the findings, Dr. Flores stated in an MD Anderson news release “We found that IAPP is involved in tumor regression and that amylin, the protein encoded by the IAPP gene, stops a cell’s ability to metabolize glucose, leading to programmed cell death.”
Therapeutics for type 1 and type 2 diabetes includes a medication called Pramlintide (composed by a synthetic analogue of amylin) that in this study was found to regress tumors in p53-deficient thymic lymphomas, representing a novel approach to target p53-deficient cancers.
Concerning the results, Dr. Flores explained that “The p53 family interacts extensively in cellular processes that promote tumour suppression. Thus, a clear understanding of this interplay in cancer is needed to treat tumors with p53 alterations.”
This study was multi-funded by the National Cancer Institute, the Cancer Prevention and Research Institute of Texas, the Hildegardo E. and Olga M. Flores Foundation, Mr. and Mrs. Melvyn N. Klein, the Leukemia and Lymphoma Society, the Rita Allen Foundation and The V Foundation for Cancer Research.