Tumor growth and maintenance requires a complex set of perturbations in cellular metabolism. Among these metabolic changes, oncogenic cells preferentially utilize sugar and amino acids in anabolic reactions to produce nucleotides required for the cellular growth, energy homeostasis, and excess dNTPs necessary for replication of genetic material of parental oncogenic cells. The de novo nucleotide biosynthetic pathway which synthesizes nucleotides from sugar and amino acid building blocks is a frequent target for chemotherapeutics seeking to combat cancer. However, current chemotherapies which use this approach often demonstrate significant toxicities in normal cells. Furthermore, many cancers have mechanisms to evade these approaches. There is a need to identify targets which can efficiently inhibit nucleotide biosynthesis specifically in cancerous cells.
Investigators at the University of California, San Francisco have identified a target which can be utilized for inhibition of the nucleotide biosynthetic pathway. This target is a key component for the production of pyrimidines, purines and pyridines. Since it is specific to proliferating cells, inhibition of this target may effectively avoid toxicity in normal cells while killing the oncogenic cells. The investigators have demonstrated the utility of this target in mouse and human oncogneic cell lines, wherein inhibition of the target resulted in cell death of Myc over-expressing cells but not wild type normal cells. It should be noted that MYC oncogene is a master regulator of normal cell growth, cell proliferation and metabolism. Myc couples cell cycle machinery with energy metabolism and ensures that adequate cellular resources are attained for cell growth and DNA synthesis. Thus, inhibiting the novel target has potential to restrain nucleotide biosynthesis and thereby inhibit the cancer-causing mechanism inherent within Myc overexpressing cells, thus killing them. The investigators are in the process of chemically screening compounds to inhibit this target. There is potential to collaborate and develop this technology rapidly.
|United States Of America||Issued Patent||9,765,337||09/19/2017||2012-205|