UCLA researchers in the Department of Molecular and Medical Pharmacology have uncovered novel biomarkers to predict cancer sensitivity to PNP inhibitors.
BACKGROUND:
A common hallmark of cancer is the alteration of cellular metabolism. To sustain growth and proliferation, cancer cells must produce sufficient and balanced pools of deoxyribonucleotide triphosphates (dNTPs) for DNA replication and repair. Impaired nucleotide pools impair biosynthetic pathways and are toxic to cancer cells. Several drugs targeting dNTP biosynthesis have been explored for cancer treatment, but they have been found to be ineffective when administered alone: one such class of drug is purine nucleotide phosphorylase (PNP) inhibitors, a class that includes the drugs forodesine and ulodesine. Therefore, a currently unmet need exists to effectively target the alteration of cellular metabolism as a novel treatment pathway for cancer.
INNOVATION:
UCLA researchers screened a panel of human cancer cell lines for sensitivity to PNP inhibition and uncovered that sensitive cell lines all shared a deficiency of one key enzyme. The knockout of this enzyme in a cancer cell line caused the administration of PNP inhibitors to become lethal. Several solid tumor cell line models were deficient in this key enzyme, and pharmacological PNP inhibition was highly effective in these models. This work demonstrates that PNP inhibitors (including forodesine and ulodesine) may have utility in treating both hematological cancers and solid tumors characterized by low expression of this key enzyme.
POTENTIAL APPLICATIONS:
• Detection of hemopoietic and solid tumor susceptible to treatment by PNP inhibitors
• New drug target for potential combination therapies to regulated dNTP biosynthesis
ADVANTAGES:
• Allows for targeted use of PNP inhibitors on susceptible cancers
DEVELOPMENT-TO-DATE:
A panel of human cancer cell lines was screened for sensitivity to PNP inhibition. The role of the key enzyme was confirmed in a CRISPR knockout cell line that became sensitive to PNP inhibitors.