Back to the Basics of Anti-folate Therapy for Improved Cure of Pediatric Cancer

Key Words: Anti-folate therapy, Pediatric cancer, Methotrexate, Cellular response to folate deprivation, Cancer-specific dependency on folate, Folate metabolism

The standard of care for pediatric blood malignancies is the metabolic drug methotrexate (MTX). MTX inhibits the activity of the essential vitamin folate, an enzymatic cofactor known for its major role in both normal hematopoiesis and in proliferation of transformed blood cells. Fast proliferating cells require more folate to feed their increased need for nucleotides and are sensitive to MTX. MTX is considered an effective drug with a five-year survival rate that exceeds 85%. However, MTX therapy falls short in two main aspects: 1] Prognosis of young patients with hematologic tumors that reach the patient’s brain is unfortunately grave because these are not effectively cured by MTX.  2] MTX-induced toxicities interfere with the children’s normal development and can cause life-long complications.

To address MTX therapy’s significant drawbacks, an understanding of the differential sensitivity of normal and transformed hematopoietic cells is required. However, even though the response of cells to folate deprivation dictates their survival following MTX therapy, the molecular response to folate was never portrayed; It is not clear if folate is sensed directly by specialized sensors, and if folate deprivation induces a signal transduction response, and what are the proteins that take part in this response.

My preliminary results indicate a cellular response to folate deprivation that includes a transcriptional adjustment and that enables survival of cancer cells cultured in low folate. I propose to portray the components of the cellular response and their function using genetic and biochemical approaches. Additionally, I will search for cancer-specific vulnerabilities to folate deprivation using comparative genomic screens in transformed and non-transformed cells.

Once achieved, our expanded understanding of the cellular response to folate deprivation will enable specific targeting of cancer cells treated by MTX and will improve the efficacy of the drug, as well as reduce toxicity in healthy cells.