Folate receptors and transporters: biological role and diagnostic/therapeutic targets in cancer and other diseases

Abstract

Folate receptors and transporters and one-carbon metabolism continue to be important areas of study given their essential roles in an assortment of diseases and as targets for treatment of cancer and inflammation. Reflecting this, every 2 years, the Folate Receptor Society organizes an international meeting, alternating between North America and Europe, where basic and translational scientists, clinical oncologists and rheumatologists from both academia and industry convene in an informal setting. The 7th International Symposium on Folate Receptors and Transporters was held in Sant’Alessio Siculo (ME), Taormina, Italy from 1st to 5th of October 2018, organized by Dr. Mariangela Figini from Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Following the format of previous meetings, more than 50 scientists from 9 different countries attended the 2018 meeting to share ongoing developments, discuss current research challenges and identify new avenues in basic and translational research. An important feature of this meeting was the participation of young investigators and trainees in this area, two (A. Dekhne and N. Verweij) of whom were awarded fellowships to attend this meeting as a recognition of the high scientific quality of their work. This report provides a synopsis of the highlights presented in the following sessions: Barton Kamen Lecture; Targeting one-carbon metabolism in cytosol and mitochondria; Structure and biology of the one-carbon solute transporters; Physiology and pathophysiology of folate receptors and transporters; Folate receptors for targeting tumors and inflammatory diseases; Conventional and new anti-folate drugs for treating inflammatory diseases and cancer; Imaging; Ongoing clinical trials; and Chimeric Antigen Receptor cell therapies of cancer.

Current Targets and Bioconjugation Strategies in Photodynamic Diagnosis and Therapy of Cancer

“…The folate receptor (FR) was among one of the first targets for cancer therapy, in particularly FR isoform α (FRα). This isoform of FR is the most efficient in folate uptake and has been found to be highly expressed in numerous cancerous, including gastric, lung, brain, endometrial, ovarian, and others [140][141][142]. The expression of the folate receptor is seen in normal human tissues, including kidneys [143], lungs [143], as well as the ovary and liver [144].…”

Assessment of Intracellular Delivery Potential of Novel Sustainable Poly(δ-decalactone)-Based Micelles

“…Several FA-conjugated drug delivery carriers such as liposomes, nanoparticles, micelles, dendrimers, and carbon nanotubes have been investigated for targeted cancer therapy [ 4 ]. Based on the excellent in vitro and in vivo results, a few folic acid-based drug delivery systems have been entered in clinical trials [ 5 ].…”

Schedule-Dependent Synergy Between the Histone Deacetylase Inhibitor Belinostat and the Dihydrofolate Reductase Inhibitor Pralatrexate in T-and B-cell Lymphoma Cells in vitro

“…PLX was designed to be a better substrate for RFC, but other transporters facilitating the uptake of folates and antifolates could be involved ( Gonen and Assaraf, 2012 ). These include the folate-receptor α or β (FRα,β) ( Westerhof et al, 1995a , b ; van der Heijden et al, 2009 ; Zhao et al, 2009 ; Frigerio et al, 2019 ), representing a high affinity low capacity transporter, and the proton-coupled folate transporter (PCFT), which is a high capacity transporter with an acidic pH optimum of about 5.5 ( Zhao et al, 2008 ; Matherly et al, 2018 ). PLX competitively inhibits DHFR ( DeGraw et al, 1993 ), an enzyme that converts dihydrofolate (DHF) into tetrahydrofolate (THF).…”

“…Based on these properties, PLX has been tested in several other hematological and solid tumors as a single agent and in various combinations ( Marchi et al, 2010 , 2013 ; Serova et al, 2011 ; Dovzhanskiy et al, 2012 ). Antifolates can also be considered as epigenetic drugs since they affect cellular methylation reactions, due to inhibition of one-carbon metabolism ( Frigerio et al, 2019 ).…”