The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer

Our plain-English summary of The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer, by L.H. Matherly, Z. Hou, A. Gangjee (Cancer Chemotherapy and Pharmacology, 2018).

The study

• Authors: L.H. Matherly, Z. Hou, A. Gangjee
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2018;81(1):1-15
• Type of article: Review
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

This review considers the "promise" of exploiting the proton-coupled folate transporter (PCFT) for selective therapeutic targeting of cancer. PCFT was discovered in 2006 and was identified as the principal folate transporter involved in the intestinal absorption of dietary folates. The recognition that PCFT was highly expressed in many tumors stimulated substantial interest in using PCFT for cytotoxic drug targeting, taking advantage of its high level transport activity under the acidic pH conditions that characterize many tumors. For pemetrexed, among the best PCFT substrates, transport by PCFT establishes its importance as a clinically important transporter in malignant pleural mesothelioma and non-small cell lung cancer. In recent years, the notion of PCFT-targeting has been extended to a new generation of tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine compounds that are structurally and functionally distinct from pemetrexed, and that exhibit near exclusive transport by PCFT and potent inhibition of de novo purine nucleotide biosynthesis. Based on compelling preclinical evidence in a wide range of human tumor models, it is now time to advance the most optimized PCFT-targeted agents with the best balance of PCFT transport specificity and potent antitumor efficacy to the clinic to validate this novel paradigm of highly selective tumor targeting.

In plain English

This was a review article, not a new study. The authors reviewed published research on the proton-coupled folate transporter (PCFT). PCFT is a protein that carries folates and some cancer drugs into cells, and it works best in acidic conditions like those found in many tumors. The drug pemetrexed, approved in the US for malignant pleural mesothelioma in 2004, is carried by PCFT. The review described an earlier study of mesothelioma patients treated with pemetrexed. In that study, patients whose tumors had low PCFT levels had significantly lower rates of disease control and shorter overall survival. The review also described laboratory work on new experimental compounds, such as AGF94 and AGF154. These are taken up selectively by PCFT rather than the reduced folate carrier, but also enter through folate receptors. In mice carrying human mesothelioma and other tumors, these compounds showed antitumor activity. The main side effect reported was modest weight loss that reversed. The authors listed several unresolved questions. They concluded that the preclinical evidence supports moving the best of these compounds into the clinic. The review does not discuss asbestos.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published research
• Who was studied: No study population of its own. The review covered earlier laboratory studies (cancer cell lines, tumors grown in mice) and studies of human tumor specimens, including 124 malignant pleural mesothelioma specimens analysed in an earlier study (reference 70).
• Exposure: Not asbestos. The review concerns cancer drugs carried by PCFT: pemetrexed (PMX) and a new group of experimental 6-substituted pyrrolo[2,3-d]pyrimidine antifolates (for example AGF94 and AGF154).
• Main results:
  • In an earlier study of mesothelioma patients treated with pemetrexed (reference 70), in both a test group (73 patients) and a validation group (51 patients), those with low PCFT levels had significantly lower rates of disease control and shorter overall survival.
  • In the same earlier work, in 35 malignant pleural mesothelioma specimens from patients treated with pemetrexed, low PCFT protein levels went along with significantly shorter overall survival.
  • An earlier analysis of 80 cancer cell lines (reference 33) found substantial PCFT expression in 52 of 53 cell lines from solid tumors. PCFT levels were low to undetectable in leukemias.
  • The new thienoyl compounds were taken up selectively by PCFT rather than by the reduced folate carrier (RFC). AGF94 and AGF154 are also taken up through folate receptors, so the review describes them as dual folate receptor- and PCFT-targeted.
  • In earlier mouse experiments, AGF94 and/or AGF154 showed antitumor effects against early- and late-stage H2452 malignant pleural mesothelioma (reference 36), as well as lung and ovarian cancer grown in immunodeficient mice. Toxicity was minimal: modest weight loss that reversed completely after therapy.
  • In the mesothelioma mouse experiments shown in Fig. 6, AGF94 had stronger antitumor effects than the standard agents (gemcitabine, and cisplatin in the early-stage trial).
  • In cell culture tests on H460 lung cancer and IGROV1 ovarian cancer cells, AGF94 killed far more cells than pemetrexed.
• The authors' conclusion: The authors concluded that preclinical evidence from several tumor models suggests it is time to move the most optimized PCFT-targeted agents into the clinic.
• Limitations the authors state:
  • The authors stated that important questions remain unresolved. These include how PCFT is regulated and how resistance to PCFT-targeted agents develops.
  • The authors noted that all the new compounds reported so far are also taken up to some degree through folate receptors, so none is fully selective for PCFT.
  • The authors noted that an earlier study found severe hypoxia (very low oxygen) caused complete, reversible loss of pemetrexed's activity. They considered its relevance to tumors in the body uncertain.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Pleural Mesothelioma, Non-Small Cell Lung Cancer, De Novo.

Related studies

• Therapeutic targeting malignant mesothelioma with a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate via its selective uptake by the proton-coupled folate transporter — C. Cherian, S. Kugel Desmoulin, et al. (2013)
• The human proton-coupled folate transporter: Biology and therapeutic applications to cancer — S.K. Desmoulin, Z. Hou, et al. (2012)
• Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds — G. Li Petri, B. El Hassouni, et al. (2020)
• Malignant pleural mesothelioma: a therapeutic challenge — G. Dimitrakakis, T. BinEsmael, et al. (2011)
• Pharmacokinetic evaluation of pemetrexed — J.B. Sørensen (2011)
• Safety of Same-Day Vitamin B12 Supplementation in Patients Receiving Pemetrexed for the Treatment of Non-Small-Cell Lung Cancer or Pleural Mesothelioma: A Retrospective Analysis — Z. Schlei, W. Tan, et al. (2018)

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