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New Biomarker Could End Mesothelioma Resistance to Chemotherapy

Researchers at VU University Medical Center believe that a newly-identified mesothelioma biomarker could reduce resistance to chemotherapy in mesothelioma patients. In the study titled “Role of proton-coupled folate transporter in pemetrexed-resistance of mesothelioma: clinical evidence and new pharmacological tools,” the team wrote:

Thymidylate synthase (TS) has a predictive role in pemetrexed-treatment of mesothelioma. However, additional chemoresistance mechanisms are poorly understood. Here we explored the role of the reduced-folate carrier (RFC/SLC19A1) and proton-coupled folate-transporter (PCFT/SLC46A1) in antifolate-resistance in mesothelioma.

Pemetrexed (trade name Alimta), is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug, and is classified as an "antimetabolite." According to Chemocare, “antimetabolites are very similar to normal substances within the cell.”  When the cells integrate substances such as pemetrexed into themselves during growth, “the cells lose the ability to divide.” Because they are cell-cycle specific, antimetabolites act on the cells at precise phases in the cells' replication cycle.

Antimetabolites are classified “according to the substances with which they interfere.” Pemetrexed is classified as an “antifolate” antimetabolite, so the drug wields its chemotherapeutic effect by “disrupting production of folate, which is essential for cell replication.” Pemetrexed is currently one of just two chemotherapy drugs specifically approved for the treatment of mesothelioma.

In the study, researchers determined PCFT, RFC and TS RNA and PCFT protein levels by quantitative-RT-PCR of frozen tissues and immunohistochemistry of tissue-microarrays, respectively, in two cohorts of pemetrexed-treated patients. The researchers wrote, “data were analyzed by t-test, Fisher/log-rank test and Cox-proportional models. The contribution of PCFT expression and PCFT -promoter methylation on pemetrexed activity were evaluated in mesothelioma cells and spheroids, through 5-aza-2'-deoxycytidine-mediated demethylation and siRNA-knockdown.”

The results of the analysis showed:

  • Pemetrexed-treated patients with low-PCFT had significantly lower rates of disease control, and shorter overall-survival (OS), in both the test (N = 73, 11.3 vs. 20.1 months, P = 0.01) and validation (N = 51, 12.6 vs. 30.3 months, P = 0.02) cohorts. Multivariate analysis confirmed PCFT independent prognostic role.
  • Low-PCFT protein levels were also associated with shorter OS. Patients with both low- PCFT and high-TS levels had the worst prognosis (OS, 5.5 months), whereas associations were neither found for RFC nor in pemetrexed-untreated patients.
  • PCFT silencing reduced pemetrexed sensitivity, while 5-aza-2'-deoxycytidine overcame resistance.

“These findings identify for the first time PCFT as a novel mesothelioma prognostic biomarker,” wrote the team, “prompting prospective trials for its validation.” Moreover, “preclinical data suggest that targeting PCFT-promoter methylation might eradicate pemetrexed-resistant cells characterized by low-PCFT expression.”

 

Sources

Giovannetti, E., and P.A. Zucali. "Role of Proton-coupled Folate Transporter in Pemetrexed-resistance of Mesothelioma: Clinical Evidence and New Pharmacological Tools." Annals of Oncology. National Center for Biotechnology Information, 01 Sept. 2017. Web. 16 Oct. 2017.

"Pemetrexed." Chemocare.com. Cleveland Clinic, 18 June 2017. Web. 16 Oct. 2017.