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Novel targets in mesothelioma may aid in developing treatment strategies

WCLC 2019
Phase 2, ADAM
Malignant pleural mesothelioma exhibits characteristic changes in microRNA (miRNA) levels, and they are predominantly downregulated. Many have a tumour suppressor function; some are overexpressed and appear to function as onco-miRNAs. These changes in miRNA expression provide avenues to develop new therapeutic approaches.

Whilst the majority of miRNA studies in malignant pleural mesothelioma have focused on miRNA mimics, recent studies suggest that antisense inhibitors have similar potential. The recent FDA approval of the first siRNA therapy –together with ongoing clinical trials of a number of miRNA mimic drugs– means that gene silencing drugs have moved from concept to reality. Continued preclinical studies and early phase clinical trials are needed to determine the true potential of miRNA-targeting in the treatment of malignant pleural mesothelioma [1].

Another field of interest is CDKN2A/MTAP deletion; this is the most common copy number alteration in malignant pleural mesothelioma and is known to be a poor prognostic factor. CDKN2A loss may be targeted by restoring p16ink4a or blocking MDM2, whilst MTAP codeletion may be targeted via inhibition of PRMT5, MAT2A, or methionine depletion [2].

A different approach in possible mesothelioma treatment is taken by Szlosarek et al. who targeted arginine metabolism [3]. This pathway is dysregulated in mesothelioma with deficiency of the rate-limiting enzyme arginosuccinate synthetase 1 (ASS1) being 3-fold higher in sarcomatoid and biphasic compared with epithelioid tumours. ASS1 inactivation via promoter methylation diverts the precursor aspartate for enhanced pyrimidine synthesis via carbamoyl-phosphate synthetase 2 (CAD), accounting in part for increased tumorigenesis. However, loss of ASS1 generates a collateral dependence on exogenous arginine for growth (auxotrophy) that may be exploited with arginine-degrading enzymes, such as arginine deiminase and arginase.

A randomised phase 2 trial of pegargiminase (ADI-PEG20, pegylated arginine deiminase) monotherapy in patients with ASS1-deficient mesothelioma revealed a 1.2-month progression-free survival benefit over best-supportive care only (3.2 vs 2.0 months; HR 0.56; P=0.03) [3]. The restricted mean overall survival was 15.7 months for the pegargiminase group versus 12.1 months for the best-supportive care group, for a difference of 3.6 months (P=0.13). Pegargiminase was well tolerated with a 13.6% grade 3-4 allergic rate, including anaphylactoid reactions and serum sickness, Thus, the ADAM trial is the first proof of principle study to show a survival benefit using an ASS1 biomarker-directed strategy (although the progression-free survival primary endpoint was modest). Currently, more research is ongoing in a phase 2/3 trial in mesothelioma, and combinations of pegargiminase with immune checkpoint blockade and modulators of resistance pathways seem to be promising areas for further development [3].

  1. Reid G, et al. ES03.01. WCLC 2019.
  2. Fennell DA, et al. ES03.02. WCLC 2019.
  3. Szlosarek P, et al. ES03.04. WCLC 2019.

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