An RNAi therapeutic, DFP-10825, for intraperitoneal and intrapleural malignant cancers

Our plain-English summary of An RNAi therapeutic, DFP-10825, for intraperitoneal and intrapleural malignant cancers, by H. Ando, T. Ishida (Advanced Drug Delivery Reviews, 2020).

The study

• Authors: H. Ando, T. Ishida
• Journal: Advanced Drug Delivery Reviews
• Published: 2020;154-155:27-36
• Type of article: Review
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

RNA interference (RNAi), a potent post-transcriptional gene-silencing action, has received considerable attentions as a novel therapeutic tool to treat intractable cancers. In recent days, we have developed a novel RNAi-based therapeutic formulation, DFP-10825, for the treatment of intractable advanced cancers developed in coelomic cavities. DFP-10825 was composed of chemically synthesized short hairpin RNA (shRNA) against thymidylate synthase (TS), a key enzyme for cancer proliferation, and cationic liposomes, and achieved high therapeutic effect on the mouse models of peritoneally disseminated gastric and ovarian cancers and malignant pleural mesothelioma without severe side effects by intracoelomic direct treatment. We further designed a freeze-dried DFP-10825 formulation for mass industrial production. DFP-10825 is undergoing in pre-clinical phase and goes to clinical trials. This review introduces a DFP-10825 formulation, a potent novel RNAi-based therapeutic maximizing the benefit of RNAi molecule (shRNA).

Copyright © 2020. Published by Elsevier B.V.

In plain English

This was a narrative review in which the authors described their own development of DFP-10825, an RNA interference therapeutic made of chemically synthesized short hairpin RNA (shRNA) against thymidylate synthase (TS) complexed with cationic liposomes, intended for direct injection into the peritoneal or pleural cavity. The review summarised previously published mouse experiments: a single intraperitoneal treatment suppressed growth of peritoneally disseminated SLOV3 ovarian tumours and extended survival, further prolonged by added paclitaxel; intraperitoneal DFP-10825 suppressed MKN45 and NCI-N87 gastric tumours more than oral S-1, with no significant body weight loss. For malignant pleural mesothelioma, described as often caused by asbestos exposure with over 20 years latency, pemetrexed combined with TS shRNA was more cytotoxic in MSTO-211H-Luc cells, and intrapleural DFP-10825 plus pemetrexed inhibited pleural tumour development in an orthotopic mouse model more than pemetrexed alone. Freeze-dried lipoplex formulations produced a therapeutic effect equivalent to the conventional lipoplex after intraperitoneal administration in the gastric cancer mouse model. The authors concluded DFP-10825 could be a promising strategy; it remains pre-clinical, and they received funding from Delta-Fly Pharma.

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: narrative review by the developers of DFP-10825, summarising their own preclinical work and listing RNAi candidates in clinical trials
• Who was studied: Not a human study; the review covered mouse models (peritoneally disseminated SLOV3 ovarian carcinoma, MKN45 and NCI-N87 gastric carcinoma, orthotopic MSTO-211H-Luc malignant pleural mesothelioma) plus cultured mesothelioma cells, and a table of 56 RNAi candidates in clinical trials
• Exposure: The intervention reviewed was DFP-10825: chemically synthesized shRNA against thymidylate synthase complexed with cationic liposomes (DC-6-14, DOPE, DOPC), given by intraperitoneal or intrapleural injection, alone or with paclitaxel or pemetrexed; asbestos is mentioned only as the usual cause of malignant pleural mesothelioma
• Main results:
  • In mice with peritoneally disseminated SLOV3 ovarian carcinoma, a single intraperitoneal DFP-10825 treatment suppressed tumour growth and extended survival; adding intraperitoneal paclitaxel enhanced the effect
  • In peritoneally disseminated MKN45 and NCI-N87 gastric carcinoma mouse models, intraperitoneal DFP-10825 suppressed tumour growth and showed a greater suppressive effect than oral S-1
  • No significant body weight loss was observed with intraperitoneal DFP-10825 treatment regimens in the mouse models
  • After intraperitoneal injection, the TS shRNA was retained in the peritoneal cavity and accumulated selectively in disseminated tumours without transfer into blood circulation or into liver, spleen and kidney
  • In MSTO-211H-Luc human mesothelioma cells, pemetrexed combined with TS shRNA transfection was more cytotoxic than pemetrexed alone
  • In the orthotopic MPM mouse model, intraperitoneal pemetrexed combined with intrapleural DFP-10825 inhibited development of pleural disseminated tumours more than pemetrexed alone, and imaging showed prolonged pleural retention of DFP-10825
  • Freeze-dried lipoplex formulations (FD-lipoplex-1, FD-lipoplex-2) had particle size and zeta-potential almost comparable with the conventional lipoplex and, given intraperitoneally, produced a therapeutic effect equivalent to the conventional lipoplex in the peritoneally disseminated gastric cancer mouse model
  • Of the RNAi therapeutic candidates in clinical trials tabulated by the authors, none used the intraperitoneal or intrapleural route
• The authors' conclusion: The authors concluded that DFP-10825, still in a non-clinical GLP safety study, could be a promising strategy for patients with intractable advanced cancers and peritoneally disseminated metastasis, and they expressed the belief it will reach the market
• Limitations the authors state:
  • The authors noted that chemically synthesized exogenous shRNA should be less efficient at gene silencing than exogenous siRNA or shRNA expressed from plasmid DNA
  • The authors stated the product is in the pre-clinical phase and has not yet entered clinical trials
  • The authors declared research funding from the company collaborating on the formulation

Topics

Medical terms in this study, explained in our Lexicon: Ovarian Cancer, Pleural Mesothelioma, Clinical Trial.

Related studies

• An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma — A. Linton, Y.Y. Cheng, et al. (2014)
• Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model — A.S. Abu Lila, C. Kato, et al. (2016)
• Synergistic Enhancement of Cellular Uptake With CD44-Expressing Malignant Pleural Mesothelioma by Combining Cationic Liposome and Hyaluronic Acid-Lipid Conjugate — Y. Sakurai, A. Kato, et al. (2019)
• Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas — A. Shukla, J.M. Miller, et al. (2013)
• Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma — R. Sciarrillo, A. Wojtuszkiewicz, et al. (2019)
• Anticancer property of bromelain with therapeutic potential in malignant peritoneal mesothelioma — K. Pillai, J. Akhter, et al. (2013)

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