Irofulven
Irofulven or 6-hydroxymethylacylfulvene (also known as HMAF and MGI-114) is an experimental cancer drug.<ref name="pmid18388315">Template:Cite journal</ref><ref name="pmid8913837">Template:Cite journal</ref> It belongs to the family of drugs called alkylating agents.
It inhibits the DNA replication of cultured cells deficient in the nucleotide excision repair pathway.<ref name="pmid17118344">Template:Cite journal</ref><ref name=":0">Template:Cite journal</ref>
Irofulven is an analogue of illudin S, a sesquiterpene toxin found in the Jack 'o' Lantern mushroom (Omphalotus illudens). The compound was originally synthesized by Dr. Trevor McMorris and found to have anticancer properties in mice by Dr. Michael J Kelner.<ref>Template:Cite journal</ref>
Licensing and Clinical development
The drug was created and patented by the University of California, San Diego (UCSD), and subsequently licensed to the US biotech company MGI Pharma. Eisai acquired MGI in 2007, and the license was returned to UCSD, which then re-licensed the potential cancer drug to Lantern Pharma in 2015. Soon after, the drug was again sub-licensed to Oncology Venture, now known as Allarty Therapeutics A/S.
The drug has undergone a number of clinical trials, mostly for late-stage tumors as well as ovarian and prostate cancers, usually preceded by treatment with carboplatin and paclitaxel. A multi-center phase 2 trial involving patients with Recurrent or Persistent Ovarian Epithelial or Primary Peritoneal Cancer was well tolerated but irofluven demonstrated modest activity as a single agent.<ref>Template:Cite journal</ref> Previously, a European Phase I study in combination with cisplatin showed substantial evidence for anti-tumor activity. In that study, irofulven showed rapid elimination and high interpatient variability. Platinum and irofulven pharmacokinetics did not suggest drug-drug interactions.<ref>Template:Cite journal</ref>
Despite modest successes demonstrating limited efficacy for late stage tumors that were statistically not significant enough to support broader clinical trials, Allarty decided to stratify patient populations with companion diagnostic tools (biomarkers) to predict outcomes, and thus select that sub-set of patients through DRP (Drug Response Predictors), for whom treatment with irofulven would be most effective. Allarty initiated two Phase 2 drug-screening studies at two Danish University Hospitals for late-stage prostate cancers, wherein 300 patients have been included to be screened, of which only 27 are to be selected for the Phase 2 trial.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}Template:Dead link</ref> In 2021, Lantern Pharma reacquired the rights to the development and commercialization of irofulven. At that time, 9 of the intended 27 patients had been a part of the study which saw an increase of median overall survival from 2.6 to 5.4 months.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The study was still ongoing as of late 2024.<ref name=":1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Since it was first synthesized, research with irofulven has decreased dramatically over the past decade with only one clinical trial currently being run.<ref name=":1" /> A study published in 2021 showed cells with nucleotide excision repair (NER) deficiencies were susceptible to iroflaven while cells without these NER deficiencies were not overly affected. The deficiency of tumors in NER was seen as a potential identifier for patient candidates.<ref name=":0" /> Since this discovery, research has increased with researchers calling irofulven a "previously abandoned" anticancer drug.<ref>Template:Cite journal</ref><ref name=":0" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Synthesis
A synthesis of irofulven has been reported.<ref>Template:Cite journal</ref>
Mechanism
Using the AP-site-sequencing method click-code-seq, researchers from ETH Zurich found that irofulven-induced DNA modifications accumulate predominantly in AA dimers and promoters as well as non-transcribed strands of genes, which likely reflects the action of TC-NER.<ref>Template:Cite journal</ref>