The findings provide evidence that the MYC family of oncogenes is a driver of resistance.
Between 10% of 15% of lung cancers are small cell lung cancer. It is a stunningly aggressive form of the disease, with a short doubling time and early metastasis. In most cases, even if the cancer responds to platinum-based doublet chemotherapy, the responses are short lived. Almost all patients relapse within months with drug-resistant disease — and without benefit from effective second-line therapy.
But researchers from Monash University in Australia, may have found a drug that offers these patients new hope: Fimepinostat is “incredibly effective” in SCLC, says co-author Daniel Gough, Ph.D., and “doubles lung cancer survival time.”
Members of the MYC family of oncogenes, MYCL1, MYCN, and MYC are amplified in approximately 20% of SCLCs and are associated with worse outcomes. In their study, these researchers confirmed that MYC-overexpression is more frequent following platinum – etoposide chemotherapy.
Their findings, reported in the Journal of Experimental & Clinical Cancer Research, provide direct evidence that MYC is a “potent driver of resistance” both in vitro and in vivo.
Alternatives to platinum-based therapy are an urgent unmet clinical need, the researchers say. To identify novel drugs, they screened a library of 355 kinase inhibitors that might act against platinum-resistant MYC-expressing SCLC cell lines. They identified drugs that have previously been shown to be effective against SCLC, including PLK1, Aurora kinase A and CDK inhibitors. However, the most effective drug was the novel dual PI3K and HDAC inhibitor, fimepinostat.
When they put it to the test in a mouse study, fimepinostat by itself reduced tumor volume and significantly increased survival. Combining it with carboplatin and etoposide was even more effective, “very significantly” reducing tumor mass and extending survival even more, with median survival of 54.5 days.
Unlike some drugs, such as PLK1 inhibitors, which have failed in clinical testing due to toxicity, fimepinostat has a known safety profile, having been granted orphan drug approval for the treatment of relapsed/refractory diffuse large B-cell lymphoma. It has also entered phase I clinical testing for pediatric brain tumors with a high incidence of MYC amplification.
It is important to note, the researchers say, that fimepinostat was effective regardless of the MYC-expression status of the cell line. Their data show single-agent efficacy at concentrations achievable in patients. They also found significantly less toxicity in normal lung epithelium, suggesting that fimepinostat could be an effective treatment for SCLC while preserving normal lung epithelium.