‘Insights into a new drug for non-Hodgkin’s lymphoma’ – Written by Charlotte Harrison, Science Writer.
A team of researchers from have delved into the mechanism of a promising new anticancer drug that is set to enter clinical trials.
The study, published in Oncotarget, investigated the mechanism of action of a new-generation acylfulvene compound called LP-284 in cell and animal models of non-Hodgkin’s lymphoma (NHL). The research focused on mantle cell lymphoma and double-hit lymphoma as these NHL subtypes have high unmet need.
A better alkylating agent
Alkylating agents have been successful cancer therapies for decades due to their ability to damage DNA in fast-growing tumour cells and prevent cells from replicating. The compound at the centre of the current study, LP-284, is an acylfulvene – a class of alkylating agents that are selectively cytotoxic to cancer cells.
First, the researchers showed that, unlike other acylfulvenes that have been tested in clinical trials, LP-284 does not require PTGR1 prostaglandin reductase for bioactivation. This property of LP-284 is important because it means that the compound will likely work in the many haematological cancer cells that have low PTGR1 expression.
Broad activity
The researchers showed that LP-284 inhibited the survival of a panel of haematological cancer cell lines, including fifteen NHL cell lines. The potency of LP-284 was in the nanomolar range (approx. 350-600nM) and notably, the compound inhibited the growth of a drug-resistant cell line. Moreover, the activity of LP-284 was not affected by TP53 mutation status, which is typically associated with poor prognosis in NHL patients.
At a cellular level, a key mechanism of LP-284 was the induction of the repair of double-strand DNA breaks. The researchers also showed that LP-284 is particularly lethal in cells that have a deficient DNA damage response; such cells are a feature of some types of NHL.
Towards the clinic
In mice, LP-284 treatment prolonged the survival of a mantle-cell lymphoma model, and was more effective than the proteasome inhibitor bortezomib and the Bruton’s tyrosine kinase inhibitor ibrutinib. These two drugs are used in NHL but are not curative.
In addition, LP-284 inhibited the tumour growth of xenografts that did not respond to bortezomib or ibrutinib; one cycle of LP-284 treatment led to near-complete tumour regression.
The authors note that LP-284 has the potential to treat patients that are refractory to Bruton’s tyrosine kinase or proteasome inhibitors, especially people with unfavourable genetic features. Biomarkers of LP-284 activity are the next step of research.
The authors highlight how this current study “paves the rationale for clinical studies in NHL with DNA damage repair deficiency”. Indeed a Phase 1 clinical trial is anticipated to start this year.
