A step closer a new myeloma drug
In a study published in the scientific journal Clinical Cancer Research, researchers at Karolinska Institutet present a new drug candidate for the form of blood cancer known as multiple myeloma. The drug is called melflufen and is now to undergo larger clinical trials run by a pharmaceutical company. The researchers also hope that the drug, which seeks out the cancer tumours and activates cell death, will eventually be useable against other forms of cancer.
"We've been working together with chemists from Chalmers University of Technology in Gothenburg and pharmacologists at Uppsala University to build small peptides with DNA reactive components that bind to DNA in the cancer cells," says principal investigator Professor Rolf Lewensohn. "Just like proteins, peptides consist of a chain of amino acids. The effect of the drug depends, in part, on the structures of its amino acid sequence."
The drug is absorbed into the tumour through the action of peptidases, enzymes that break the bonds of the amino acid chains. The active DNA-binding component is then delivered to the nucleus and DNA of the tumour cell, where it causes damage and subsequently cell death. The amount of peptidases needed for the release of the active component in the drug varies from tumour to tumour, and determines the efficacy of the drug. The effect of the drug is also controlled by the ability of the tumour to protect itself from the very objective of the drug, namely to cause damage to its DNA.
In the present study, which is published in Clinical Cancer Research, the researchers show that cancer cells taken from patients with multiple myeloma, a form of tumour that affects the bone marrows plasma cells, are sensitive to melflufen and are destroyed through, amongst other processes, programmed cell death. They also show that cancer cells from patients exhibiting resistance to a number of other multiple myeloma drugs are highly sensitive to melflufen, which opens up new treatment options. It was known from before that the stromal cells (connective tissue) of the bone marrow can prevent cell death in myeloma cells; the present study shows that melflufen can activate cell death even in the presence of these cells.
"We'll now be studying opportunities for developing the drug principle and looking into what other forms of tumour the drug is active against," says Professor Lewensohn.
Melflufen has undergone a phase I clinical trial in Sweden and is now due for a larger clinical trial (phase II) on patients in the USA and Europe. The clinical trials are being conducted in collaboration with researchers at the Dana Farber Cancer Institute in Boston, USA, under the auspices of Oncopeptides AB, a drug company of which Professor Lewensohn was co-founder. The project was also presented recently at the European Hematology Association's 18th Conference in Stockholm.
In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells.
Clin. Cancer Res. 2013 Jun;19(11):3019-31