Antiparasitic derived drug combat blood cancer
In order to promote survival, cancer cells rely on different signaling pathways. A new drug with promising preclinical evidence is proposed by scientists at the University of Alberta that could work in blood cancers by targeting signaling pathways of B-cells.
In mouse models, the PCLX-001 compound introduction resulted in significant regression of the tumor. The compound completely cleared lymphoma that previously had stopped responding to the standard therapies CHOP and Rituxan of Roche. A detail of the study is reported in Nature Communications.
Pacylex Pharmaceuticals, which is a spinout of the University of Alberta, is planning for a phase I trial of the drug in colon, leukemia, breast, and lymphoma cancers. Pacylex Pharmaceuticals is part of the Merck Invention Accelerator, Edmonton, Alberta.
PCLX-001 is an NMT enzyme inhibitor. Because NMTs assures the viability of parasites, NMT inhibitors, which are small-molecule, have been developed. PCLX-001 is derived from a drug that is currently under study for the treatment of African sleeping sickness.
NMTs expression increases during cancers, and hence NMTs have been proposed to be anti-cancer targets. The team of researchers, the University of Alberta, screened PCLX-001 against 300 cell lines in this study. Growth is inhibited by this drug at far higher levels in lymphoma, myeloma, and leukemia, compared to other cancer cells.
How does the drug function?
NMTs mediates myristoylation in humans. Myristoylation is defined as the process of adding the fatty acid myristate to proteins. This cellular process is part of the cell signaling system and is important for the interaction of proteins with cell membranes.
The team discovered that there are lesser copies of NMTs in blood cancers, making them more sensitive to PCLX-001. As a result, myristoylation in malignant lymphoma cells is affected more so than in normal B cells.
The main pathway leveraged by lymphoma cells in order to avoid normal programmed cell death is the B-cell receptor (BCR) signaling. PCLX-001 is a potent inhibitor of this key signaling pathway. The team discovered that along with other downstream BCR signaling proteins, the levels of Src-family tyrosine kinases (SFKs) are reduced by PCLX-001 as well.
According to scientists, the ability of the drug to suppress BCR signaling is superior to that of SFK inhibitor Sprycel by Squibb and BTK inhibitor Imbruvica by Johnson & Johnson and AbbVie.
The test on two lymphoma mouse models for the effect of PCLX-001 showed that PCLX-001 significantly reduced the growth of tumor cells, and on the application of higher doses, it induces complete remission. The team further reported that large B-cell lymphoma that was refractory to common CHOP, RICE, and DHAP regimens, responded to the high-dose drug and resulted in complete regression of the tumor in six of the eight mice studied.
For inspiration in developing new therapies, scientists have been investigating pro-survival signaling in cancer cells. Recently, a group of researchers from China discovered that AKT inhibitor MK-2206 from Merck blocked the wnt and EGF signaling pathway. This pathway activates a gene that has a significant contribution to the crippling of T cells of the immune system.
Luc Berthiaume, who is the senior author of this study on PCLX-001, is hopeful that the clinical testing of the drug will be on the move by the end of this year. He added that the team sees large therapeutic potential in the compound PCLX-001. This compound can kill cancer cells in much lower concentration than what is required to kill normal cells.
Antiparasitic derived drug combat blood cancer.
