New research from Arizona State University’s (ASU) Biodesign Institute has found that leukaemia drug ibrutinib, marketed by Janssen under the Imbruvica brand name, could be instrumental in developing new cancer treatments.
The drug was first approved by the US Food and Drug Administration (FDA) in 2013 for treating leukaemia, given its ability to inhibit Bruton’s tyrosine kinase (BTK) in white blood cells. The drug was approved in Europe for the treatment of chronic lymphocytic leukaemia in October 2014.
The Biodesign Institute’s research builds on the use of kinase inhibitors, an increasingly prominent method of treating cancer. These target receptor tyrosine kinases (RTKs) which protrude from cell surfaces and bind with signalling molecules. As such they are able to activate cancer-related pathways in almost every type of cancer. Tackling RTKs could mean halting of the growth and progression of tumours.
The study found that ibrutinib can target ERBB4, a relatively unexplored member of the RTK family. When exposed to the drug, human cancer cell growth was limited, while tumour size in mice was reduced.
ERBB4 is of great interest to the medical community. Recent studies have linked it to melanoma and lung cancer, as well as an altered version being seen in breast cancer, neuroblastoma, colon cancer and non-small cell lung cancer. There are also indications that ERBB4 may play a role in diseases such as amyotrophic lateral sclerosis, autism and schizophrenia.
The study’s lead author Dr. Femina Rauf said: "No one has done a systematic study for drugs for ERBB4. Researchers tend to concentrate on EGFR and ERBB2 because these are attractive targets in the cancer field. Recent reports have found many mutations in ERBB4, especially in lung cancer and in melanoma, suggesting this receptor may play an important role in oncogenesis or the development of cancer."
A new screening process
The ASU researchers made use of a novel drug-screening process. A microarray platform created by Biodesign Institute director Dr Joshua LaBaer was used to test 108 different protein kinases and 30 non-kinases. The platform allows researchers to see the proteins’ interactions with each other, as well as with nucleic acids such as DNA and RNA or pathogens found in blood.
LaBaer said of the screening method: “It demonstrated that the proteins on these arrays are functionally active in a manner that reflects their natural activity and enables us to screen for their responses to selective drugs...provid(ing) a tool that would enable us to look for off-target responders to drugs or determine how specific acquired mutations might affect drug response.”
Examining proteins often proves difficult as they are delicate structures, which lose functionality if folded incorrectly. Because of this, printing them onto slides is an inefficient and labour-intensive process. In the ASU study, the researchers used a new technology known as a nucleic acid programmable protein array (NAPPA). This allows for a more efficient system for protein screening. The NAPPA array does not print proteins onto a microarray slide, but rather synthesises them with DNA known as plasmids, allowing for a more natural folding of the protein and thus protecting their structure.
In addition to its findings on ibrutinib, the study also validated NAPPA technology as an unbiased drug-screening platform.