An important class of drug used to treat cancer patients could be used to treat brain aneurysms, according to new research published this week.
Brain aneurysms are a bulge in a blood vessel caused by a weakness in the blood vessel wall.
As blood passes through the weakened blood vessel, blood pressure causes a small area to bulge outwards.
They can develop anywhere in the body but are most common in the abdominal aorta (the artery that carries blood away from the heart) and the brain.
It’s difficult to estimate exactly how many people are affected by brain aneurysms as they usually cause no symptoms until they rupture, but experts believe it could be anywhere from 1 in 100 to as many as 1 in 20 people.
Treatment is difficult, involving complex surgery which is currently only attempted in select cases.
In a notable example, Game of Thrones actress Emilia Clarke suffered from two aneurysms while filming the series, undergoing surgery as a result.
Working in collaboration with colleagues at University of Washington School of Medicine in Seattle, USA, scientists at the University of Sussex may now have found a safer and more efficient possible treatment involving receptor tyrosine kinase inhibitors, a class of drug currently used to treat cancer.
Conventional cytotoxic chemotherapy involving DNA-interacting agents and indiscriminate cell death is no longer the future of cancer management.
While chemotherapy is not likely to completely disappear from the armamentarium; the use of targeted therapies in combination with conventional treatment is becoming the standard of care in human medicine.
Tyrosine kinases are pivotal points of functional cellular pathways and have been implicated in malignancy, inflammatory, and immune-mediated diseases.
Pharmaceutical interventions targeting aberrant tyrosine kinase signaling has exploded and is the second most important area of drug development.
The “Valley of Death” between drug discovery and approval threatens to blunt the enormous strides in cancer management seen thus far.
Kinase inhibitors, as targeted small molecules, hold promise in the treatment and diagnosis of cancer.
However, there are still many unanswered questions regarding the use of kinase inhibitors in the interpretation and management of cancer.
Comparative oncology has the potential to address restrictions and limitations in the advancement in kinase inhibitor therapy.
Kinases as an Attractive Drug Target
Protein kinases are considered to be the second most important group of drug targets after G-protein-coupled receptors [16,17].
Aberrant kinase activity is implicated in a large variety of diseases, particularly those involving inflammatory or proliferative responses, such as cancer, rheumatoid arthritis, cardiovascular and neurological disorders, asthma and psoriasis.
Directly or indirectly, hundreds of human diseases have been connected to protein kinase dysfunction.
The ability to modulate kinase activity therefore represents an attractive therapeutic strategy for the treatment of human illnesses [18].
Kinase activity is typically regulated by interconverting between two structural conformations via phosphorylation of key amino acid residues, shifting the balance between active and inactive.
These two states are characterized by movements in conformationally mobile loops that border or block the ATP binding site of the kinase.
For this reason, the dissociation constant for ATP may be significantly higher for the inactive conformation than for the active conformation.
This kinase activation model provides the framework for drugs designed to interact with specific kinase domains.
A large number of kinase inhibitors selectively target the inactive conformation, whereas other compounds bind to both conformations with similar affinity [19,20,21].
Inhibitors that bind to the inactive conformation likely face weaker competition with cellular ATP.
The potential result is enhanced activity in vivo, acting primarily to shift equilibria between conformational states to prevent kinase activation, indirectly inhibiting activity [22].
The modulation of kinase activity can be achieved through either direct or indirect strategies (Figure 1).
Imatinib (Gleevec; Novartis) is the prototype of direct protein-tyrosine kinase inhibitors that inhibits the BCR-ABL phosphorylation activity through blocking ATP binding.
Imatinib has been approved for the treatment of patients with BCR-ABL positive chronic myeloid leukemia (CML) and patients with Kit (CD117)-positive gastrointestinal stromal tumors. BCR-ABL is the constitutively active tyrosine kinase in CML and in certain forms of acute lymphoblastic leukemia.
Imatinib also inhibits the kinase activity of platelet derived growth factor receptor, stem-cell factor receptor and c-kit.
Indirect kinase inhibition involves disruption of protein-protein interactions. Cetuximab (Erbitux; ImClone/Bristol-Myers Squibb) is a monoclonal antibody that selectively binds to the extracellular domain of human epidermal growth factor receptor (EGFR), and competitively inhibits binding of epidermal growth factor (EGF) to its receptor tyrosine kinase.
Bevacizumab (Avastin; Genentech) is the first anti-angiogenesis cancer drug approved by the FDA.
Bevacizumab binds to human vascular endothelial growth factor A (VEGF-A), and prevents it from binding to its receptor tyrosine kinases, Flt-1/VEGFR1 and KDR/VEGRF2.
Inhibition of VEGF signaling interferes with tumor blood vessel development, a process that is crucial for tumor growth and metastasis [23].
The activation loop of the protein kinase domain regulates access to the ATP binding site. The conformation of a conserved Asp-Phe-Gly (DFG) motif within the activation loop is used to categorize the binding mode of inhibitors. The common types of kinase—kinase inhibitor interactions include: (a) Type I inhibitors (red star) bind the ATP binding site (grey) of the protein kinase domain (green). The aspartate side chain in the conserved DFG motif at the beginning of the activation loop (black) faces into the active site; (b) Type II inhibitors bind a flipped conformation of the DFG motif in which the aspartate side chain faces outwards; (c) Allosteric ligands bind to binding pockets (white) that do not overlap with the active site of the kinase. The DFG motif conformation is not important. These binding pockets can be adjacent to the active site or distant from the active site.
Compounds that bind to protein kinases outside of the ATP-binding pocket may possess advantages over ATP-competitive counterparts.
Drugs can be administered at concentrations closer to their biochemical inhibition constant, as inhibition is not affected by fluctuations in the cellular concentration of ATP.
There is a potential for greater selectivity as residues outside the ATP binding pocket tend to be less conserved.
In certain cases, noncompetitive inhibitors can be substrate selective, inhibiting the activity of a kinase against only a subset of its targets.
Rapamycin, the first noncompetitive kinase inhibitor to be identified, is a cyclic macrolide that inhibits the protein kinase mammalian target of rapamycin (mTOR) [24].
MEK1 inhibitor PD098059, the first synthetic noncompetitive kinase inhibitor to be described, acts by binding to inactive MEK1 and preventing its phosphorylation by the upstream kinase Raf [25,26].
Several such inhibitors, termed allosteric, have been described, targeting kinases such as Akt, and inhibitor of nuclear factor kappa-B kinase (IKK-2) [27,28].
The target regions for most kinase inhibitors are intracellular. As small molecules, kinase inhibitors enter the cell by diffusion down the concentration gradient that exists across the membrane.
The rate at which this process occurs, and the rate of active efflux, are important determinantsof the intracellular bioavailability of a kinase.
How quickly the intracellular inhibitor concentration reaches a steady state and the relative concentrations of inhibitor inside and outside the cell at steady state rely on the relative lipophilicity vs. hydrophilicity characteristics of the drug.
The rate that it permeates the cellular membrane and non-specific binding to proteins and may affect the route of administration and dosing schedule [29,30].
Expression of drug efflux pump transporters has been shown to reduce the steady-state intracellular drug concentration, although most mammalian cells in culture appear to have less efflux activity for kinase inhibitors compared to chemotherapeutics such as doxorubicin.
Using sophisticated next generation DNA sequencing technologies, teams in Washington lead by Manuel Ferreira, Associated Professor of Neurological Surgery, identified a new genetic basis of a form of brain aneurysm (mutations PDGFRB).
This was unexpected, as mutations in this gene have been previously identified in completely different human developmental disorders.
Mark O’Driscoll, Professor of Human Molecular Genetics at the Genome Damage and Stability Centre at the University of Sussex, then found that multiple disease-associated mutations in PDGFRB caused a specific abnormality in its encoded protein.
This abnormality causes its activity to remain locked in a hyper-active form, referred to as gain-of-function variants – in effect, causing the protein to always be ‘turned-on’.
Publishing their findings in this months’ edition of the American Journal of Human Genetics, the Sussex team also demonstrated that this abnormal form of the protein can, in some cases, be countered by a drug which is currently used in cancer treatments.
Professor O’Driscoll said: “This is an extremely exciting discovery which shows how basic lab-derived observations on a genetic level can move into a clinical setting and start making big changes to public healthcare and treatments.
“Our research focused primarily on understanding the genetic and cellular mechanisms underlying a particular type of aneurysm.
“By finding a new genetic basis in some patients, we were also able to demonstrate that a known cancer drug could counter this genetic basis in most instances.
“Understanding the genetics behind diseases like this is crucial in identifying possible treatments and next steps – and that is exactly what our part in this new research has shown.
“The lead authors and our collaborators on this paper based in the US, are now working on the next stages to test this drug further.”
Drug repurposing is not unheard of, and there are already some success stories including the use of thalidomide as a treatment for leprosy as well as a blood cancer called multiple myeloma.
Dr. Manuel Ferreira, lead author of the report from the University Of Washington School Of Medicine, said, “We are now very close to treating these aneurysm patients with PDGFRB variants with specific receptor tyrosine kinase inhibitors.”
More information: Yigit Karasozen et al, Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms, The American Journal of Human Genetics (2019). DOI: 10.1016/j.ajhg.2019.03.014
Journal information: American Journal of Human Genetics
Provided by University of Sussex
