Using a Protein to Fight Brain Cancer
June 20, 2017
Excerpted from Scientia — There is an urgent need for new therapies to target challenging, difficult-to-treat cancers such as glioblastoma, the most common, but highly aggressive form of brain cancer. Glioblastoma has a particularly high mortality rate largely from the tumor’s ability to resist treatment.
To meet this need, BGU’s Prof. Varda Shoshan-Barmatz, former director of the National Institute for Biotechnology in the Negev, renowned researcher in the field of mitochondrial biology and member of BGU’s Department of Life Sciences, is exploring VDAC1, a key protein in the metabolic adaptations during cancer development.
Using VDAC1, Prof. Shoshan-Barmatz has developed treatments that either kill cancer stem cells or lead to their reprogramming, reversing their properties to those of non-cancerous cells.
The Hallmarks of Cancer Development
A cell undergoes changes and acquires several traits that mediate its transformation from normal to malignant. These acquired traits, often referred to as the “hallmarks of cancer,” enable the cell to thrive when under normal circumstances it would die.
In her research, Prof. Shoshan-Barmatz “hijacks” two important hallmarks of cancer development and survival, turning them against cancer cells.
The Mitochondria – The Cellular Power Plant
Metabolic reprogramming and avoidance of cell death are two of several acquired traits of cancer cells that rely on the rewiring of an organelle called the mitochondrion. In addition to serving as the cell’s powerhouse, mitochondria also play a pivotal role in regulating programmed cell death, commonly referred to as “apoptosis.”
Apoptosis allows the efficient removal of unnecessary or menacing cells. Consequently, deficiencies in the regulation of apoptosis are linked to numerous diseases, including neuronal degenerative diseases, tumorigenesis, autoimmune disorders, and viral infections.
In cancer, resistance to apoptosis contributes not only to tumor development, but also to resistance to conventional anticancer therapies, such as radiation and chemotherapy. In her research, Prof. Shoshan-Barmatz discovered a new mechanism for activating apoptosis and developed novel molecules to activate this mechanism as a strategy for treating cancer.
VDAC1 – A Novel Molecular Target
VDAC1, a protein that resides within the mitochondrial outer membrane, is over-expressed in cancer cells. Prof. Shoshan-Barmatz has shown that it is required for their development and survival.
The expression levels of VDAC1 are increased in many cancers, including breast, lung and glioblastoma. Thus, VDAC1 is emerging as a promising target for controlling apoptosis.
Novel Strategies for Cancer Therapies
Further research by Prof. Shoshan-Barmatz and her team has led to the emergence of several potential strategies for cancer therapy. The first involves the screening, identification and development of several novel, patent-protected small molecules that can activate the pro-apoptotic activities of the protein.
A second strategy involves VDAC1-based peptides, a chain of amino acids derived from VDAC1 sequence serving as the binding sites for anti-apoptotic proteins, which impair energy homeostasis and minimize the anti-apoptosis self-defense mechanisms of cancer cells.
To date, over 40 versions of cell-penetrating VDAC1-based peptides have been designed and screened, and the three shortest, most stable and effective at inducing cell death in cancer cell lines (without affecting non-cancerous cells) have been identified.
Investigations with these peptides have been conducted in animal models of lung, breast and liver tumors, all showing equal success in inhibiting both tumor growth and the metastasis of melanoma to the lung or the brain.
A third strategy involves the silencing of VDAC1 expression using molecules called small interfering ribonucleic acids (siRNAs).
Using glioblastoma as a platform for “proof of concept,” the potentiality of siRNAs was tested. Silencing of VDAC1 expression resulted in significant inhibition of tumor development.
These molecules led to the establishment of a company, ViDAC Pharma, Ltd., that is currently carrying out a phase II clinical study on non-melanoma skin cancers, and treatments for other cancers are under development.
Implications of VDAC1-Based Therapeutics
Prof. Shoshan-Barmatz’s work has demonstrated that VDAC1 plays a fundamental role in mediating how cancer cells acquire the metabolic and apoptotic adaptations necessary for development and progression.
These findings represent a major breakthrough in the development of anti-cancer strategies that are capable of simultaneously targeting numerous hallmarks of cancer development. Prof. Shoshan-Barmatz’s new anti-cancer agents have broad therapeutic impact and are expected to result in huge clinical benefits.