A new goal to fight cancer
There is an urgent need for new methods of treating severe and hard-to-reach types of tumors. A leading researcher in the field of mitochondrial biology, Professor Varda Shoshan-Barmatz from Ben-Gurion University in Israel is studying the protein VDAC1, which plays a key role in the metabolic and apoptotic adaptation of cancer cells. Perhaps it will become a promising target for antitumor drugs.
The problem of glioblastoma
In most cases, glioblastoma begins with a headache, which appears more and more often over time, accompanied by nausea and vomiting, visual impairment. With the progression of the disease, seizures, speech disorders, frequent mood swings, personality changes appear. The patient is referred for magnetic resonance imaging: tumor foci are detected in the brain.
Glioblastoma is the most common type of brain tumor. It is characterized by an aggressive malignant course and practically does not respond to therapy. 88% of patients die within 14-36 months after diagnosis, despite surgical treatment, targeted and radiation therapy. The low survival rate is associated with the resistance of the tumor to all known methods of treatment.
Heterogeneous in origin, glioblastoma consists of populations of different cells, one of which is glioma stem cells. These are self-renewing cells in the tumor that can become malignant. As a rule, they are in an inactive state, so they are resistant to chemotherapy, which targets dividing cells. In this mode, stem cells "wait out" treatment. As soon as the chemotherapy is over and the tumor is almost destroyed, they wake up and begin to actively divide. There is a recurrence of the tumor.
Therefore, there is an urgent need for new methods of treatment that would destroy the tumor entirely, including cancer stem cells.
Features of tumor development
A normal cell undergoes changes and acquires several characteristics that accompany its transformation into a malignant one. These acquired traits allow her to survive when under normal circumstances she would have died. The cell acquires the ability to produce its own growth factors and reprogram the metabolism to support constant growth. In addition, mechanisms are included that allow sharing and avoiding signals of programmed death. This uncontrolled growth leads to the formation of a mass; as soon as it reaches a certain size (approximately 2 mm), the growth of blood vessels starts, which provide it with nutrients and oxygen necessary to increase and grow into the surrounding tissues.
Given that these adaptation mechanisms are key to cancer development, it is necessary to understand the algorithms needed to develop potential therapy strategies. In his research, Professor Shoshan-Barmats uses two important processes of development and survival of cells that turn them into cancer cells.
Mitochondria – the energy station of cells
Reprogramming of metabolism and cell survival in spite of apoptotic signals are two of several acquired signs of cancer cells, which are carried out due to the restructuring of the work of an important organelle – mitochondria.
Mitochondria are located in the cytoplasm in isolation or next to other organelles (for example, the endoplasmic reticulum), where they interact with other cellular structures through several mechanisms. They play a fundamental role in the metabolism of various substrates for energy production in the form of an energy-carrying molecule of adenosine triphosphate (ATP), which is necessary for the cell to provide vital processes.
Mitochondria also perform other functions, including synthesis of important compounds (cholesterol and others), regulation of cell acidity, calcium homeostasis, communication between organelles, cell proliferation and aging, and the development of diseases. Since cancer cells reprogram metabolism, including at the expense of mitochondria, Shoshan-Barmats investigated the possibility of reprogramming metabolism and changes in oncogenic properties of the tumor.
In addition to its primary purpose as a cell powerhouse, mitochondria are also crucial in regulating programmed cell death – apoptosis. This is an evolutionarily developed and genetically regulated process that is laid down during embryonic development and maintains homeostasis in the tissues of an adult organism. Apoptosis allows you to effectively remove unnecessary or dangerous cells. Dysregulation of apoptosis is associated with numerous diseases, including neurodegenerative diseases, oncogenesis, autoimmune disorders and viral infections. In cancer, resistance to apoptosis contributes not only to tumor growth, but also to resistance to traditional therapies such as radiation or chemotherapy. In her work, Shoshan-Barmats described the mechanism of triggering apoptosis and discovered molecules involved in this process that could become a potential target for antitumor therapy.
VDAC1 is a promising target
Professor Shoshana-Barmats and her colleagues from Ben-Gurion University in Israel have been searching for new methods of treating severe cancers – glioblastoma, liver cancer and others. They conducted a study on the mitochondrial protein volt-dependent anion channel (VDAC1) as a therapeutic target for cancer treatment.
VDAC1 is a barrier protein that is located in the thickness of the outer membrane of the mitochondria and forms large pores. Through them, metabolites and ions are transported into the mitochondria from the cytoplasm and back. VDAC1 is the main regulator of mitochondrial and cellular metabolism.
The amount of VDAC1 is significantly increased in cancer cells. The Shoshan-Barmats group has shown that it is necessary for their development and survival. It has also been recognized as a key protein in mitochondrial-mediated apoptosis: it promotes the release of intermembrane apoptotic proteins into the cytoplasm. Thus, VDAC1 is a potential target for controlling apoptosis.
It is important to note that VDAC1 serves as a nodal protein that provides interaction of various components of the cytoplasm, endoplasmic reticulum, mitochondria and other proteins that together regulate the vital activity of the cell and the process of apoptosis. The most important of these proteins belong to the family of hexokinases, a group of enzymes that catalyze the first stage of glucose metabolism (glycolysis). One of the characteristics of aggressive and poorly differentiated tumors is the high rate of glycolysis due to overexpression of VDAC1-related hexokinase in cancer cells. Their glucose consumption is higher than that of ordinary cells. This feature is used when performing positron emission tomography.
Recently, the understanding of the role of hexokinase and VDAC1 interaction has changed. Two hexokinases, hexokinase-1 (HK-1) and hexokinase-2 (HK-2) are overexpressed in cancer cells, and by interacting with VDAC1, gain direct access to ATP in mitochondria. Glucose metabolism increases. Interestingly, the interaction of HK-1 and HK-2 with VDAC1 also prevents apoptosis. Thus, this connection contributes not only to the reprogramming of metabolism in cancer cells, but also to their ability to evade apoptosis. The scientists identified the VDAC1 sites serving for interaction with HK-1 and HK-2, and used them as the basis for the development of trap proteins. Interacting with HK-1 and HK-2, they interfered with their contact with VDAC1 and, thus, "normalized" cancer cells.
New cancer treatment strategies
Further research by Professor Shoshan-Barmats and her colleagues led to the emergence of several potential cancer treatment strategies.
The first strategy involves the search, identification and development of several small molecules that can activate apoptotic activity in cells. By affecting HK-1 and HK-2 and apoptosis mediated by the VDAC1 protein, these molecules can lead to cell death. Based on them, the pharmaceutical company ViDAC Pharma has created an experimental drug that is currently undergoing phase II clinical trial for the treatment of non-melanoma skin cancer.
The second strategy involves a VDAC1-based peptide. This is a chain of amino acids, the sequence of which repeats that part of the VDAC1 protein to which HK-1, HK-2 and other anti-apoptotic proteins bind. More than 40 versions of peptides capable of penetrating into the cell have been developed and tested. As a result, three most suitable chains were identified – the shortest, most stable and most effective for inducing apoptosis in cancer cell lines, which also had no effect on healthy cells. These peptides were tested on mouse models of cancer. They reduced the formation of energy in tumor cells, inhibited proliferation and invasion into surrounding tissues, and induced cell death, including cancer stem cells. Peptides had these effects regardless of the type of tumor and the degree of maturity of cancer cells, healthy cells were not affected.
Studies with VDAC1-like peptides were conducted on animal models of lung, breast and liver tumors. In all experiments, it was possible to obtain a positive result: tumor growth stopped, metastasis did not occur. Good results were also obtained in testing on a model of chronic lymphocytic leukemia. This work was awarded the prestigious three-year prize of the American Leukemia and Lymphoma Society (American Leukemia & Lymphoma Society).
Professor Shoshan-Barmats and her group demonstrated the ability of the Tf-D-LP4 peptide created on the basis of VDAC1 to effectively induce the death of cancer cells in the group of genetically determined glioblastoma, cancer stem cells from glioblastoma, as well as in animal models of human glioblastoma. The Tf-D-LP4 peptide is able to overcome the blood-brain barrier and have a broad effect, disrupting the metabolism of tumor cells, dramatically reducing the growth of tumor foci, reducing invasiveness and proliferation and, importantly, increasing the survival rate of mice by more than 5 months (equivalent to several years in humans) after the end of treatment. Thus, TfD-LP4 creates an innovative therapeutic strategy that is able to prevent the replication of not only mature cells, but also glioma cancer stem cells in the tumor, reducing the frequency of recurrence and metastasis.
The third strategy is based on the excessive production of VDAC1 in cancer and includes suppression of its expression using small interfering ribonucleic acids (siRNA). Instead of interfering with cellular metabolism and activating apoptosis at the protein level, the researchers decided to stop its synthesis. Deoxyribonucleic acid (DNA) is the genetic code that determines the sequence of amino acids of all proteins in the body. The genes in the DNA are copied to the matrix RNA (mRNA), which is then translated into proteins. If this process is interrupted, the protein will not be synthesized, and all cellular functions associated with it will be lost. Specific siRNAs (modified for stability) have been developed which interrupt the translation of the VDAC1 protein from its mRNA template. Studies have shown that this leads to a deficiency of VDAC1 and, as a result, the cessation of growth, disruption of energy production and the stopping of abnormal metabolism in cancer cells. Experiments on mouse models of cervical cancer, lung cancer and glioblastoma have shown that the siRNA protein VDAC1 inhibits tumor growth and causes tumor regression.
Using glioblastoma as a platform for proof of concept, the potential of siRNA was tested in several cell lines, in cells obtained from the body of patients, on mouse models of subcutaneous or intracranial orthotopic glioblastoma. Stopping the expression of VDAC1 led to a significant suppression of tumor growth. When siRNA nanoparticles were placed inside, they managed to reach the brain, where they were able to reverse the metabolic reprogramming of tumor cells, stopped their proliferation and transformed glioma cancer stem cells into normal neuron-like brain cells.
Future results of VDAC1 therapy
Professor Shoshan-Barmats demonstrated that the VDAC1 protein plays a fundamental role in the metabolic and apoptotic adaptation of cancer cells. These results represent a major achievement in the development of antitumor therapy strategies that can simultaneously affect several mechanisms of cancer development. VDAC1 is an important checkpoint in oncology and, therefore, a new target for therapy with huge potential. Professor Shoshan-Barmats' new anti-cancer drugs may have a broad therapeutic effect and are expected to lead to a breakthrough in the treatment of not only glioblastoma, but also other types of cancer.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Scientia: Professor Varda Shoshan-Barmatz – Mitochondria – A Novel Target in the Fight Against Cancer.