Rare Disease Report

Overcoming DNA Repair Mechanisms to Beat Brain Cancer

FEBRUARY 16, 2017
Jeffrey Bacha & Dennis Brown PhD
DNA, or deoxyribonucleic acid, is a molecule that carries the genetic instructions governing the growth and development of our cells and ourselves as a whole.   Our genetic code is maintained within DNA as a sequence made up of chemical base pairs. The base pairs align along a sugar backbone forming structure similar to a twisted ladder with the base pairs forming the rungs.  
Our DNA is constantly under attack from environmental agents like skin cancer-causing UV rays and environmental toxins that induce mutations. Our body employs a rigorous system of checks and balances to address this damage through numerous DNA repair mechanisms, thus making DNA repair an important area of research in cancer biology. 
Guanine is one of the bases comprising our DNA.  A point on our DNA known as the “O6 position of guanine” is one of the most frequent sites DNA-damage from tobacco smoke and other environmental pollutants.  These carcinogens attack our DNA by making subtle but highly mutagenic changes to DNA at the O6 position of guanine.  Left unrepaired these alterations can lead to cancer and other diseases.    
Luckily, our bodies have an effective sentry against these attacks in the form of a DNA repair enzyme called “MGMT.”  MGMT (also known as O6-alkylguanine DNA alkyltransferase, AGT or AGAT) is a DNA repair protein that guards against carcinogenic damage at the O6 position of guanine by removing the unwanted alkyl groups. Because of its importance, MGMT can be detected at high levels in nearly all tissues of our body.   In fact, there is a strong association with low MGMT expression and the formation of many cancers.
This is where the story of MGMT’s benefit takes an ironic twist of fate in the case of a highly aggressive form of brain cancer called glioblastoma multiforme (also known as GBM).  About 15,000 new patients are diagnosed with GBM each year in the United States.  Prognosis for GBM patients is generally poor.  Median survival from diagnosis is approximately 15 months, a figure which has remained constant for decades in spite of the substantial advances researchers have made in the fight against cancer as a whole.  
One challenge in treating brain cancer is that our brain has its own security system known as the blood brain barrier.  The blood brain barrier allows the entry of essential nutrients while preventing the entry of harmful substances, and unfortunately, most anti-cancer medicines. The small number of medicines that can readily cross the blood brain barrier limit the number of treatments available to doctors in treating GBM and other brain tumors.  
Unfortunately, the few chemotherapies that readily cross the blood brain barrier and have been approved to treat GBM such as temozolomide and the nitrosoureas (BCNU, CCNU) are alkylating agents that attack the tumor’s DNA at the O6 position of guanine, the site protected by MGMT.  Because most patients have a high expression of the MGMT enzyme, these chemotherapies are rendered useless and GBM continues its rapid and deadly growth unchecked.  
The amount of MGMT in our cells is governed by the expression of the gene which encodes for the MGMT repair protein.  This gene can be turned off or “silenced” if the promoter region of the gene is highly methylated, which interrupts production of MGMT.  A GBM patient who is “MGMT-unmethylated” will express high levels of MGMT than a patient who is “MGMT-methylated” leading to resistance to currently available GBM chemotherapy and poor prognosis.
In a 2011 study, the median survival for patients with a methylated MGMT promoter was 21.7 months compared with 12.7 months for patients without.  
Simply put, high expression of MGMT is the culprit in the lack of response and rapid death in up to two-thirds of GBM patients.  New therapies that are unaffected by the MGMT DNA repair enzyme are desperately needed in the fight against GBM.  
VAL-083 is a “first-in-class,” small-molecule chemotherapeutic that demonstrated clinical activity against a range of cancers including GBM in historical clinical trials sponsored by the U.S. National Cancer Institutes. 
VAL-083 is similar to drugs like temozolomide and the nitrosoureas in that they all readily cross the blood brain barrier to attack brain cancer at its DNA.  However, a subtle nuance may just make all the difference in the world for GBM patients: VAL-083’s anti-cancer activity is imparted by damaging the tumor’s DNA at the N7 position of guanine – not O6.  
Based on this unique mechanism of action, researchers have recently demonstrated that VAL-083’s anti-tumor activity against GBM tumor cells is unaffected by the expression of MGMT.
These data combined with data from prior clinical trials sponsored by the US National Cancer Institutes that establish VAL-083’s activity against GBM, are giving cancer researchers hope that VAL-083 may provide a new therapeutic option for GBM patients whose tumors are resistant to currently available therapy due to high expression of MGMT.
Clinical trials of VAL-083 in MGMT-unmethylated GBM are underway at the University of Texas MD Anderson Cancer Center and additional international clinical trials are being planned.  

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