Lost My Wife To Glioblastoma: MGMT and How It Affects Treatment

When Christina was first diagnosed with Glioblastoma (GBM) in February 2020 our lives went upside down.  The threat of losing my wife to cancer prematurely became a disturbing reality.   The emotions that my darling and I experienced were confused and disorganized; we were unable to think clearly.

The first thought we had was to learn as much as we could about this cancer.  After the first few days information was pouring in and it was difficult to digest all at once because it was so much as diverse.  The most terrifying discovery was that GBM is the most common primary malignant brain tumor in adults and it has an exceedingly low median overall survival of only 15 months(1).

Biopsy and tumor debulking with postoperative adjuvant radiotherapy and chemotherapy with alkylating agents, in the case of Christina, temozolomide(TMZ), are the most commonly carried out treatment. Towards the end of her life, she was also treated with bevacizumab, a monoclonal antibody used as anti-angiogenic therapy (10).

I am going to write a series of posts to document my research and what I learned about Glioblastoma (GBM) and my naive ideas related to how to gain the upper hand to improve the poor prognosis for GBM cancer patients from the perspective of a chemist.

During my "short" chemistry career, from 1984 until 1998, I worked in the syntheses of diagnostic reagents and drugs with anti-cancerogenic properties.  Because of that, I thought that perhaps I could help my wife, and in my delusion even save her.

Based on the current standard of care for GBM patients and what I have been able to learn I believe that there is a lot of room for science to help people affected with this and other terrible cancers.

What is MGMT and How It Affects Treatment

When cell DNA is damaged in a cell, cellular DNA repair mechanisms are activated with the objective to maintain the genetic information and "fix" the alteration.  

Cell DNA can be damaged by the environment, but it can also happen in the very process of DNA replication during cell division creating mutations.  While proofreading cellular enzymes normally recognize and try to correct many of these errors some of these mutations survive the repair process.  Some of these mutations lead to evolution but other mutations lead to cancer.

In a DNA damaging chemotherapy, Oxygen in position 6 of Guanine is susceptible to being alkylated with alkylating agents.  Methylguanine -DNA methyltransferase, MGMT, is a DNA repair enzyme that is induced by genotoxic stress.

The objective to treat GBM cancer cells with alkylating agents is to damage the cellular DNA inducing apoptosis cell death (5) because the genetic codification has been altered and the cellular replication has been affected; it cannot copy its cellular information.  However, after this DNA modification, the cell activates the MGMT gene as a response to the damage and attempts to correct the DNA adulteration, and more specifically, removes the methyl alkyl group which has been attached to the Oxygen-6 of the Guanine base.  For this reason, assessing the MGMT has become very important in predicting the effectiveness of alkylating chemotherapeutic agents in the treatment of GBM.  In the absence of this repair enzyme, cells are more susceptible to TMZ.

The DNA repair process is known in the literature as MGMT Promoter Methylation, and it is assessed in laboratories after a tumor sample is tested.  There are numerous techniques for this assessment (2) however, no uniform consensus has been reached in regards to which technique is the most appropriate in clinical practice.

In the case of Christina, the immunohistochemistry of her tumor showed that the MGMT Promoted Methylation was MGMT Methylated.  

What does this mean?

This test predicted that her tumor would respond well to an alkylating agent such as TMZ(9).  The same reference indicates that for the unmethylated variant, TMZ would have no effect and in most cases, the patient would not be exposed to the toxicity of the chemotherapy, although this is still up for debate, and in some cases, a combined treatment for MGMT Unmethylated with other agents offers some improvement in the prognosis.

How does this Work?

Genes are segments of deoxyribonucleic acid (DNA) that contain the code for a specific protein that functions in one or more types of cells in the body. Chromosomes are structures within cells that contain a person's genes(10).

A gene has a promoter (11) region and an end containing the coded information which is transferred to RNA for making proteins, in this case, MGMT, remember it is mentioned above that MGMT is a protein, an enzyme, responsible for repairing DNA.

When the promoter region of the MGMT gene is methylated then the gene is not able to produce MGMT to repair the DNA.  The MGMT Promoter Methylation is very useful to predict the treatment with alkylating agents.

What Could I Have Done to Save My Wife?

As it turned out; nothing.  However, I do not think that we have lost the battle yet and perhaps others could be saved.  In my next post, I would like to explore how MGMT inhibitors (4) work, what we know about them, and ideas that I have that perhaps could make the current standard of care more effective.  I will return to this post and references to continue to present my ideas.

Can we do something earlier in the process and instead of inhibiting the action of the DNA preparing enzyme MGMT, inhibit the promoter section of the MGMT inhibitor specifically?  I imagine that that is what the alkylating agent is also doing.

I refuse to believe that this is it for people like my wife.

References:

1. Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review
2. Methylguanine-DNA methyltransferase (MGMT)
3. Temozolomide Approval
4. MGMT Inhibitors
5. Chemotherapeutic Approaches for Targeting Cell Death Pathways
6. Difference Between Necrosis and Apoptosis
7. DNA Damage & Repair: Mechanisms for Maintaining DNA Integrity
8. The Structure of DNA
9. Methylguanine Methyltransferase Testing in Glioblastoma: When and How?
10. How Bevacizumab works as Anti-angiogenic therapy
11. Genes And Chromosones
12. Promoter