When a disease has the word “acute” in the title, it usually implies a bleak prognosis. This is especially true in the case of cancers. Acute Myeloid Leukemia (AML) is a classic example. It is a type of blood cancer that affects the myeloid cells inside the bone marrow.
With a median patient age of 68, AML is more common in older adults, but can also affect younger individuals. It is one of the most common types of adult leukemia, with around 20,000 new cases reported each year in the United States.
In oncology, “acute” usually implies an aggressive, fast-evolving disease that leaves you a shorter window for effective treatment. Cancerous cells in AML can multiply and overwhelm healthy blood cells in weeks after onset.
This is reflected in the median survival rate which is just 9 months. The 5-year survival rate is also quite low at 30%. The prognosis for younger patients is, however, much better at above 50% across 5 years.
Each year, AML kills at least 10,000 people in the US and close to 150,000 globally. In the last decade, considerable resources have been funneled into developing new drugs to treat this disease, with limited success.
Now, scientists at the VCU School of Medicine in Richmond, Virginia have discovered a critical weakness in the cancer genes. This discovery could pave the way for more effective targeted treatment protocols. The study was published in the online journal Nature.
To better understand the true significance of this breakthrough, we must first take a quick look at why AML is such a tough nut to crack.
Genetic and Biological Advantages Make AML Treatment-Resistant
Like many dangerous cancers, AML is not just a single disease. Instead, it is a spectrum of different types or sub-types, caused by various combinations of genetic mutations. Some important ones include FLT3, NPM1, TP53, DNM3TA, and CEBPA.
The bone marrow is a nursery for blood cells created from myeloid stem cells. Mutations allow AML to hijack this nursery and start churning out immature blood cells that refuse to die and flood the blood.
Certain unique aspects of the bone marrow microenvironment (low oxygen, immunosuppressive zones, presence of growth factors) allow cancer cells to evade the immune system as well as chemotherapy drugs.
The Role Played by the MCL -1 Protein
In many cancers including AML, the ability of cancer cells to evade programmed cell death (apoptosis) is a critical factor. In the body, cell death is regulated by an interplay between different proteins belonging to the BCL-2 family.
One group of proteins protects cells (anti-apoptotic), while the other group is designed to trigger cell death (pro-apoptotic). A delicate interplay between these two groups ensures the necessary balance in a healthy body.
Cancers upset this balance, increasing the level of anti-apoptotic proteins while simultaneously reducing the pro-apoptotic proteins. One protein that is often seen in high levels in various leukemia types is MCL-1 (myeloid cell leukemia 1 protein).
When MCL-1 levels are high, it is a bad sign as it allows cancer cells to resist chemotherapy, the immune cells, and any other stressors that would otherwise kill them off. Drugs that inhibit MCL-1 could help reduce the survivability of cancer cells.
Mixed Results With MCL-1 Inhibitors
Scientists have already created several drugs capable of suppressing MCL-1 action. However, these MCL-1 inhibitors have a major side effect that unfortunately renders them somewhat useless in treating leukemia. Here is what happens:
- The drugs block the function of MCL-1
- Cancer cells detect the increased threat of apoptosis and react
- New signaling pathways allow cancer cells to make more anti-apoptotic proteins, including MCL-1
In other words, blocking the MCL-1 protein has a paradoxical impact on the levels of MCL-1 in cancer cells – they increase, making the disease more resistant to treatment. This is where the VCU study comes into prominence.
Combining MCL-1 Inhibitors with SRC Inhibitors Offers Better Results
Scientists at the VCU Massey Comprehensive Cancer Center explored different ways to overcome the issue of MCL-1 accumulation in malignant cells. Existing research has already shown that other drugs can also reduce MCL-1 expression in leukemia patients.
One class of drugs in particular is noted for this impact – SRC inhibitors. They block SRC kinases, signaling proteins that affect various cellular processes like cell survival, proliferation, and immune system activation.
In AML and other types of leukemia, SRC kinases often go into overdrive, ensuring that the cancer cells have a better chance of survival. Armed with this knowledge, the VCU Massey research team attempted to combine MCL-1 and SRC inhibitors.
Both drug classes had only a marginal impact when administered separately. However, when administered in tandem, the following results were observed:
- The combination sharply increased cell death in AML cancer cells
- Healthy, non-cancerous blood cells were spared
- MCL-1 creation in cancer cells is also significantly reduced
The drug cocktail also disrupted various critical signaling pathways used by cancer cells to evade programmed cell death and immune cells. These findings indicate that AML and other types of blood cancers rely heavily on both MCL-1 and SRC kinases for survival.
Key Takeaways and Caveats of the Study
The MCL-1 inhibitors developed so far have also shown other unwanted side effects like the risk of cardiac toxicity. Major pharma companies like AstraZeneca, Servier, and Amgen are in the process of developing newer generations of inhibitors without any cardiac side effects.
In the meantime, the exact nature of the signaling pathways affected by the combination of MCL-1/SRC inhibitors is still unknown. Before we can move ahead with any clinical trials, these mechanisms need to be fully understood.
The VCU Massey research is important because it might give us a foundation for a more effective AML treatment in the future. What we have discovered so far is highly promising – SRC inhibitors did a good job of mitigating the MCL-1 upregulation in mice models.
Success in future research could pave the way for combination therapies that can effectively snuff out AML cells without causing too many adverse side effects. It could offer a ray of hope for patients who are suffering from a relapse of AML after first-line treatments.
