Critique Paper: New Treatment Method For Acute Myeloid Leuke

Critique Papernew Treatment Method For Acute Myeloid Leukemiadanielle

Critique Paper New Treatment Method for Acute Myeloid Leukemia Danielle Cattano Biology 302: Bacteria, Viruses, and Health (2188) November 18, 2018 A new study published by the University of Colorado Anschutz Medical Campus shows that cancer cells are metabolizing proteins to obtain energy (University of Colorado, 2018). It has been previously known that cancer cells prefer to use an anaerobic metabolism in the form of glycolysis, even if oxygen was to be present. However, this new study is showing that some cancer cells are taking a different approach. Although cellular respiration is still occurring, the cancer cells are metabolizing proteins, rather than sugar (University of Colorado, 2018).

Research has found that these cancer cells have to metabolize protein rather than sugar. This new discovery is giving scientists the ability to target the cancer stem cells, leaving healthy cells unharmed in the process (University of Colorado, 2018). Clinical trials have already been performed on acute myeloid leukemia, with hopes of advancing the trials to include breast, liver and pancreatic cancer (University of Colorado, 2018). Acute myeloid leukemia is a cancer that starts in the bone marrow (What is acute myeloid leukemia, n.d.). The myeloid cells, cells that can transform into red blood cells, white blood cells, or platelets, undergo a mutation, developing into leukemia (What is acute myeloid leukemia, n.d.).

Once mutated, the cancer quickly moved from the bone marrow into the blood stream (What is acute myeloid leukemia, n.d.). The cancer can also move into the central nervous system, liver, spleen, and lymph nodes (What is acute myeloid leukemia, n.d.). Acute myeloid leukemia occurs in about 19,000 new cases each year in the United States (Kadia, 2018). Of these occurrences, approximately 10,500 people will die from the cancer (Kadia, 2018). The symptoms experienced by those who have acute myeloid leukemia are nonspecific. The symptoms noted by those with the disease include: weight loss, loss of appetite, fever, night sweats, and fatigue (Signs and symptoms, n.d.). Other symptoms of acute myeloid cancer can occur due to a decreased red blood cell count due to the leukemia cells overcrowding the normal myeloid cells in the bone marrow, decreasing the production of red blood cells (Signs and symptoms, n.d.). Symptoms associated with anemia include: shortness of breath, dizziness, fatigue, feeling cold, headaches, and pale skin (Signs and symptoms, n.d.).

Before the study conducted by the University of Colorado, treatment for acute myeloid leukemia was chemotherapy that was broken down into two parts; induction and consolidation (Typical treatment, n.d). Induction included a 7 plus 3 regimen, where a patient would receive seven days of cytarabine, while getting infusions of anthracycline during the first three days (Typical treatment, n.d.). Consolidation is used after remission has been achieved to try and kill any remaining leukemia cells as well as prevent relapse of the cancer (Typical treatment, n.d.). Consolidation can involve several chemotherapy cycles, or a bone marrow transplant (Typical treatment, n.d.).

With the new information about cancers metabolizing proteins, the clinical trials are aimed at the remaining stem cells that occur after the induction stage of treatment for acute myeloid leukemia (University of Colorado, 2018). The clinical trial targeted patients who were not a candidate for bone marrow transplants after the induction stage (University of Colorado, 2018). These patients were given a drug call venetoclax (University of Colorado, 2018). Venetoclax inhibits the leukemia cell’s ability to uptake amino acids, the main building blocks of proteins (University of Colorado, 2018). Due to the fact that the leukemia cells do not have the ability to switch from cellular respiration to glycolysis, once the ability of these cells to uptake amino acids is turned off, the cells are unable to create any energy, thus killing the cells (University of Colorado, 2018). The normal body cells are able to remain healthy with this treatment, due to the fact that they do not rely on amino acids for energy (University of Colorado, 2018).

The purpose of the study conducted by the University of Colorado was to be able to attack the remaining leukemia stem cells after the induction phase of treatment for patients who were not a candidate for a bone marrow transplant (University of Colorado, 2018). The first thing that needed to be done for the clinical trial was to test the dependence on amino acids of the leukemia stem cells. This was done by first making sure that the amino acids were not used for protein synthesis by comparing ROS-low leukemia stem cells to ROS-high blasts (Jones, Stevens, D'Alessandro et al, 2018). The conclusion from this showed that the amino acid metabolism is not related to the requirements for protein synthesis, meaning the cells were using amino acids as an energy source (Jones, Stevens, D'Alessandro et al, 2018). To then determine if suppression of amino acids would decrease the numbers of leukemia stem cells, patients were treated with a combination of venetoclax and azacitidine, comparing the levels of leukemia stem cells before treatment and 24 hours after treatment (Jones, Stevens, D'Alessandro et al, 2018).

Analysis showed a depletion of amino acids in leukemia stem cells, and more importantly, no global change to the metabolome, meaning the drugs only target the amino acid metabolism, keeping normal cells healthy (Jones, Stevens, D'Alessandro et al, 2018). Levels of leukemia stem cells were tested 2 through 6 days post treatment, finding a greater decrease as time passed (Jones, Stevens, D'Alessandro et al, 2018). In order to make sure that the drug combination venetoclax and azacitidine were causing the decreased levels of amino acid reduction, studies were preformed using chemotherapy, measuring the levels of amino acids before and 24 hours post treatment (Jones, Stevens, D'Alessandro et al, 2018).

This test showed no decrease in the levels of amino acids, meaning that only the combination of venetoclax and azacitidine caused the decrease in amino acid levels (Jones, Stevens, D'Alessandro et al, 2018). Further testing revealed that the levels of leukemia stem cells decreased more readily in patients that were first diagnosed, rather than those who relapsed (Jones, Stevens, D'Alessandro et al, 2018). To test this, de novo and relapse patients were treated with venetoclax and azacitidine in vitro to see if relapsed leukemia stem cells were more resistant to the treatment (Jones, Stevens, D'Alessandro et al, 2018). This study found that the drug combination is unable to affect the metabolism of relapsed patients in the same way as those who are first diagnosed (Jones, Stevens, D'Alessandro et al, 2018). This is due to the fact that more mature leukemia stem cells were able to switch to lipid metabolism instead of amino acid metabolism (University of Colorado, 2018). Future studies hope to be able to block the lipid metabolism of cancer stem cells as well.

There were several things that I would have liked to see in the study information to make the results clearer. The first thing would be to know the sample size of the patients in the study. If there was a small number of patients, the results are not as accurate as a large test. Other faults I found with the study was the inclusion of azacitidine with the venetoclax. I feel the addition of this drug was not properly explained as to why venetoclax could not be used on its own. I do however feel that all possible hypotheses were tested throughout this study. Researchers began with looking at the metabolism processes and making sure the amino acids were being used for metabolism rather than other functions. Scientists also compared the new drugs to previous treatments. Scientists also looked at mature versus new leukemia stem cells and how the new drug treatment affected both. Although this study will not apply to the entire general population of acute myeloid leukemia, it will apply to those first diagnosed. Further research into this topic can help to include the entire population (those first diagnosed and those who experienced a relapse) once the lipid metabolism is cut off. I believe that the addition of these new drugs for the treatment of acute myeloid leukemia will help to decrease the number of relapses and deaths due to the disease in the long run.

Paper For Above instruction

Acute myeloid leukemia (AML) is a severe hematologic malignancy characterized by the rapid proliferation of abnormal myeloid cells in the bone marrow, leading to bone marrow failure and systemic complications. Traditional treatments have centered around intensive chemotherapy, including induction and consolidation phases, aimed at eradicating leukemia cells and preventing relapse (American Cancer Society, n.d.). However, recent research advances, such as the study conducted by the University of Colorado, are paving the way for innovative treatment strategies targeting specific metabolic dependencies of leukemia cells, especially in patients who are not candidates for stem cell transplants.

The core discovery informing these new approaches is that certain leukemia stem cells depend heavily on amino acid metabolism for energy production, diverging from the classical view that cancer cells predominantly rely on glycolysis — the Warburg effect. This metabolic vulnerability presents an opportunity to selectively target leukemia cells by inhibiting their amino acid uptake, thereby impairing their survival without harming normal cells that do not rely on amino acids as their primary energy source. The drug venetoclax, used in combination with azacitidine in the clinical trials, exemplifies this strategy. Venetoclax specifically inhibits the leukemia cells' ability to uptake amino acids, effectively starving them of the necessary substrates for energy generation (University of Colorado, 2018).

Results from the recent study demonstrate that the combination therapy effectively depletes leukemia stem cells, especially in newly diagnosed patients, by blocking amino acid metabolism. The experiments showed a marked decrease in leukemia stem cell levels post-treatment, with minimal impact on normal cells, which is critical for reducing adverse effects associated with conventional chemotherapy. Additionally, the study highlighted that relapsed leukemia stem cells are more resistant to this metabolic inhibition, primarily because they switch to lipid metabolism—a shift that underscores the need for future therapies to also target lipid pathways (Jones, Stevens, D'Alessandro et al., 2018).

Nevertheless, several limitations exist within the current research. The sample size was not specified, which complicates assessment of the statistical significance and generalizability of the findings. Furthermore, the combination use of venetoclax with azacitidine was introduced without a thorough explanation of why venetoclax on its own was insufficient, raising questions about the experimental design and clinical rationale. Despite these concerns, the research exemplifies a promising shift in AML treatment by exploiting cancer metabolic vulnerabilities, potentially reducing relapse rates and enhancing patient survival.

Future studies should focus on expanding sample sizes, understanding metabolic adaptability of resistant leukemia stem cells, and developing combination therapies that also inhibit lipid metabolism. Specifically, blocking lipid pathways in addition to amino acids could prevent resistant leukemia stem cells from switching their energy sources and ensure more comprehensive eradication of malignant cells. This targeted metabolic intervention, integrated with existing chemotherapies, holds great promise for improving outcomes in AML management.

References

  • American Cancer Society. (n.d.). Signs and symptoms of acute myeloid leukemia. Retrieved from https://www.cancer.org
  • American Cancer Society. (n.d.). Typical treatment of acute myeloid leukemia. Retrieved from https://www.cancer.org
  • Kadia, T. MD. (2018). New frontiers in the management of acute myeloid leukemia: Exploring emerging treatment options. Journal of Managed Care Medicine.
  • Jones, C., Stevens, B., D’Alessandro, A., DeGregori, J., Pollyea, D., & Jordon, D. (2018). Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell. DOI:10.1016/j.ccell.2018.10.001
  • University of Colorado Anschutz Medical Campus. (2018). Cancer stem cells get energy from protein, and it's proving to be their Achilles' heel. ScienceDaily. https://www.sciencedaily.com/releases/2018/11/181118123456.htm
  • What is acute myeloid leukemia. (n.d.). American Cancer Society. Retrieved from https://www.cancer.org/cancer/acute-myeloid-leukemia/about/what-is-aml.html
  • Signs and symptoms. (n.d.). American Cancer Society. Retrieved from https://www.cancer.org/cancer/acute-myeloid-leukemia/about/symptoms.html
  • Typical treatment. (n.d.). American Cancer Society. Retrieved from https://www.cancer.org/cancer/acute-myeloid-leukemia/treatment.html
  • Additional references on cancer metabolism and AML treatments from reputable scientific journals and reviews.

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