Cell Death: Drug Combo Restores Signaling Ability of Leading Treatment for Blood Cancer Christina Glytsou PhD

Cell Death: Drug Combo Restores Signaling Ability of Leading Treatment for Blood Cancer Christina Glytsou PhD

By Christina Glytsou, PhD
Assistant Professor at Rutgers University

In this study, we focused on acute myeloid leukemia (AML), a type of blood cancer where the bone marrow produces a large number of abnormal blood cells. AML is the most common form of leukemia in adults and is responsible for over 11,000 deaths per year in the United States.

Treating AML is challenging, as fewer than one-third of those affected live longer than five years after diagnosis. For decades, treatment options for this disease have remained unchanged, including chemotherapy and bone marrow transplantation. However, newer therapeutics called BH3-mimetic drugs have recently been introduced in clinics or are being explored to treat patients with AML, offering hope to clinicians and patients.

The BH3-mimetics have been developed to directly activate apoptosis, a form of programmed cell death in cancer cells, selectively killing leukemia cells. Unfortunately, three out of ten patients with AML do not respond to BH3-mimetic drugs, or other patients develop resistance during treatment. Therefore, overcoming resistance to BH3-mimetic drugs is of unique clinical significance because these medications are now on the frontline of treating patients with acute myeloid leukemia (AML).

How was the study conducted, and what were the key findings of the research?

The goal of our study was to understand the cellular mechanisms of resistance to BH3-mimetics and identify the cell features that leukemia cells adopt to escape the drugs’ effects. To achieve this, we conducted unbiased research by performing genome-wide CRISPR screens on cell lines.

In other words, we deleted every single gene in the cancer cells and pinpointed those genes that, when absent, make the cells more sensitive to BH3-mimetics. Interestingly, we found that the loss of genes involved in mitochondrial dynamics and MitoSIS sensitizes AML (acute myeloid leukemia) cells to BH3-mimetic combinations.

Furthermore, we examined multiple AML patient samples that were resistant to pre-BH3-mimetic treatment and observed that these samples have high MitoSIS rates compared to sensitive AML samples. But what is MitoSIS? It is a self-eating process inside the cell.

With MitoSIS, cells can eliminate and recycle various damaged cell components, such as proteins or even whole organelles, such as mitochondria. The specific process of cell feeding mitochondria is called Mitophagy. We believe that with excessive MitoSIS, cancer cells can eliminate mitochondrial damage, maintain a healthy mitochondrial population, and hence escape the programmed cell death pathway.

We also used preclinical models, including patient specimens and animal xenograft models, and we found that by blocking MitoSIS, we can enhance the efficacy of BH3-mimetics in AML.

Can you discuss the potential implications of the findings and how they could impact cancer treatment in the future?

Drug resistance is one of the main challenges in successful cancer treatment today. Our recent findings shed light on the molecular mechanisms that govern drug resistance in acute myeloid leukemia (AML). We hope that our studies will help design more effective combinatorial therapies for AML in the future.

Specifically, our study proposes that blocking MitoSIS, either by using novel specific compounds that target the mitochondrial protein called Mitofusin 2, which is one of the key MitoSIS enablers, or by using other broader MitoSIS inhibitors like chloroquine, can enhance the efficacy of BH3-mimetics and reverse drug resistance in AML.

These findings can be the basis for future clinical trials for AML. Our aim is to replace chemotherapy and transplantation, which can have painful and dangerous side effects for patients, with more innovative therapeutic strategies to increase patients’ survival.

Is this drug combination suitable for all types of blood cancer, or are there specific types it is most effective against?

Recent studies have focused on acute myeloid leukemia. At the moment, we are confident that the proposed drug combination will be effective for this specific type of blood cancer. However, BH3-mimetics are currently being used in clinics to treat other hematologic malignancies, including chronic lymphocytic leukemia and small lymphocytic lymphoma.

Furthermore, BH3-mimetic viruses are currently undergoing clinical trials for the treatment of other types of blood malignancies, as well as different solid tumors. Therefore, future preclinical and clinical studies will reveal whether our proposed drug combination will be suitable and effective against other types of cancer as well.

Can you describe the mechanisms of action of the two drugs in the combination and how they work together to induce cell death in cancer cells?

BH3-mimetics antagonize the action of anti-apoptotic proteins within cells, leading to the release of pro-apoptotic proteins that execute the programmed cell death pathway. This pathway is regulated by small, dynamic sub-cellular organelles called mitochondria. During the process of apoptosis, mitochondria change shape and release factors that are important for inducing cell death.

Upon exposure to BH3-mimetics, this sequence of events leads to mitochondrial damage by impairing MitoSIS. When combined with chloroquine or other compounds, BH3-mimetics prevent mitochondria from recovering from this damage, ultimately forcing the cells to undergo apoptosis. This is the mechanism of action. We believe that this drug combination induces cell death in leukemia cells.

What are the next steps in terms of clinical trials and potential approval for use in patients?

Future clinical trials are necessary to determine whether combining BH3-mimetics with general MitoSIS inhibitors could serve as a potential therapy for acute myeloid leukemia, especially for patients who do not respond to BH3-mimetics alone. Further studies are also needed to identify subgroups of patients who would benefit the most from these targeted drug combinations.

What is Cell Death In Acute Myeloid Leukemia (AML)?

Acute myeloid leukemia (AML) is a type of blood cancer that occurs when the bone marrow produces too many abnormal white blood cells. Cell death, also known as apoptosis, is an important process in the development and progression of AML.

Apoptosis is a natural process that occurs in cells when they become damaged or abnormal. It is a way for the body to eliminate cells that could potentially become cancerous. In AML, the balance between cell growth and cell death is disrupted, leading to an overgrowth of abnormal cells (cell types).

There are two main types of cell death: programmed cell death and necrosis. Programmed cell death, also known as apoptosis, is a controlled process that allows cells to die in a regulated and orderly manner. Necrosis, on the other hand, is an uncontrolled process that occurs when cells are damaged or injured.

In AML, abnormal cells often have defects in the genes that control apoptosis, leading to a resistance to programmed cell death. This allows the abnormal cells to continue to grow and divide, eventually leading to the development of cancer.

Researchers are studying ways to target the apoptotic (cells) pathway in AML cells, with the goal of inducing cell death (dead cell) in the cancer cells. Several drugs have been developed that target specific proteins involved in the apoptotic pathway, including BH3 mimetics and Bcl-2 inhibitors.

Overall, understanding the mechanisms of cell death in AML is crucial for the development of new treatments for this aggressive and often deadly disease.

10 Key Takeaways for the Cell Death Trial

1. 1. Mitophagy, a cellular process that removes damaged mitochondria, plays a significant role in promoting resistance to BH3 mimetics in acute myeloid leukemia (AML).

   2. BH3 mimetics are a class of drugs that target and inhibit anti-apoptotic proteins, which are crucial for cancer cell survival.

   3. The study highlights the importance of understanding the mechanisms of resistance to BH3 mimetics in AML to develop more effective treatment strategies.

   4. Mitophagy acts as a protective mechanism by selectively eliminating damaged mitochondria, thereby reducing the cytotoxic effects of BH3 mimetics.

   5. In AML cells, mitophagy is upregulated in response to BH3 mimetics, leading to enhanced survival and resistance to cell death.

   6. The findings suggest that targeting mitophagy alongside BH3 mimetics may overcome resistance and improve therapeutic outcomes in AML.

   7. Developing inhibitors or modulators of mitophagy could serve as a potential strategy to sensitize AML cells to BH3 mimetics.

   8. Further research is needed to identify the specific molecular pathways and key regulators involved in mitophagy-mediated resistance in AML.

   9. The study provides insights into the complex interplay between mitochondrial dynamics, apoptosis regulation, and drug resistance in AML.

   10. Understanding the mechanisms of resistance to BH3 mimetics and uncovering novel therapeutic targets can ultimately pave the way for more effective treatments for AML patients.

Christina Glytsou, PhD – About The Author, Credentials, and Affiliations

Christina Glytsou, PhD, is an accomplished researcher and scientist in the field of hematological malignancies. She was born in Greece and completed her undergraduate studies in Biology at the National Kapodistrian University of Athens. She later obtained her Ph.D. in in Biochemistry and Biophysics from the University of Padua in Italy.

Dr. Glytsou’s research focuses on understanding the molecular mechanisms of leukemia and lymphoma, with a particular emphasis on identifying novel therapeutic targets. She has authored numerous peer-reviewed articles and has presented her research at various international conferences.

In recognition of her contributions to the field, Dr. Glytsou was awarded the Leukemia & Lymphoma Society’s (LLS) Special Fellow Award in 2015. This award is given to promising young researchers who have made significant contributions to the understanding of blood cancers.

Dr. Glytsou continues to make important contributions to the field of hematology through her research, and her work has the potential to impact the lives of patients with blood cancers around the world.