Revolutionary Drug Combination Revives Power of Leading Treatment to Slay Blood Cancer Cells

Despite the promise of new medications that can combat acute myeloid leukemia, leukemic cells have a knack for outsmarting the drugs and evading their effects within a year.

Recent studies using both human tissue samples and mouse models have discovered an unexpected cause of resistance to the widely prescribed drug venetoclax in leukemia cells: a rapid increase in the breakdown and turnover of mitochondria. These small, power-producing structures inside cells have a much larger role than just energy production, as they can also signal cells to die in adverse conditions.

In cancer, the process of “programmed cell death” often goes awry. Mitochondria, the cellular powerhouses, can also self-destruct through a process known as mitophagy, which stops them from sending out hazardous “death signals”. This offers an important protective mechanism against the detrimental effects of damaged mitochondria.

Researchers at NYU Langone Health and its Perlmutter Cancer Center have discovered a way that leukemia cells can evade the deadly power of venetoclax, a BH3 mimetic drug. By utilizing mitophagy, or the process of cells consuming their own mitochondria, leukemia cells can survive in spite of the effects of the drug. This breakthrough offers new insight into how cancer cells can become resistant to medical treatments.

Researchers at Cancer Discovery recently made an exciting discovery: a link between increased expression of certain genes and mitophagy, as well as drug resistance, in leukemia patients. In a study of 20 leukemia patient samples, the levels of Mitofusin-2 (MFN2) and other genes associated with mitophagy were found to be significantly higher than in normal controls.

What’s more, the leukemic patients with drug resistance had even higher expression levels of these genes than those without drug resistance. The findings suggest the potential for targeted therapies to combat drug resistance in leukemia patients.

In a new experiment involving mice with bone marrow transplants from acute myeloid leukemia patients, the drug chloroquine was found to restore the ability of venetoclax to kill the cancer cells. Chloroquine is a known mitophagy inhibitor, suggesting that it may be a possible treatment for this type of cancer.

The groundbreaking potential of BH3 mimetic drugs like venetoclax to treat acute myeloid leukemia makes overcoming resistance to these medications a crucial clinical challenge. Christina Glytsou, PhD, a former postdoctoral researcher at NYU Grossman School of Medicine and now an assistant professor at Rutgers University, co-led the study that is helping to address this important issue. With this research, we are one step closer to making these treatments more effective for those who need them most.

Acute myeloid leukemia is a formidable foe, with a grim prognosis of five-year survival rates of fewer than one-third of those affected. Despite the challenge, researchers at NYU Grossman’s Department of Pathology are working to maximize the impact of existing therapies and improve outcomes for those living with the disease. Co-lead investigator Xufeng Chen, PhD, has stated that “it is important to maximize the impact of existing therapies” for those battling acute myeloid leukemia.

Our preclinical research suggests that combining BH3 mimetics such as venetoclax with MFN2 or general mitophagy inhibitors could be an effective new therapy for acute myeloid leukemia. Current treatments are often hindered by drug resistance, but this novel approach could offer a promising solution. Senior investigator Iannis Aifantis, PhD, is hopeful that this could be a breakthrough for those suffering from this disease.

The Hermann M. Biggs Professor and Chair of the Department of Pathology at NYU Grossman and Perlmutter, Dr. Efstathios Aifantis, has announced the research team’s plans to design a clinical trial to test the efficacy of combining chloroquine with venetoclax in the prevention of drug resistance in people with acute myeloid leukemia. If proven successful, this new approach could revolutionize the treatment of this life-threatening disease.

The researchers uncovered a significant finding: not only was MFN2 overly active in people with drug-resistant disease, but cancer cells exposed to similar cell-death-inducing compounds showed a remarkable increase in mitophagy rates – doubling in fact. This is a major breakthrough as it opens up new avenues for future treatments of cancer.

The team’s new study, along with previous research examining misshapen mitochondria in drug-resistant leukemic cells, have confirmed that increased mitophagy was the source of the problem.

To test this further, the researchers conducted experiments on cancer cells that were engineered to lack MFN2, and found that these cells were significantly more sensitive to drugs like venetoclax compared to cells with functional MFN2. These findings suggest that mitophagy could be a key factor in determining drug resistance in cancer.

Acute myeloid leukemia strikes over 11,500 Americans every year, making it the most common form of adult leukemia. Originating in the bone marrow, this blood cancer causes an alarming buildup of abnormal cells. Fortunately, treatments like chemotherapy, targeted drug therapies, and even bone marrow transplantation are available to help combat this deadly disease.

This research was funded by a variety of sources, such as the National Institutes of Health grants P30CA016087, P30CA013330, R01CA178394, R01CA173636, R01CA228135, R01CA229086, R01CA242020, and K99CA252602, as well as the Leukemia & Lymphoma Society and AstraZeneca, who provided several BH3 mimetic drugs used in the experiments. Together, these resources enabled us to undertake this incredible study and uncover novel insights.

NYU Langone Health is proud to announce that renowned researcher, Dr. Efstathios Aifantis, has secured additional research funding from AstraZeneca. All policies and practices of NYU Langone Health are being strictly followed to ensure a successful partnership.

The NYU Langone study, spearheaded by Glytsou, Chen, and Aifantis, is further bolstered by a number of other esteemed investigators. Wafa Al-Santli, Hua Zhou, Bettina Nadorp, Soobeom Lee, Audrey Lasry, Zhengxi Sun, Dimitrios Papaioannou, Michael Cammer, Kun Wang, and Aristotelis Tsirigos have all joined the cause.

Additionally, Emmanouil Zacharioudakis and Evripidis Gavathiotis from Albert Einstein College of Medicine, Tomasz Zal, Malgorzata Anna Zal, Bing Carter, Jo Ishizawa, and Michael Andreeff from the University of Texas MD Anderson Cancer Center, and Raoul Tibes from AstraZeneca in Cambridge have all contributed to the research effort and have even filed a patent on mitofusin inhibition based on their findings!

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