MFN2

-- Future clinical trials to determine if combination chloroquine and venetoclax addresses disease comeback NEW YORK, April 24, 2023 /PRNewswire/ -- Despite the promise of new medications that promote cancer cell death in people with acute myeloid leukemia, leukemic cells often adopt features that let them evade the drugs' effects within a year. Now, new research using human tissue samples and mouse models has found that resistance of leukemia cells to a widely prescribed drug called venetoclax occurs because of a rapid increase in the breakdown and turnover of mitochondria, structures inside the cell that help power its functions. In addition to their role in producing energy, mitochondria also tell cells to die under certain adverse conditions. This process of "programmed cell death" often goes wrong in cancer. Damaged mitochondria can also undergo a form of "self-eating" termed mitophagy that prevents them from sending "death signals." Led by scientists at NYU Langone Health and its Perlmutter Cancer Center, the study showed that mitophagy helps leukemia cells to evade the killing effects of venetoclax, a drug in a class of medications known as BH3 mimetics. Publishing in the journal Cancer Discovery online April 24, researchers found that the levels of several genes associated with mitophagy were increased in 20 leukemia patient samples compared with normal controls. The level of these genes was even higher in samples from leukemia patients with drug resistance than in those leukemic patients who were not. Particularly notable was the increased expression of the gene for Mitofusin-2 (MFN2), which codes for a key protein in the outer mitochondrial membrane. Further experiments using mice into which bone marrow from acute myeloid leukemia patients was transplanted showed that the drug chloroquine, a known mitophagy inhibitor, restored the ability of venetoclax to kill the cancer cells. "Overcoming resistance to BH3 mimetic drugs like venetoclax is of unique clinical significance because these medications are often used for treating people with acute myeloid leukemia," said study co-lead investigator Christina Glytsou, PhD, a former postdoctoral researcher at NYU Grossman School of Medicine and now an assistant professor at Rutgers University. "Acute myeloid leukemia is notoriously difficult to treat, with fewer than a third of those affected living longer than five years after their diagnosis, so it is important to maximize the impact of existing therapies," said study co-lead investigator Xufeng Chen, PhD, an instructor in the Department of Pathology at NYU Grossman. "Our preclinical findings suggest that combining BH3 mimetics like venetoclax with either MFN2 or general mitophagy inhibitors could possibly serve as a future therapy for acute myeloid leukemia, as current drug treatments are stalled due to drug resistance," said study senior investigator Iannis Aifantis, PhD. Aifantis, the Hermann M. Biggs Professor and chair of the Department of Pathology at NYU Grossman and Perlmutter, says the research team plans to design a clinical trial to test whether chloroquine, when used in combination with venetoclax, prevents drug resistance in people with acute myeloid leukemia. Speaking about other study results, the researchers say they not only found that MFN2 was overly active in people with drug-resistant disease, but also that cancer cells exposed to similar cell-death-inducing compounds demonstrated a doubling in mitophagy rates. Additional testing in cancer cells engineered to lack MFN2 showed increased sensitivity to drugs similar to venetoclax compared with cells that had functional MFN2. The new study and previous research by the team showing misshapen mitochondria in drug-resistant leukemic cells confirmed that increased mitophagy was the source of the problem. Acute myeloid leukemia, the most common form of adult leukemia, originates in the bone marrow cells and involves the rapid buildup of abnormal blood cells. The blood cancer results in the deaths of more than 11,500 Americans annually. Current treatments include chemotherapy and a limited number of targeted drug therapies. Bone marrow transplantation has also been used when other options fail. Funding support for the study was provided by National Institutes of Health grants P30CA016087, P30CA013330, R01CA178394, R01CA173636, R01CA228135, R01CA229086, R01CA242020, and K99CA252602. Additional funding support was provided by the Leukemia & Lymphoma Society and by AstraZeneca, which provided several of the BH3 mimetic drugs used in these experiments. Aifantis has received additional research funding from AstraZeneca. This arrangement is being managed in accordance with the policies and practices of NYU Langone Health. Besides Glytsou, Chen, and Aifantis, other NYU Langone study investigators are Wafa Al-Santli, Hua Zhou, Bettina Nadorp, Soobeom Lee, Audrey Lasry, Zhengxi Sun, Dimitrios Papaioannou, Michael Cammer, Kun Wang, and Aristotelis Tsirigos. Other study co-investigators are Emmanouil Zacharioudakis and Evripidis Gavathiotis, at Albert Einstein College of Medicine in New York, who have filed a patent on mitofusin inhibition based on this research; Tomasz Zal, Malgorzata Anna Zal, Bing Carter, Jo Ishizawa, and Michael Andreeff, at the University of Texas MD Anderson Cancer Center in Houston; and Raoul Tibes, at AstraZeneca in Cambridge, the United Kingdom. Media Inquiries David March 212-404-3528 [email protected] STUDY LINK SOURCE NYU Grossman School of Medicine and NYU Langone Health

NEW YORK, April 24, 2023. Despite the promise of new medications that promote cancer cell death in people with acute myeloid leukemia, leukemic cells often adopt features that let them evade the drugs' effects within a year. Now, new research using human tissue samples and mouse models has found that resistance of leukemia cells to a widely prescribed drug called venetoclax occurs because of a rapid increase in the breakdown and turnover of mitochondria, structures inside the cell that help power its functions. In addition to their role in producing energy, mitochondria also tell cells to die under certain adverse conditions. This process of "programmed cell death" often goes wrong in cancer. Damaged mitochondria can also undergo a form of "self-eating" termed mitophagy that prevents them from sending "death signals." Led by scientists at NYU Langone Health and its Perlmutter Cancer Center, the study showed that mitophagy helps leukemia cells to evade the killing effects of venetoclax, a drug in a class of medications known as BH3 mimetics. Publishing in the journal Cancer Discovery online April 24, researchers found that the levels of several genes associated with mitophagy were increased in 20 leukemia patient samples compared with normal controls. The level of these genes was even higher in samples from leukemia patients with drug resistance than in those leukemic patients who were not. Particularly notable was the increased expression of the gene for Mitofusin-2 (MFN2), which codes for a key protein in the outer mitochondrial membrane. Further experiments using mice into which bone marrow from acute myeloid leukemia patients was transplanted showed that the drug chloroquine, a known mitophagy inhibitor, restored the ability of venetoclax to kill the cancer cells. "Overcoming resistance to BH3 mimetic drugs like venetoclax is of unique clinical significance because these medications are often used for treating people with acute myeloid leukemia," said study co-lead investigator Christina Glytsou, PhD, a former postdoctoral researcher at NYU Grossman School of Medicine and now an assistant professor at Rutgers University. "Acute myeloid leukemia is notoriously difficult to treat, with fewer than a third of those affected living longer than five years after their diagnosis, so it is important to maximize the impact of existing therapies," said study co-lead investigator Xufeng Chen, PhD, an instructor in the Department of Pathology at NYU Grossman. "Our preclinical findings suggest that combining BH3 mimetics like venetoclax with either MFN2 or general mitophagy inhibitors could possibly serve as a future therapy for acute myeloid leukemia, as current drug treatments are stalled due to drug resistance," said study senior investigator Iannis Aifantis, PhD. Aifantis, the Hermann M. Biggs Professor and chair of the Department of Pathology at NYU Grossman and Perlmutter, says the research team plans to design a clinical trial to test whether chloroquine, when used in combination with venetoclax, prevents drug resistance in people with acute myeloid leukemia. Speaking about other study results, the researchers say they not only found that MFN2 was overly active in people with drug-resistant disease, but also that cancer cells exposed to similar cell-death-inducing compounds demonstrated a doubling in mitophagy rates. Additional testing in cancer cells engineered to lack MFN2 showed increased sensitivity to drugs similar to venetoclax compared with cells that had functional MFN2. The new study and previous research by the team showing misshapen mitochondria in drug-resistant leukemic cells confirmed that increased mitophagy was the source of the problem. Acute myeloid leukemia, the most common form of adult leukemia, originates in the bone marrow cells and involves the rapid buildup of abnormal blood cells. The blood cancer results in the deaths of more than 11,500 Americans annually. Current treatments include chemotherapy and a limited number of targeted drug therapies. Bone marrow transplantation has also been used when other options fail. Funding support for the study was provided by National Institutes of Health grants P30CA016087, P30CA013330, R01CA178394, R01CA173636, R01CA228135, R01CA229086, R01CA242020, and K99CA252602. Additional funding support was provided by the Leukemia & Lymphoma Society and by AstraZeneca, which provided several of the BH3 mimetic drugs used in these experiments. Aifantis has received additional research funding from AstraZeneca. This arrangement is being managed in accordance with the policies and practices of NYU Langone Health. Besides Glytsou, Chen, and Aifantis, other NYU Langone study investigators are Wafa Al-Santli, Hua Zhou, Bettina Nadorp, Soobeom Lee, Audrey Lasry, Zhengxi Sun, Dimitrios Papaioannou, Michael Cammer, Kun Wang, and Aristotelis Tsirigos. Other study co-investigators are Emmanouil Zacharioudakis and Evripidis Gavathiotis, at Albert Einstein College of Medicine in New York, who have filed a patent on mitofusin inhibition based on this research; Tomasz Zal, Malgorzata Anna Zal, Bing Carter, Jo Ishizawa, and Michael Andreeff, at the University of Texas MD Anderson Cancer Center in Houston; and Raoul Tibes, at AstraZeneca in Cambridge, the United Kingdom. SOURCE NYU Grossman School of Medicine and NYU Langone Health Posted: April 2023 Related articles Genentech Announces Full FDA Approval for Venclexta Combinations for Acute Myeloid Leukemia - October 16, 2020 AbbVie Announces US FDA Approval of Venclexta (venetoclax) as a Chemotherapy-Free Combination Regimen for Previously Untreated Chronic Lymphocytic Leukemia Patients - May 15, 2019 Genentech Announces FDA Grants Venclexta Accelerated Approval for People With Newly-Diagnosed Acute Myeloid Leukemia or Those Who Are Ineligible For Intensive Induction Chemotherapy - November 21, 2018 Genentech Announces FDA Approval for Venclexta Plus Rituxan for People With Previously Treated Chronic Lymphocytic Leukemia - June 8, 2018 FDA Approves Venclexta (venetoclax) for Chronic Lymphocytic Leukemia with 17p Deletion - April 11, 2016 FDA Grants Priority Review for Venetoclax New Drug Application - January 12, 2016 Pivotal Phase II Study Showed Nearly 80 Percent of People with Hard-to-treat Type of Chronic Lymphocytic Leukemia Responded to Investigational Medicine Venetoclax - December 6, 2015 Venclexta (venetoclax) FDA Approval History

Despite the promise of new medications that promote cancer cell death in people with acute myeloid leukemia, leukemic cells often adopt features that let them evade the drugs' effects within a year. Despite the promise of new medications that promote cancer cell death in people with acute myeloid leukemia, leukemic cells often adopt features that let them evade the drugs' effects within a year. Now, new research using human tissue samples and mouse models has found that resistance of leukemia cells to a widely prescribed drug called venetoclax occurs because of a rapid increase in the breakdown and turnover of mitochondria, structures inside the cell that help power its functions. In addition to their role in producing energy, mitochondria also tell cells to die under certain adverse conditions. This process of "programmed cell death" often goes wrong in cancer. Damaged mitochondria can also undergo a form of "self-eating" termed mitophagy that prevents them from sending "death signals." Led by scientists at NYU Langone Health and its Perlmutter Cancer Center, the study showed that mitophagy helps leukemia cells to evade the killing effects of venetoclax, a drug in a class of medications known as BH3 mimetics. Publishing in the journal Cancer Discovery online April 24, researchers found that the levels of several genes associated with mitophagy were increased in 20 leukemia patient samples compared with normal controls. The level of these genes was even higher in samples from leukemia patients with drug resistance than in those leukemic patients who were not. Particularly notable was the increased expression of the gene for Mitofusin-2 (MFN2), which codes for a key protein in the outer mitochondrial membrane. Further experiments using mice into which bone marrow from acute myeloid leukemia patients was transplanted showed that the drug chloroquine, a known mitophagy inhibitor, restored the ability of venetoclax to kill the cancer cells. "Overcoming resistance to BH3 mimetic drugs like venetoclax is of unique clinical significance because these medications are often used for treating people with acute myeloid leukemia," said study co-lead investigator Christina Glytsou, PhD, a former postdoctoral researcher at NYU Grossman School of Medicine and now an assistant professor at Rutgers University. "Acute myeloid leukemia is notoriously difficult to treat, with fewer than a third of those affected living longer than five years after their diagnosis, so it is important to maximize the impact of existing therapies," said study co-lead investigator Xufeng Chen, PhD, an instructor in the Department of Pathology at NYU Grossman. "Our preclinical findings suggest that combining BH3 mimetics like venetoclax with either MFN2 or general mitophagy inhibitors could possibly serve as a future therapy for acute myeloid leukemia, as current drug treatments are stalled due to drug resistance," said study senior investigator Iannis Aifantis, PhD. Aifantis, the Hermann M. Biggs Professor and chair of the Department of Pathology at NYU Grossman and Perlmutter, says the research team plans to design a clinical trial to test whether chloroquine, when used in combination with venetoclax, prevents drug resistance in people with acute myeloid leukemia. Speaking about other study results, the researchers say they not only found that MFN2 was overly active in people with drug-resistant disease, but also that cancer cells exposed to similar cell-death-inducing compounds demonstrated a doubling in mitophagy rates. Additional testing in cancer cells engineered to lack MFN2 showed increased sensitivity to drugs similar to venetoclax compared with cells that had functional MFN2. The new study and previous research by the team showing misshapen mitochondria in drug-resistant leukemic cells confirmed that increased mitophagy was the source of the problem. Acute myeloid leukemia, the most common form of adult leukemia, originates in the bone marrow cells and involves the rapid buildup of abnormal blood cells. The blood cancer results in the deaths of more than 11,500 Americans annually. Current treatments include chemotherapy and a limited number of targeted drug therapies. Bone marrow transplantation has also been used when other options fail. Funding support for the study was provided by National Institutes of Health grants P30CA016087, P30CA013330, R01CA178394, R01CA173636, R01CA228135, R01CA229086, R01CA242020, and K99CA252602. Additional funding support was provided by the Leukemia & Lymphoma Society and by AstraZeneca, which provided several of the BH3 mimetic drugs used in these experiments. Aifantis has received additional research funding from AstraZeneca. This arrangement is being managed in accordance with the policies and practices of NYU Langone Health. Besides Glytsou, Chen, and Aifantis, other NYU Langone study investigators are Wafa Al-Santli, Hua Zhou, Bettina Nadorp, Soobeom Lee, Audrey Lasry, Zhengxi Sun, Dimitrios Papaioannou, Michael Cammer, Kun Wang, and Aristotelis Tsirigos. Other study co-investigators are Emmanouil Zacharioudakis and Evripidis Gavathiotis, at Albert Einstein College of Medicine in New York, who have filed a patent on mitofusin inhibition based on this research; Tomasz Zal, Malgorzata Anna Zal, Bing Carter, Jo Ishizawa, and Michael Andreeff, at the University of Texas MD Anderson Cancer Center in Houston; and Raoul Tibes, at AstraZeneca in Cambridge, the United Kingdom.