Researchers Find Natural Mechanism to Sensitize Cancer to Immunotherapy

AHA Publisher — Mon, 07 Mar 2022 08:00:02 +0000

Michigan Medicine – University of Michigan via Newswise – Researchers at the University of Michigan Rogel Cancer Center found that a cytokine, a category of protein that acts as messengers in the body, and a fatty acid can work together to trigger a type of cell death previously defined by studies with synthetic molecules. The study, published in Cancer Cell, looked at cell cultures and in vivo mouse experiments to see how the release of a T-cell cytokine called interferon gamma combined with arachidonic acid, a fatty acid, leads to a type of cell death called ferroptosis via targeting the enzyme ACSL4. Ferroptosis has been found to occur in tumor cells and play a role in cancer immunity. Understanding how ferroptosis occurs could open pathways to make immunotherapy treatments more effective. “Targeting ACSL4 may help in understanding and expanding possible immunotherapy options,” said Weiping Zou, M.D., Ph.D., director the Center of Excellence for Cancer Immunology and Immunotherapy and lead researcher on this study. Zou explains that this natural mechanism begins when activated T-cells release interferon gamma, a signaling protein. “It’s well known that interferon gamma is involved in anti-tumor responses,” said Zou. “But in this study, we defined a new way that it works.” This study shows that combining interferon gamma with arachidonic acid, a fatty acid found in the tumor microenvironment, activates ACSL4, alters tumor cell lipid pattern, and naturally induces tumor cell ferroptosis. “ACSL4-dependent tumor ferroptosis is a mode of action of killer T cells,” said Zou. “Targeting ACSL4 sensitizes cancer to immunotherapy.” Zou’s lab was the first to identify a role for ferroptosis in cancer immunity and therapy, highlighting the possibility of targeting this pathway to improve the effectiveness of immunotherapy in people with cancer. While immunotherapy has dramatically changed outcomes in melanoma, lung cancer and other cancer types, the treatments work for only about 30% of people with cancer. These new findings add more knowledge to how ferroptosis works in patients with cancer, which Zou hopes will prompt further investigation. “This study raises a lot of questions for us to keep exploring, particularly around the basic biology of cell ferroptosis, including the involvement of different fatty acids and dietary lipids, the different roles immune cells play in ferroptosis, and how to target ACSL4 and ferroptosis pathways,” Zou said. “For now, there are many unknowns, but we’ll continue to work in this space.” To read the original article click here.

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Researchers Identify New Drug Combination That Can Treat Acute Myeloid Leukemia

AHA Publisher — Fri, 22 Jan 2021 08:00:57 +0000

Sanford Burnham Prebys Medical Discovery Institute via News-Medical Net – Scientists have identified two drugs that are potent against acute myeloid leukemia (AML) when combined, but only weakly effective when used alone. The researchers were able to significantly enhance cancer cell death by jointly administering the drugs that are only partially effective when used as single-agent therapies. The study, a collaboration between Sanford Burnham Prebys Medical Discovery Institute and the University of Glasgow, was recently published in the journal Nature Communications. Our study shows that two types of drugs, MDM2 inhibitors and BET inhibitors, work synergistically to promote significant anti-leukemia activity. The results were surprising because previous research had shown that each drug on its own had modest benefit against AML. The new research provides scientific rationale to advance clinical studies of the drug combination in patients with AML.” (Peter Adams, Ph.D, Study Senior Author and Professor, Sanford Burnham Prebys Medical Discovery Institute) There are many types of AML, and different cases have different chromosome changes, gene mutations and epigenetic modifications, making it difficult for researchers to find novel therapies that will work for a substantial proportion of patients. Although much progress has been made toward finding effective treatments in recent years, the long-term overall survival has stagnated. According to the American Cancer Society, the five-year survival rate for adults with AML remains less than 30%. Notably, TP53, the most frequently mutated gene in all human cancers, is found unaltered in about 90% of AML patients. Since the product of the TP53 gene, p53, acts to suppress tumors, scientists have sought drugs that reactivate or boost its anti-cancer powers in AML, which should provide a clinical benefit. However, such drugs on their own have been disappointing in AML. “We were interested in combining MDM2 and BET inhibitors because each showed encouraging pre-clinical activity, but limited activity when given to patients as a single agent,” says Adams. “Previous research had shown that MDM2 inhibitors activate p53, and BET inhibitors suppress genes associated with leukemias–but not p53. “Our research unexpectedly showed that like MDM2 inhibitors, BET inhibitors activate p53, but through a different pathway. BET inhibitors mute the power of a protein called BRD4, which we found is a p53 suppressor in AML,” says Adams. “Between the two drugs, you end up with a ‘double whammy’ effect that fully unleashes the anti-cancer activity of p53. “Better therapies for AML are desperately needed,” adds Adams. “This study illustrates that targeting BRD4 as part of a combination therapy holds promise for patients diagnosed with this very dangerous disease.” To read the original article click here.

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cancer cell death Archives - Amazing Health Advances

Researchers Find Natural Mechanism to Sensitize Cancer to Immunotherapy

Researchers Identify New Drug Combination That Can Treat Acute Myeloid Leukemia