PI3Kγ

Before Infinity Pharmaceuticals shut down, eganelisib was fast-tracked by the FDA for potential use in triple-negative breast cancer in combination with other drugs. Just in time for a summer COVID wave to remind us that SARS-CoV-2 is here to stay, researchers at the University of California, San Diego (UCSD) have published new findings that show an experimental cancer drug developed by a now-bankrupt biotech can suppress the virus in lung tissue.  In a July 3 article in Science Translational Medicine, the UCSD team established that levels of damage-causing immune cells called myeloid cells are raised in the lungs of people with COVID-19 and other infections, like methicillin-resistant staphylococcus aureus (MRSA). Targeting an enzyme called phosphatidylinositol 3,4,5-kinase gamma (PI3Kγ) with the small molecule inhibitor eganelisib—a clinical-stage anti-cancer agent developed by Infinity Pharmaceuticals, which declared Chapter 11 bankruptcy in October 2023—reduced the number of myeloid cells in the lungs and improved the survival rate of mice infected with either COVID-19 or MRSA.  “Other drugs were tested early during the COVID-19 crisis for similar effects, with only modest success,” Judith Varner, Ph.D., the paper’s senior author who also studied eganelisib on behalf of Infinity, said in a press release. “Our work is significant because this is the first time this particular approach of targeting the myeloid cells specifically has been shown to be effective in COVID.”  Myeloid cells release immune pathway signaling proteins called cytokines and are thus an essential part of the immune system. But the inflammation they cause can go awry and lead to life-threatening lung damage, as happens in some patients with COVID-19 as well as those who are co-infected with flu and MRSA.  PI3Kγ is a key component of this process because it helps myeloid cells move into virus-infected organs. It does the same thing in cancerous tissues, which was the logic behind eganelisib’s mechanism of action. Stopping PI3Kγ’s activity stops myeloid cell migration, ameliorating tissue damage.  Before Infinity shut down, eganelisib was fast-tracked by the FDA for potential use in triple-negative breast cancer in combination with other drugs. A phase 1 study on that indication was completed in May 2024. Clinical trials for its use in urethral cancer, head and neck cancer and renal cell carcinoma were also underway.  Now, the team behind the research hopes that it will lead drug companies to develop compounds similar to eganelisib to treat COVID-19, MRSA and other diseases that cause myeloid-cell-driven organ damage. Varner also said in the release that she hopes the latest findings will lead to more funding for her team to continue their work in a range of disease settings.  Fierce has reached out to UCSD for comment.

MONDAY, July 8, 2024 -- An experimental cancer drug might be able to help prevent the organ damage caused by severe COVID infections, a new study finds. The drug, called eganelisib, inhibits an immune system enzyme called PI3K gamma that boosts damaging inflammation in cancerous tumors. But lab studies in mice and human tissue showed that eganelisib could also be effective in suppressing organ-damaging inflammation caused by COVID, according to findings published July 3 in the journal Science Translational Medicine . COVID is mainly known as a lung disease, but severe cases are known to damage the heart, gastrointestinal system, kidneys, brain and nervous system. This damage contributes to Long COVID -- a debiltating condition where symptoms that last months and years beyond the initial infection. The P13K gamma enzyme causes a type of white blood cell called myeloid cells to flood tumor tissue, creating inflammation that worsens cancer, researchers said. Myeloid cells are meant to work quickly to kill potentially deadly bacteria and viruses, including the coronavirus behind COVID, researchers said. Unfortunately, they can do a lot of damage if the immune system overreacts to a severe infection, said senior researcher Judith Varner , a professor of pathology and medicine at the University of California, San Diego (UCSD). “If you have a little infection, myeloid cells come in, kill bacteria, release alerts that recruit even more potent killer immune cells, and produce substances that can heal the damage,” Varner explained in a UCSD news release. “But if you get an infection that's too strong, you get overproduction of these alert signals and the substances they release to kill these infective agents can also kill yourself,” Varner added. “That's what happens in COVID-19.” In lab tests, researchers found that eganelisib can keep myeloid cells from doing damage to human tissue and infected lab mice. “We sequenced COVID-19 patient lung tissue and showed that when patients have COVID-19, a lot of their lung cells are killed and there's a huge increase in myeloid cells,” Varner said. “We also found the same thing in infected mice.” “When we treated with the drug, we showed that eganelisib prevents entry of myeloid cells into tissue so they can’t do all that damage,” Varner added. “Further studies will determine if it can actually reverse damage.” Eganelisib had similar results in mice infected with MRSA, researchers said. Most approved COVID drugs target the virus, either by preventing infection or inhibiting the virus’ spread, researchers said. Eganelisib works by targeting the person’s immune system, preventing a damaging overreaction that causes tissue scarring. No other drug with a similar approach to treating COVID has been approved yet. Eganelisib received fast-track designation from the U.S. Food and Drug Administration in 2020, but has not yet been approved. The company that developed the drug, Infinity Pharmaceuticals, declared bankruptcy in 2023. Varner said she hopes these results will lead drugmakers to develop other PI3K gamma inhibitors to treat infectious diseases like COVID and MRSA. “We hope that this research will help us obtain funding to continue investigating this approach in other disease settings,” Varner added. Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

Investigators discovered that a subset of myeloid and lymphoid leukemias depend on a molecular complex called PI3Kgamma for survival. The study provides both mechanistic and preclinical evidence supporting the rapid initiation of clinical trials for patients with acute myeloid leukemia (AML) to test an existing medicine that inhibits the complex, called eganelisib, both alone and in combination with the most used AML chemotherapy, cytarabine. Boston -- A team of Dana-Farber Cancer Institute investigators discovered that a subset of myeloid and lymphoid leukemias depend on a molecular complex called PI3Kgamma for survival. The study provides both mechanistic and preclinical evidence supporting the rapid initiation of clinical trials for patients with acute myeloid leukemia (AML) to test an existing medicine that inhibits the complex, called eganelisib, both alone and in combination with the most used AML chemotherapy, cytarabine. The study was published in Nature. "Given what we've observed, we can move very quickly to take these medicines, which appear to be safe and well tolerated, to patients with AML," says principal investigator Andrew Lane, MD, PhD, a clinician-scientist in the Adult Leukemia Program at Dana-Farber. "We are planning clinical trials to start hopefullywithin the next year." Treatment for AML has advanced in the last decade, but most patients ultimately relapse after treatment. Therapies that target AML-related mutations have provided options for subsets of patients, though the cancer eventually evolves to evade the therapy. The Dana-Farber team took a different approach to searching for therapeutic targets. Rather than focusing on mutations, first author Qingyu Luo, MD, PhD, a research fellow in Lane's lab, used genome wide CRISPR interference to search for genes that AML cells rely on to grow. He found a promising hit. A subset of leukemia cells relied on a gene called PI3KR5 to survive. That gene produces an important portion of the PI3Kgamma complex. This hit was attractive in part because the PI3Kgamma complex had been studied before, though not in AML. In addition, a medicine already existed to inhibit it. This drug, eganelisib, has been tested in trials for certain solid tumors to enhance cancer immunotherapy. What Luo and Lane had found, however, was a completely different mechanism of action in which the drug might work directly on leukemia cells to stop their growth. To validate this hypothesis, the team treated animal models harboring patient-derived leukemia xenografts with eganelisib. They found that the leukemia xenografts predicted to be highly dependent on PI3Kgamma shrank, and the animal models survived longer when treated with eganelisib. Looking at The Cancer Genome Atlas Data (TCGA), the team found that patients with AML predicted to be sensitive to eganelisib don't do as well in terms of survival on existing therapies compared to those with negative biomarkers. This finding suggests that this patient group, which can be identified by high levels of PI3KR5 expression, has a need for new medicines and could potentially benefit from treatment with eganelisib. "This is a drug that is ready to be tested in patients with AML," says Lane. "It's already been used in clinical trials for many patients with solid tumors." Luo, who initiated this research to improve existing therapies for AML, also treated animal models of leukemia with cytarabine alone and with eganelisib plus cytarabine. The team found that those treated with a combination of eganelisib and cytarabine survived longer than those treated with cytarabine alone, regardless of the leukemia's sensitivity to PI3Kgamma inhibition alone. The observations suggested that the two medicines worked synergistically. Luo investigated and found that PI3Kgamma, when inhibited, also results in the suppression of a leukemia cell metabolic process called oxidative phosphorylation (OXPHOS). Leukemia cells depend on OXPHOS for energy, and suppression of OXPHOS can result in their demise. Luo also discovered that leukemia cells that survive standard treatment with cytarabine tend to be more dependent on PI3Kgamma than they were prior to treatment. These surviving leukemia cells -- which are the cause of AML relapse -- could be vulnerable to combination therapy with eganelisib and cytarabine. "We want synergy, where two drugs mesh with each other," says Luo. "Through inhibition of PI3Kgamma, eganelisib has this downstream effect of suppressing an energy pathway important in AML relapse." The team is now focused on designing clinical trials for patients. "This study provides the scientific rationale for a clinical application and also helps us understand where the discoveries apply to the needs of our patients," says Lane. "Dana-Farber is one of the unique places where you can go from molecular biology in the lab to testing in models based on patient samples and then to rapidly initiating a clinical trial on the basis of this science."