Repurposed Cancer Drug May Help Prevent Damage From COVID-19 Infection

Twelve years ago, cancer researchers at University of California San Diego identified a molecule that helps cancer cells survive by shuttling damaging inflammatory cells into tumor tissue. In new research, they show that the same molecule does the same thing in lung tissue infected with COVID-19 — and that the molecule can be suppressed with a repurposed cancer drug. The work, published in Science Translational Medicine, represents a new approach to preventing irreversible organ damage in infectious diseases like COVID-19 and methicillin-resistant Staphylococcus aureus (MRSA).

The two key players in this scenario are inflammatory cells called myeloid cells, and an enzyme called PI3K gamma (phosphatidylinositol 3,4,5-kinase gamma). Myeloid cells belong to our innate immune system — the immunity we’re born with before we’re exposed to pathogens in the environment — and work very quickly to kill deadly agents like SARS-CoV-2, the virus that causes COVID-19.

“Our work shows that drugs that can prevent the recruitment of damaging myeloid cells into tissues that are infected with severe agents like COVID-19 or MRSA have a significant benefit in preserving tissue function if given early enough in an infection,” says Judith Varner, Ph.D., professor in the Departments of Pathology and Medicine at UC San Diego School of Medicine, co-leader of the Solid Tumor Therapeutics program at UC San Diego Moores Cancer Center, and the study’s senior author.

"This is the first time this particular approach of targeting myeloid cells specifically has been shown to be effective in COVID. We hope that our research will help us obtain funding to continue investigating this approach in other diseases." Judith Varner, Ph.D.

Most other COVID-19 drugs target the virus, either preventing infection in the first place or preventing the virus from making more of itself after infection. The current approach targets the host, keeping the immune system from overreacting or fibers building up in the lungs.

Myeloid cells protect us, but they can also do a lot of damage, says Varner. “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. 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. That's what happens in COVID-19.”

PI3K gamma promotes the movement of myeloid cells into cancerous tissues, as found in the team’s work with cancer twelve years ago. In the current work, they show that PI3K gamma also helps move myeloid cells into tissues infected with SARS-CoV-2. That led them to reason that a cancer drug that inhibits PI3K gamma, called eganelisib, might be effective in suppressing inflammation in COVID-19 by suppressing PI3K gamma’s ability to move myeloid cells into infected tissue.

Reference: Shepard RM, Ghebremedhin A, Pratumchai I, et al. PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections. Science Trans Med. 2024;16(754):eadi6887. doi: 10.1126/scitranslmed.adi6887

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