Drug reprograms macrophages, suppresses prostate and bladder tumors

Recent research from the Johns Hopkins Kimmel Cancer Center, Bloomberg~Kimmel Institute for Cancer Immunotherapy, and Johns Hopkins Drug Discovery has revealed a groundbreaking therapy that reprograms immune cells to combat hard-to-treat prostate and bladder cancers in mice. This novel approach was detailed in a study published on May 3 in the journal Cancer Immunology Research.

Immunotherapies have revolutionized cancer treatment by enabling the immune system to recognize and attack tumors. However, these therapies have shown limited success against aggressive forms of prostate and bladder cancers. The research team, led by Jelani Zarif, Ph.D., identified immune cells known as macrophages as key players in this resistance. Typically, macrophages can either support immune responses or suppress them, aiding tumor growth by hindering the activity of T-cells.

The goal of Zarif's team was to convert these immune-suppressive macrophages into anticancer agents, enhancing the efficacy of immunotherapies and standard cancer treatments. Their previous work suggested that macrophages' behavior could be influenced by the availability of the amino acid glutamine. When macrophage precursor cells, monocytes, are cultured without glutamine, they become immune-activating. Conversely, the presence of glutamine leads to immune-suppressive macrophages.

The researchers hypothesized that blocking macrophages' access to glutamine could shift their function towards tumor suppression. They focused on a drug known as 6-diazo-5-oxo-L-norleucine (DON), which deprives tumors of glutamine. Despite its potential, DON was abandoned decades ago due to severe gastrointestinal side effects.

In collaboration with Barbara Slusher, Ph.D., and Jonathan Powell, M.D., Ph.D., the team explored an experimental drug called JHU083. This prodrug remains inactive in the body until it reaches the tumor, where it converts to its active form, blocking glutamine and minimizing side effects. JHU083 has shown promise in shrinking tumors and extending survival in animal models with various cancers.

Zarif's research demonstrated that JHU083 effectively halted glutamine usage in prostate and bladder cancer cells in mice, thereby reducing tumor growth and inducing tumor cell death. The drug reprogrammed macrophages into immune-boosting cells, which not only attacked tumors directly but also recruited T-cells and natural killer cells to the site of the tumor. Interestingly, combining JHU083 with a checkpoint inhibitor, another type of immunotherapy, did not enhance its efficacy, likely due to the already heightened antitumor activity induced by JHU083.

Zarif sees potential in JHU083 for treating tumors characterized by immune-suppressive macrophages and low T-cell presence. This drug could also benefit patients whose cancers do not respond to current checkpoint inhibitors.

Future plans include clinical trials to assess JHU083's effectiveness in patients with resistant prostate or bladder cancers. The team also aims to explore whether combining JHU083 with other treatments could further enhance its anticancer properties.

This significant study included contributions from researchers Monali Praharaj, Fan Shen, Alex J. Lee, Liang Zhao, and others from Johns Hopkins. The work received support from the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the Prostate Cancer Foundation, the National Institutes of Health, and the Maryland Cigarette Restitution Fund.

Johns Hopkins University has filed patent applications for technologies described in this study, with several researchers listed as inventors. The relationships of Slusher, Powell, and Rais with Dracen Pharmaceuticals are managed according to the university's conflict-of-interest policies.