The Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy and Johns Hopkins Drug Discovery conducted research that found a new therapy has the potential to shrink prostate and bladder cancers that are difficult to treat in mice. The study was published online in the journal Cancer Immunology Research on May 3.Association for Cancer Research.
Immunotherapies have transformed cancer care by helping the immune system to identify and combat tumors. However, these treatments, which increase the production and activation of T-cells that destroy tumor cells, have not been successful in treating aggressive prostate and bladder cancers. The oncology field has been attempting to understand why these therapies are not effective in these cancers and how to improve their effectiveness, explains Jelani Zarif, Ph.D., the senior author of the study and the Robert E. Meyerhoff Endowed Professor and associate professor of oncology at Johns Hopkins. Zarif and his colleagues are working to address this issue.It was suspected that macrophages, a type of immune cell, were responsible for certain conditions that support tumor growth and inhibit T-cell activity, which hinders the body’s ability to fight cancer. Zarif’s team aims to change these immune-suppressing macrophages into cells that can fight cancer, in order to improve the effectiveness of cancer treatments. These macrophages that suppress the immune system depend on the amino acid glutamine. Previous research by Zarif and his colleagues showed that precursor cells of macrophages, called monocytes, can become immune-activating macrophages if certain conditions are met.The researchers grew the cells in a lab without using glutamine. In contrast, when the cells were grown with glutamine, they turned into immune-suppressing macrophages. Zarif and his team suggested that drugs which prevent immune cells from accessing glutamine could change the balance of macrophages to the immune-stimulating type, leading to tumor shrinkage. Studies have indicated that a drug called 6-diazo-5-oxo-L-norleucine (DON) can starve tumors of glutamine and shrink those that rely on it for growth. However, the drug was abandoned as a cancer therapy decades ago due to its toxic effects on the gastrointestinal system.
Zarif opted for an experimental glutamine-blocking drug called JHU083, developed by Barbara Slusher, Ph.D., and Jonathan Powell, M.D., Ph.D. The drug is a prodrug that is converted into an active drug by cells in the body. JHU083 is designed to be converted into its active form inside the tumor, minimizing the risk of harmful side effects in other parts of the body. Research indicates that the drug is effective in shrinking tumors and reducing cancer spread.
The drug JHU083 has been modified by Barbara Slusher and her team to circulate in an inactive form throughout the body and only becomes active once it enters cancer cells. This targeted approach allows for a lower dosage to be given, reducing the risk of side effects. Studies have demonstrated that JHU083 blocks the use of glutamine in prostate and bladder tumors in mice, leading to reduced tumor growth and increased survival rates in animals with various types of cancer. These include cancers of the skin, colon, blood, brain, and certain treatment-resistant breast cancers.
JHU083 has shown the ability to induce cell death in tumor cells and convert immune-suppressing macrophages into immune-boosting macrophages. The transformed macrophages proved to be effective in eliminating tumor cells and recruiting tumor-killing T-cells and natural killer cells to the tumors. Additionally, the addition of a checkpoint inhibitor immunotherapy did not enhance the effects of JHU083, indicating that the treatment already triggered significant antitumor immune activity in the treated tumors.
According to Zarif, JHU083 holds potential as an anti-cancer therapy for tumors with immune-suppressing macrophages and a low presence of T-cells.
Zarif suggests that JHU083 could potentially be a promising treatment for tumors that are unresponsive to checkpoint inhibitors. Zarif and colleagues from Johns Hopkins University are planning to conduct a clinical trial of JHU083 in patients with prostate or bladder cancer that doesn’t respond to treatment, in order to determine whether it can reduce tumor size and prevent the spread of cancer. They also aim to investigate whether combining JHU083 with other treatments can enhance its effectiveness against tumors. The study’s co-authors include Monali Praharaj, Fan Shen, Alex J. Lee, Liang Zhao, Thomas R. Nirschl, Debebe Theodros, Alok K. Singh, Xiaoxu Wang, Kenneth M. Adusei, Kara A. Lombardo, and Raekwon A.Williams, Laura A. Sena, Elizabeth A. Thompson, Ada Tam, Srinivasan Yegnasubramanian, Edward J. Pearce, Robert D. Leone, Jesse Alt, Rana Rais and Drew M. Pardoll from Johns Hopkins received support from the Bloomberg∼Kimmel Institute for Cancer Immunotherapy, a Prostate Cancer Foundation Young Investigator Award, the National Institutes of Health/National Cancer Institute (grant K22 CA237623), the National institutes of Health (grants #R01CA283649 and #R01CA229451) and a Maryland Cigarette Restitution Fund grant (#FHB33CRF) for their work. The Johns Hopkins University has filed patent applications related to technologies described in the study.The paper lists Slusher, Powell, Leone, Rais and Alt as inventors. Additionally, Slusher, Powell and Rais are co-founders of and consultants for Dracen Pharmaceuticals. Johns Hopkins University is managing these relationships in accordance with its conflict-of-interest policies.
