A team of Dana-Farber Cancer Institute investigators have discovered that a subset of myeloid and lymphoid leukemias depend on a molecular complex called PI3Kgamma for survival. This finding has led to 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, published in Nature, provides both mechanistic and preclinical evidence supporting the potential effectiveness of this approach.
Treatment for AML has improved over the last decade, but most patients ultimately relapse after treatment. The Dana-Farber team took a different approach, using genome wide CRISPR interference to search for genes that AML cells rely on to grow, rather than focusing on mutations. They identified a subset of leukemia cells that depend on a gene called PI3KR5, which produces an important portion of the PI3Kgamma complex. This complex had been studied before but not in AML, and a medicine, eganelisib, already existed to inhibit it.
In animal models harboring patient-derived leukemia xenografts, treatment with eganelisib resulted in the shrinkage of leukemia xenografts predicted to be highly dependent on PI3Kgamma, leading to longer survivability in the animal models. Analysis of The Cancer Genome Atlas Data (TCGA) showed that patients with AML predicted to be sensitive to eganelisib do not fare as well on existing therapies, indicating a need for new treatments. Combining eganelisib with cytarabine in animal models resulted in longer survival compared to cytarabine alone, regardless of the leukemia’s dependence on PI3Kgamma.
Further research by the team revealed that the combination of eganelisib and cytarabine worked synergistically, with eganelisib inhibiting PI3Kgamma and suppressing a leukemia cell metabolic process called oxidative phosphorylation (OXPHOS). Leukemia cells rely on OXPHOS for energy, and its suppression can result in their demise. Additionally, surviving leukemia cells that cause AML relapse were found to be more dependent on PI3Kgamma post-cytarabine treatment, making them vulnerable to a combination therapy of eganelisib and cytarabine.
The team is now focused on designing clinical trials for patients based on their findings. By rapidly translating their laboratory research into potential clinical applications, they hope to provide new effective treatment options for patients with AML. The team’s unique approach of targeting the PI3Kgamma complex, combined with traditional chemotherapy, shows promising results in animal models and TCGA data, highlighting the potential of this combination therapy in AML treatment. This study provides a scientific rationale for the clinical application of eganelisib and cytarabine combination therapy and offers insight into the needs of patients with AML.
