Lab mouse
New research suggests the FOXM1 protein plays an important role in acute myeloid leukemia (AML) progression, and targeting FOXM1 could improve AML treatment.
With a retrospective study, researchers showed that overexpression of FOXM1 was associated with increased resistance to chemotherapy and inferior overall survival.
Subsequent preclinical research showed that ixazomib inhibits FOXM1, exhibits antileukemic activity, and sensitizes AML cells to chemotherapy.
Irum Khan, MD, of the University of Illinois in Chicago, and her colleagues reported these findings in JCI Insight.
Previous research showed that AML patients with NPM1 mutations have a higher rate of remission with chemotherapy, and the NPM1 protein affects the location and activity of FOXM1. NPM1 keeps FOXM1 in the nucleus where it can activate other cancer-promoting genes.
When the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell’s cytoplasm, where it can’t interact with DNA. This may explain why AML patients with NPM1 mutations have a better response to chemotherapy and are less likely to relapse.
With the current research, Dr Khan and her colleagues further explored the role of FOXM1 in AML.
Retrospective analysis
The multicenter, retrospective study began with data from 111 adults with AML. They had intermediate-risk cytogenetics and a median age of 61.
Eighty-eight patients received induction with cytarabine and an anthracycline, and 80 achieved a complete remission with or without count recovery.
FOXM1 expression data were available for 74 of these patients. Fifty patients achieved remission with 1 cycle of induction, and 24 required more than 1 cycle.
“[Patients] with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus,” Dr Khan said.
The patients who failed their first line of induction had a more than 2-fold increase in the percentage of nuclei expressing FOXM1 in their bone marrow (P=0.004). And the average nuclear intensity of FOXM1 was significantly higher in the patients who failed their first line of induction (P=0.02).
The percentage of FOXM1-positive nuclei and the average nuclear intensity of FOXM1 both significantly predicted resistance to first-line chemotherapy. The odds ratio was 1.80 for a 10% increase in FOXM1-positive nuclei (P=0.005) and 2.5 for a 0.1 unit increase in nuclear intensity (P=0.02).
A multivariate analysis showed that the FOXM1 nuclear/cytoplasmic (N:C) ratio and nuclear FOXM1 intensity predicted inferior overall survival in a single institution. (Institutions were analyzed separately for survival). The hazard ratio was 4.7 for every 0.1 unit increase in N:C ratio (P=0.03) and 4.27 for every 0.1 unit increase in nuclear intensity (P=0.06).
Confirming the role of FOXM1
The researchers set out to confirm the role of FOXM1 via experiments in mice.
The team induced a FLT3-ITD-driven myeloproliferative neoplasm in a FOXM1-overexpressing transgenic mouse model.
These mice had more residual disease after treatment with cytarabine than control mice with normal levels of FOXM1.
“Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients’ FOXM1 levels and their treatment outcomes,” Dr Khan said.
Targeting FOXM1 with ixazomib
Next, the researchers showed they could produce a therapeutic response by inhibiting FOXM1 in AML. The team used ixazomib, which was shown to suppress FOXM1.
There was a 2-fold increase in apoptosis when AML patient cells were treated with ixazomib (compared to DMSO).
Ixazomib also exhibited antitumor activity in a xenograft model of AML (HL-60 cells) and reduced leukemic burden in an orthotopic model of AML (KG-1 cells).
Finally, the researchers found that ixazomib sensitized AML cells to chemotherapy. The team observed synergistic activity between ixazomib and cytarabine or 5-azacitidine.
“There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don’t have this beneficial [NPM1] mutation often face,” Dr Khan said.
“Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory.”
This research was supported by grants from the National Institutes of Health and Takeda.