Investigating Abnormal Gene Activation
Abnormal activation of SET binding protein 1 (SETBP1) gene has been found to occur frequently in a variety of myeloid neoplasms, including myeloid leukemias, and other solid tumor cancers. Activation of this gene may play a role in disease initiation or progression and is associated with poor prognosis, driving an urgent need to develop effective targeted therapies for patients.
A Promising Discovery for Targeted Therapy
Researchers at USU and HJF have identified compounds to inhibit the activity of SETBP1. Based on the discovery that interaction with XPO1 is essential for SETBP1 to induce cancer transformation, researchers have carried out screening and lead identification work to identify small molecules that could block the interaction between SETbp1 and XPO1. These compounds may be effective in treating cancers associated with SETbp1 overexpression or missense mutations.
Applications
USU and HJF have identified compounds and methods may be effective for treating a variety of human myeloid.
- Primary acute, secondary, chronic, or atypical chronic myeloid leukemias
- Chronic and juvenile myelomonocytic leukemia
- Chronic myeloid leukemia blast crisis
- Myelodysplastic syndrome
- Chronic neutrophilic leukemia
- Breast, colorectal, lung, ovarian, prostate, skin, liver, pancreatic, kidney, endometrial, esophageal, gastric, head, and neck cancers.
Advantages
Further research into the molecular mechanisms uncovered by HJF’s research is likely to lead to highly targeted therapies. HJF’s currently identified compounds tested in preclinical studies show promising results, including:
- Colony inhibition: Treatment inhibited colony formation and induced cytotoxicity in cells with SETBP1 overexpression or missense mutations.
- Induced differentiation: The number of mature neutrophils in the test culture increased significantly following treatment.
- Prolonged survival: Treatment prolonged the survival and decreased the spleen size in mice with leukemia induced by SETBP1 missense.
- Reduced transcription: Treatment reduced SETBP1target transcription levels at 12 hours post treatment.
- Growth inhibition on solid tumor cells: Treatment inhibited growth.
Status
Development: preclinical proof of concept completed
Patent: patent pending