A study demonstrates the efficacy of a peptide drug in AML
A study, led by researchers from Albert Einstein College of Medicine and Aileron Therapeutics, has demonstrated the therapeutic potential of an investigational drug called ALRN-6924 in the life-threatening cancer acute myeloid leukemia (AML).
The study (Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia) was published this week in the journal Science Translational Medicine.
Tumor suppressor genes inhibit the development of tumors. But the expression or activity of tumor suppressor genes is often lost or reduced in cancer cells. One of the most well-studied tumor suppressor genes, p53, is often inactivated via two endogenous inhibitors MDMX
and MDM2, which are frequently overexpressed in cancers such as AML. Disrupting the interactions of p53 with MDMX and MDM2 is a promising approach to treat these cancers.
The stapled peptide ALRN-6924, developed by Aileron Therapeutics, is designed to reactivate p53-mediated tumor suppression by inhibiting MDMX and MDM2.
In this work, the researchers used in vitro and in vivo models to evaluate the effectiveness of ALRN-6924 as a therapeutic in AML. They demonstrated that ALRN-6924 strongly activated p53-dependent transcription in leukemia cells. Dual MDMX/MDM2 inhibition by ALRN-6924 suppressed cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells. Moreover, ALRN-6924 significantly improved survival in AML xenograft models.
According to senior author Dr. Ulrich Steidl, the ability of ALRN-6924 to exert its effects in both mature AML cells and immature stem cells is important because the disease will come back if stem cells are not affected.
In conclusion, the study demonstrates the efficacy of ALRN-6924 in AML. It's necessary to further investigate the potential of ALRN-6924 as a therapeutic for AML. Additionally, ALRN-6924 may have an effect in a broader range of other tumors.
AML is the most common type of acute leukemia, and it has other names including acute myelocytic leukemia, acute myelogenous leukemia, acute granulocytic leukemia, and acute non-lymphocytic leukemia. AML occurs when stem cells found in the bone marrow produce too many immature white blood cells, known as blast cells. In AML, blast cells do not develop and are unable to ward off infections.
What causes AML still remains largely unknown. There is evidence that loss or inactivation of p53 cooperates with other pathogenic events to induce AML. The p53 tumor suppressor is known to trigger cell cycle arrest, senescence, and/or apoptosis on cellular stress. The ability of p53 to limit aberrant self-renewal contributes to its tumor suppressor activity. In addition, many chemotherapeutic drugs need functional p53 to exert their antitumor effects. Therefore, p53 is believed to be an attractive target for cancer treatment, and multiple strategies for therapeutic reactivation of p53 have been developed.
The peptide ALRN-6924 is one of the drug candidates that reactivate p53. Scientists are pursuing strategies of development with ALRN-6924 as a monotherapy or combination therapy across various types of solid and liquid tumors. ALRN-6924 is now being tested in multiple clinical trials.