The Hematologist

July-August 2018, Volume 15, Issue 4

New Means to Reactivate p53 in Leukemia: A Staple Peptide Inhibitor of MDMX and MDM2

Omar Abdel-Wahab, MD Assistant Member, Attending Physician
Memorial Sloan Kettering Cancer Center, New York, NY

Published on: June 19, 2018

Carvajal LA, Neriah DB, Senecal A, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med. 2018;10: doi: 10.1126/scitranslmed.aao3003. [Epub ahead of print].

The tumor suppressor TP53 is well recognized as one of the most commonly dysregulated genes in cancer and is affected by deletions, and both loss-of-function and change-of-function mutations. Additionally, several natural inhibitors exist in the cell as endogenous inhibitors of TP53 function. These include the proteins MDMX (also known as MDM4) and MDM2. MDM2 is an E3 ubiquitin ligase that targets TP53 for destruction while MDMX represses TP53 transcriptional activity. Current efforts to therapeutically target cells bearing altered TP53 include efforts to restore the wild-type function of TP53 or deplete, inhibit function, or induce synthetic lethality of mutant TP53. Of these strategies, the therapeutic approach that has come closest to clinical development is inhibiting the interaction of MDM2 and TP53. The first such MDM2 inhibitor compounds, termed nutlins, were described in 2004.1 However, these compounds, which underwent trials in refractory myeloid leukemia patients,2 were limited by in vivo potency and poor bioavailability. Additionally, it is known that MDMX promotes MDM2 activity via direct protein-protein interactions and that efforts to inhibit MDM2-p53 interaction can be limited by MDMX activity. Thus, targeting the interactions of TP53 with both MDM2 and MDMX would be expected to have greater impact on activating wild-type TP53 function than inhibiting MDM2 alone. To this end, Aileron therapeutics, in collaboration with Dr. Ulrich Steidl’s group at Albert Einstein College of Medicine, now describe a novel therapy to inhibit TP53’s interactions with both MDMX and MDM2 using a stapled peptide inhibitor known as ALRN-6924.3 This compound is a small molecule that consists of a peptide to inhibit the binding of TP53 to both MDM2 and MDMX and a synthetic brace (or “staple”) to lock the peptide in confirmation, increase its cell penetration, and protect the peptide from proteolytic cleavage. Aileron previously completed the first clinical trial of a stapled peptide and has now taken ARLN-6924 into phase I trials in solid tumors and lymphomas with wild-type TP53 (NCT02264613) as well as refractory myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with wild-type TP53 (NCT02909972).

Upregulation of MDM2 and MDMX have been described in several cancers and result in impaired TP53 function. Dr. Steidl’s group identified that MDMX is transcriptionally upregulated in AML patients (while MDM2 is not altered in expression) compared to patients with other forms of cancer, and is specifically upregulated in leukemia-initiating cells compared to healthy hematopoietic stem cells.3 Then, in a series of studies, they found that use of ALRN-6924 reactivated wild-type TP53 transcriptional activity and signaling in AML cells, had dose-dependent cytotoxic effects on AML cells in vitro, and reduced leukemia burden in vivo. Moreover, ALRN-6924 treatment in wild-type mice resulted in no major perturbations in hematologic parameters.

During the above preclinical studies, the investigators encountered a 20-year-old female patient with metastatic breast cancer, germline deletion of one allele of TP53, and high-risk MDS (refractory anemia with excess blasts) refractory to conventional chemotherapy. After confirming that her leukemic cells retained one copy of wild-type TP53, they were able to treat the patient with ARLN-6924 under compassionate use. Although the patient was able to be treated for 30 days before passing away from infectious complications, during treatment she experienced a rapid clearance of leukemic blasts, improvement in neutropenia, and no grade 3 or 4 thrombocytopenia.3 Moreover, ARLN-6924 treatment in this patient reactivated TP53 transcriptional activity.

The above studies provide new hope for therapeutic activation of wild-type TP53 in leukemia and other forms of cancer. They also raise enthusiasm for further development of additional peptide inhibitors of protein-protein interactions in cancer. It is important to note, however, that the preclinical efficacy of ALRN-6924 was restricted to AML cell lines expressing wild-type TP53. Cells null for TP53 or with heterozygous change-of-function mutations in TP53 failed to respond to the compound.3 Thus, further efforts to develop strategies to target mutant TP53 proteins or selectively eradicated cells bearing TP53 mutations/loss remain very important.

References

  1. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844-848.
  2. Andreeff M, Kelly KR, Yee K, et al. Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res. 2016;22:868-876.
  3. Carvajal LA, Neriah DB, Senecal A, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med. 2018;10: doi: 10.1126/scitranslmed.aao3003. [Epub ahead of print].

Conflict of Interests

Dr. Abdel-Wahab indicated no relevant conflicts of interest. back to top