Targeting TP53-Y220C mutant AML
Bing Carter
PhDMD Anderson Cancer Center
Project Term: July 1, 2024 - June 30, 2027
TP53-Y220C is a recurrent hotspot TP53 mutation observed predominantly in AML and MDS among hematological malignancies. This study aims to investigate the mechanism of action and therapeutic activity of PC14586, a compound designed to bind p53-Y220C protein and stabilize it in the wild-type conformation and to develop mechanism-based combinations that improve its efficacy in TP53-Y220C mutant AML.
Despite of recent improvements in therapies against acute myeloid leukemia (AML), patients with tumor suppressor gene TP53-mutant AML respond poorly to current available therapies. Consequently, TP53 mutations are frequently enriched/selected in refractory/relapsed AML, and associated with low survival rates including the recent US FDA approved combinations of the Bcl-2 inhibitor venetoclax (VEN) with a hypomethylating agent (HMA) or low-dose Ara-C that elicit complete remission/complete remission with incomplete hematologic recovery rates of > 65% and are well tolerated by elderly AML patients. Many chemotherapeutic drugs and targeted agents kill cancer cells by inducing apoptosis, one of the cell death programs. Apoptosis induction depends highly on intact p53 signaling. Not surprisingly, patients with TP53 mutations have vastly inferior responses to various therapies including VEN-based therapies, supported by a recent pre-clinical study demonstrating that TP53 mutations confer resistance to HMA/VEN in vitro and in vivo.
Most of TP53 mutations occur in the p53 protein regions that affect the binding of p53 protein to specific DNA sequences, which are required for its normal functions. TP53-Y220C in one of the most common mutations that plays a major role in cancer initiation, progression, and resistance to therapy. Y220C mutant p53 protein creates a crevice that is suitable for structure-based drug design to restore p53 function. PC14586 (PMV Pharmaceuticals) is a compound designed to bind to the p53-Y220C mutant and restore wild-type p53 protein conformation and function.
Among various hematological malignancies, TP53-Y220C mutation is observed predominantly in AML and myelodysplastic syndrome. No effective therapies are available for patients with TP53-Y220C mutant AML. Supported by our preliminary data, we hypothesize that reactivation of p53 and p53 signaling has antileukemia activity in TP53-Y220C AML cells and stem cells and that co-targeting of MDM2 and the antiapoptotic protein Bcl-2 will be synergistic and maximize apoptogenic activity of p53 activation. In the proposed study, we will 1) investigate efficacy and mechanisms of action of PC in AML and AML stem cells with TP53-Y220C mutation, 2) test the hypothesis that selective targeting of TP53-Y220C mutant AML by PC results in synergistic apoptosis induction by concomitant inhibition of MDM2 or/and Bcl-2 and investigate mechanisms of action, and 3) test the therapeutic efficacy of PC and its combinations with MDM2 and/or Bcl-2 inhibition in vivo in mouse models. The goal is to develop a novel therapy that is effective against TP53-Y220C clones and also has the potential to eliminate leukemia clones with wild-type TP53.