Novel Therapeutic Strategies for TP53-Mutated Myeloid Malignancies: What is the Role of XPO1?

At the 2022 ASH Annual Meeting & Exposition in New Orleans, LA, Traci Kruer, PhD, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, presented data from a phase 1/2 clinical trial showing XPO1 overexpression is a mechanism of resistance to eprenetapopt and 5-azacitidine and can be therapeutically exploited to treat  patients with TP53-mutated myeloid malignancies.

Transcript:

Hello, my name is Traci Kreuer and I am a research scientist at Moffitt Cancer Center in Tampa, Florida. My research project involves determining mechanisms of resistance to therapeutics in TP53 mutated myeloid malignancies.

The project that I'm working on is to find the resistance mechanism for a drug called Eprenetapopt, which is a P53 reactivator, [combined with] azacitidine. TP53 mutated myeloid malignancies constitute about 10 to 20% of all myeloid malignancies and are extremely aggressive with an overall survival of only 6 to 12 months. We had a recent phase 1/2 clinical trial that combined eprenetapopt with azacitidine. Although the response rates were good, eventually any patient that was not eligible for transplant did relapse with the same P53 mutation. So, [I designed] a genome-wide CRISPR screen in AML cells with a TP53 mutation, and found that the protein XPO1 was one of the most significantly enriched genes.

We explored more about what the role XPO1 has in these cancers, and we saw that cells that are resistant to the drugs eprenetapopt and azacitidine have a high overexpression of the protein. Because XPO1 is known to shuttle P53 from the nucleus to the cytoplasm. We hypothesize that—in the overexpression-resistant lines—that activated P53 is being shuttled to the cytoplasm where it is no longer active, and that if we blocked this with an XPO1 inhibitor, we could reverse that.

We tested various cell lines with those 2 drugs, an XPO1 inhibitor, either selinexor or eltanexor, and eprenetapopt. We found that they are synergistic in TP53 mutated cell lines. We also found that in our mouse models, that we could get smaller tumor growth by combining the drugs. But also, we did PDX models with human samples and found that they have leukemic engraftment with a combination of the drugs. We are hopeful that this [can be] a novel therapeutic combination to help treat TP53 mutated MDS or AML patients. We've written a clinical trial protocol and hope to start it in 2023.

Source:

Kruer TL, Quintana A, Ferrall-Fairbanks M, et al. XPO1 Overexpression Is a Mechanism of Resistance to Eprenetapopt and 5-Azacitidine Therapy That Can be Therapeutically Exploited for the Treatment of TP53 Mutated Myeloid Malignancies. Presented at the ASH Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA, and virtual. Abstract 45.