Researchers at The University of Texas MD Anderson Cancer Center have published a preclinical study in Blood showing a promising new approach to treating hard-to-treat blood cancers by targeting the MYC protein.
A new cycle in cancer biology
The team, led by Michael Andreeff, M.D., Ph.D., and Yuki Nishida, M.D., Ph.D., discovered that the experimental drug GT19630 disrupts a previously unknown cycle between MYC and GSPT1. This interaction creates a “feedforward loop” that cancer cells rely on for survival. The drug binds to both proteins, marking MYC for disposal through the cell’s natural recycling system while simultaneously degrading GSPT1.
MYC is involved in approximately 70% of all human cancers and acts as a master switch regulating genes that enable cancer cell growth, division, and metabolism. For decades, scientists have struggled to develop therapies that successfully block MYC, leading many in the field to describe it as undruggable. Andreeff said the researchers found a way to eliminate both proteins.
The preclinical models of leukemia, lymphoma, and multiple myeloma were highly sensitive to GT19630. Notably, the therapy remained effective in cells with TP53 mutations, which are often associated with treatment resistance.
Targeting resistant cells
Researchers found that resistant acute myeloid leukemia (AML) cells had increased levels of MYC and GSPT1. In these preclinical models, GT19630 restored sensitivity to venetoclax, dramatically prolonging survival by more than 300% in one model. This suggests the drug may offer a path to overcome venetoclax resistance.
Acute myeloid leukemia (AML) often relapses due to resilient stem-like cells that express raised MYC levels compared to healthy blood stem cells. Advanced single-cell RNA sequencing confirmed that AML stem cells with TP53 mutations also show increased MYC activity, making them particularly vulnerable to GT19630. Normal blood stem cells, however, remained largely unaffected, indicating the drug could selectively weaken resistant cancer cells while sparing essential bone marrow function.
This distinction suggests a potential therapeutic window where the drug may selectively impact some of the most treatment-resistant leukemia cells while limiting damage to healthy bone marrow. The findings support GT19630 as a potential pathway to target MYC, though future studies are needed to determine if the strategy is safe and effective in patients. Cancers with high MYC activity may be especially vulnerable, raising the possibility of using biomarkers to identify patients most likely to respond.
