51 A first-in-class therapy designed to target MYC, one of the most sought-after and difficult targets in cancer biology, has shown promise in hard-to-treat blood cancers, according to a new preclinical study from The University of Texas MD Anderson Cancer Center published in Blood. Researchers led by Michael Andreeff,, MD, professor, and Yuki Nishida, MD, assistant professor, both of Leukaemia, found that the experimental drug GT19630 interrupts a newly discovered cycle between MYC and GSPT1. This resulted in strong anticancer activity in preclinical models of leukaemia, lymphoma, and multiple myeloma, including treatment-resistant and TP53-mutated disease. “For decades, scientists have struggled to develop therapies that successfully block MYC, leading many in the field to describe it as undruggable,” Andreeff said. “By identifying a vulnerability in the relationship between MYC and GSPT1, we found a way to eliminate both proteins and disable a pathway many cancers depend on for survival.” The MYC protein, involved in approximately 70% of all human cancers, is one of the most important drivers of cancer growth. It acts as a master switch, regulating the genes that enable cancer cells to grow, divide, and sustain their metabolism. Blocking this protein has been a high priority for cancer research, but scientists have long been unable to develop a therapy that effectively interferes with it. This study revealed a previously unknown relationship between MYC and GSPT1. MYC helps activate the GSPT1 gene, and GSPT1 helps cancer cells produce MYC proteins, creating what researchers describe as a “feedforward loop” that could be exploited therapeutically. GT19630, a new protein degrader drug, disrupts this cycle by binding to both proteins and marking MYC for disposal using the cell’s natural protein recycling system. The treatment simultaneously degrades GSPT1, causing levels of both proteins to drop significantly and demonstrating broader activity than targeting GSPT1 alone. Preclinical models of leukaemia, lymphoma, and multiple myeloma were highly sensitive to GT19630, and the therapy remained effective in cells with TP53 mutations, which are often associated with treatment resistance. GT19630 may also offer a path to overcoming venetoclax resistance in Acute Myeloid Leukaemia (AML). Researchers found that resistant AML cells had increased MYC and GSPT1 levels. In preclinical models, GT19630 restored sensitivity to venetoclax, dramatically prolonging survival by more than 300% in one model. Stem-like AML cells, which can survive treatment and contribute to relapse, often contain higher levels of MYC than normal blood-forming stem cells. Using single-cell RNA analysis, researchers also observed elevated MYC levels in TP53-mutant AML stem cells. Their heightened dependence on MYC made the AML cells more sensitive to GT19630, while normal blood-forming stem cells were less affected. This suggests a potential therapeutic window in which the drug may selectively impact some of the most treatment-resistant leukaemia cells while limiting damage to healthy bone marrow. These findings support GT19630 as a potential approach to targeting MYC, but future studies, including clinical trials, are needed to determine whether this strategy is safe and effective in patients, assess optimal dosing, and evaluate real-world benefit. Cancers with high MYC activity may be especially vulnerable to this therapy, raising the possibility of using biomarkers to identify patients most likely to respond. The encouraging activity in venetoclax-resistant AML shows significant translational promise, and further research may evaluate GT19630 as a direct treatment for resistant or relapsed AML or in combination with other therapies. Researchers note that the dual-degradation approach may open new avenues not only for blood cancers but potentially for other MYC-driven malignancies, though careful evaluation of effects on healthy cells remains essential before any patient application. “In addition to direct MYC inhibition, this approach harnesses the cell’s own natural processes to eliminate it,” Andreeff said. “This concept could help expand the use of protein degraders against challenging targets and inspire new therapeutic strategies for proteins once considered beyond the reach of conventional therapies.” The discovery of the MYC-GSPT1 feedforward loop provides a mechanistic foundation that could guide the development of related compounds, positioning GT19630 as an important step towards addressing one of oncology’s longest-standing challenges.