Shihui Liu, MD, PhD, associate professor at the Aging Institute and the University of Pittsburgh, and his co-investigators, Jie Liu, PhD, research associate professor at the Aging Institute, and Toren Finkel, MD, PhD, director of the Aging Institute, were awarded a new five-year R01 from the National Cancer Institute to develop new therapies for selectively targeting solid tumors with oncogenic RAS mutations in cancer.
Mutations in the RAS-RAF-MEK-ERK pathway occur in 46% of all human cancers. This has inspired the successful development of many small molecule inhibitors of BRAF and MEK. However, development of RAS small molecule inhibitors has not been as successful, in large part due to the lack of a sufficiently large and deep hydrophobic pocket in RAS proteins to allow for small molecule binding.
Thus, oncogenic RAS proteins have long been considered “undruggable” until the recent discovery and FDA-approval of the allele-specific covalent inhibitors Sotorasib and Adagrasib for treatment of non-small cell lung cancer (NSCLC) with the KRASG12C mutation.
However, treated patients inevitably develop drug resistance, mostly due to secondary KRAS mutations (G12D, G12R, G12V, G13D, or Q61H) that are not targeted by these inhibitors. KRASG12D allele-specific inhibitors are under preclinical development, but similar drug resistance mechanisms are also expected.
Notably, many bacterial pathogens have evolved potent protein toxins to disrupt the RAS-RAF-MEK-ERK pathway. These naturally designed potent toxins, such as anthrax toxin and DUF5, can be structurally modified to achieve high tumor specificity. DUF5 is a toxin effector domain (amino acids Glu3581-Gln4089) of MARTX (multifunctional-autoprocessing repeats-in-toxin) from Vibrio vulnificus. DUF5 was recently identified to be a potent and specific endopeptidase that cleaves and inactivates all oncogenic RAS proteins (KRAS, NRAS, and HRAS).
To address the above unmet medical needs, in this project, Dr. Liu and his colleagues will develop a potent and highly tumor-selective RAS inactivator by engineering the anthrax toxin protein delivery system and DUF5.
This tumor-selective RAS inactivator can specifically bind to the major anthrax toxin receptor CMG2 on tumor cells, strictly relying on the simultaneous presence of two distinct tumor-associated proteases, MMPs and urokinase, to specifically gain entry into tumor cells where it proteolytically inactivates RAS signaling, achieving potent selective tumor targeting (Fig.1). Preliminary data generated by Dr. Liu and his team revealed that their highly tumor-selective pan RAS inactivator displayed potent cytotoxicity to cancer cells whose survival depends on oncogenic RAS signaling.
For this new project, Dr. Liu and his colleagues will comprehensively characterize and evaluate their novel agent’s anti-tumor activity using a wide range of tumor models. Their long-term goal is to develop safe and potent therapeutics for treating oncogenic KRAS-driven human cancers. Upon completion of these studies, Dr. Liu and his colleagues expect to have developed a well-characterized, highly tumor-selective, potent and safe pan RAS inactivator with a high clinical potential for efficiently treating human cancers.
