Stapled Peptide PROTAC: A 3-in-1 Treatment for Pediatric Solid Tumors
Cancer is the leading cause of death by a disease in children ages 0-19 years old. Whereas cure rates for pediatric hematologic malignancies as a class can reach 90% or more, solid tumor cures have historically lagged and contribute disproportionately to the cancer death rate in children. A common mechanism among relapsed and treatment-resistant pediatric solid tumors is a combination of errant signaling that drives cancer cell proliferation and blocks cancer cell death. Thus, multiagent treatment that addresses multiple cancer-causing pathways is required. However, advancing new anti-cancer drug candidates, especially in combination, is especially challenging in children. First, concerns about unanticipated toxicities have long led regulators to require clinical testing in adults before children, causing considerable delays in initiating Phase 1 trials in pediatric cancer. Second, new agents must initially show safety and activity as a single agent before being applied in combination. Third, identifying effective combinations and then brokering clinical testing agreements that bring companies and their proprietary drugs together remains a formidable, logistical barrier. Finally, individual drugs have distinct properties that from a practical standpoint can thwart the delivery of both agents to the same cancer cell at the same time. Here, we combine two technologies to create a single drug that can simultaneously target three key cancer-causing mechanisms of pediatric solid tumors, effectively overcoming major barriers to clinical translation.
Project Goal:
The goal of our REACH project is to advance a new drug modality, called Stapled Peptide PROTAC (SP-PROTAC), for the treatment of relapsed and refractory pediatric solid tumors. We previously developed chemically-stabilized or "stapled” peptides capable of blocking cancer-causing proteins. Our prototype was designed to target two proteins, HDM2 and HDMX, which operate in the majority of pediatric cancers to eliminate a critical tumor suppressor protein, p53. By blocking HDM2 and HDMX, stapled p53 peptides can reactivate the p53 tumor suppressor pathway and kill treatment-resistant cancer cells. Proof-of-concept for this work was supported by a previous ASLF REACH grant and led to a Phase 1 trial in pediatric cancer. Because HDM2 eliminates p53 by tagging it for degradation, we next decided to turn this cancer-causing protein into a cancer-treating protein by linking it to a molecule that binds master regulators of signaling pathways that drive pediatric solid tumors. Using SP-PROTAC, we hijack the p53-destruction activity of HDM2 and instead "train its eye" on the master regulators.
Project Update 2024:
We used ALSF REACH funding to advance a lead SP-PROTAC to rigorous testing in pediatric solid tumors found to be distinctly susceptible to our 3-in-1 mechanism, which reactivates p53 by blocking (1) HDM2 and (2) HDMX, and (3) degrades master regulators of cancer signaling. We are eager to harness the results to compel the advancement of SP-PROTAC as a next-generation therapeutic to combat relapsed and refractory solid tumors of childhood.
