Engineering ferritin degrader-encapsulated platelets for post-surgical TNBC treatment

PROJECT SUMMARY As an aggressive and invasive type of breast cancer, triple-negative breast cancer (TNBC) has limited effective treatment options in the clinic. Chemotherapy, represented by Taxol and Abraxane, is the first-line therapy for TNBC, while TNBC patients who initially respond to chemotherapy will eventually develop drug resistance following relapse. Immunotherapy, including immune checkpoint inhibitors, has only achieved success in treating a small subset of patients with TNBC characterized by a high burden of somatic mutations. Surgery remains the major treatment option for TNBC; however, the high frequency of TNBC recurrence after surgery could lead to poor patient prognosis and high mortality. These highlight a critical unmet clinical need to develop a new therapeutic modality that can serve as effective monotherapy or synergize with current first-line treatments to prevent post-surgical TNBC recurrence. Intracellular ferritin serves as a key regulator to balance the increasing need for iron to support TNBC growth while mitigating the damage of excess iron through mineralizing and storing the intracellular iron ions. It has been well established that ferritin expression correlates positively with TNBC cell proliferation, with more ferritin concentrations in TNBC tumors than in normal breast tissues. Clinically, the serum ferritin level could serve as an indicator of disease severity in TNBC patients. In our preliminary studies, we have developed a ferritin-degrading proteolysis targeting chimeras molecule (designated DeFer) that can leverage the intracellular ubiquitin-proteasome system to degrade ferritin, leading to TNBC cell pyroptosis. In vivo anti-TNBC efficacy was substantiated on 4T1 TNBC-bearing mice. Our study suggested that ferritin can serve as a novel TNBC drug target, and its degradation could inhibit TNBC growth. In this proposal, we will further optimize the developed DeFer, investigate the underlying ferritin degradation mechanisms, and test its in vitro and in vivo anti-TNBC efficacy. Furthermore, to improve the in vivo pharmacokinetics and biodistribution of DeFer, we will load DeFer into a platelet-based delivery system to improve the circulation time and facilitate the selective accumulation at the post-surgical TNBC site. Finally, we will combine DeFer-loaded platelets with immune checkpoint inhibitors to investigate the synergistic anti-TNBC recurrence efficacy on both murine TNBC and human TNBC PDX models.