Associate Professor University of California, Irvine Irvine, California, United States
Abstract: Breast cancer is one of the most common cancers affecting women throughout the world. Breast cancer chemotherapies have been shown to cause cancer-related cognitive impairments (CRCI), negatively affecting the quality of life (QOL) for ~70% of 4 million survivors in the U.S. Often referred to as chemobrain, CRCI encompasses decreased attention, disrupted processing speeds, executive function, memory consolidation, and recall long-term post-therapy. Previously, we showed the regenerative potential of extracellular vesicles (EVs) derived from human neural stem cells (hNSCs) in reversing CRCI in brain cancer mouse models receiving cranial radiotherapy. The current study focuses on a breast cancer mouse model to assess the effectiveness of a GMP-grade hNSC (UCI-191)-derived EV to reverse chemobrain following clinically relevant adjuvant chemotherapy. Nano-sized EVs can cross the blood-brain barrier and contain bioactive cargo such as lipids, proteins, nucleic acids, and mitochondrial components. WT (C57) female mice were induced with breast cancer using murine Py230 cells. Then, mice received adjuvant chemotherapy (Adriamycin, ADR, doxorubicin, 2mg/kg; and cyclophosphamide, CYP, 50mg/kg), administered an hour apart, once weekly for four weeks. This treatment eliminated breast cancer growth. After the administration of chemotherapy, mice received IV injections (retro-orbital vein, RO) treatment of hNSC-EV once weekly for four weeks and one month later, administered learning and memory, executive function, and memory consolidation cognitive function tests. Animal brains were evaluated for neuroinflammation, gliosis, and synaptic integrity. Mice treated with ADR-CYP showed significantly reduced learning and memory, increased anxiety, decreased memory consolidation, and impaired executive function compared to ADR-CYP +EV-treated mice. Immunofluorescence and 3D algorithm-based in silico volumetric analyses revealed significant improvements in synaptic integrity and reductions in astroglial and microglial activation in the EV-treated mice. These findings demonstrate the regenerative and neuroprotective impact of GMP-grade stem cell-derived EVs in ameliorating breast cancer chemobrain that has the potential to improve QOL for millions of breast cancer survivors.
Funding Source: NIH awards: R01 CA262213 and R01 CA276212 to M. M. A. California Institute for Regenerative Medicine (CRIM( award: DISC-12400) to M. M. A.
