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The brain-penetrant cell-cycle inhibitor p28 sensitizes brain metastases to DNA-damaging agents
Sunam Mander1, Gregory S Gorman2, Lori U Coward2
1Department of Surgery, Division of Surgical Oncology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Background:
Brain metastases (BMs), the most common tumors of the central nervous system, are life-threatening with a dismal prognosis. The major challenges to developing effective treatments for BMs are the limited abilities of drugs to target tumors and to cross the blood-brain barrier (BBB). We aimed to investigate the efficacy of our therapeutic approach against BMs in mouse models that recapitulate the clinical manifestations of BMs.
Methods:
BMs mouse models were constructed by injecting human breast, lung cancer, and melanoma intracardially, which allowed the BBB to remain intact. We investigated the ability of the cell-penetrating peptide p28 to cross the BBB in an in vitro 3D model and in the BMs animal models. The therapeutic effects of p28 in combination with DNA-damaging agents (radiation and temozolomide) on BMs were also evaluated.
Results:
p28 crossed the intact BBB more efficiently than the standard chemotherapeutic agent, temozolomide. Upon crossing the BBB, p28 localized preferentially to tumor lesions and enhanced the efficacy of DNA-damaging agents by activating the p53-p21 axis. In the BMs animal models, radiation in combination with p28 significantly reduced the tumor burden of BMs.
Conclusions:
The cell-cycle inhibitor p28 can cross the BBB localize to tumor lesions in the brain and enhance the inhibitory effects of DNA-damaging agents on BMs, suggesting the potential therapeutic benefits of this molecule in BMs.
Insights
The cell-cycle inhibitor p28 effectively crosses the blood-brain barrier to target brain metastases (BMs). This peptide enhances radiation therapy, significantly reducing tumor burden in preclinical models.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Drug Delivery
Background:
- Brain metastases (BMs) are the most common central nervous system tumors with poor outcomes.
- Drug delivery across the blood-brain barrier (BBB) and tumor targeting are major challenges in BMs treatment.
- Preclinical mouse models mimicking human BMs were utilized to assess novel therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy of the cell-penetrating peptide p28 in treating BMs.
- To investigate p28's ability to cross the intact BBB.
- To assess the combined therapeutic effects of p28 with DNA-damaging agents.
Main Methods:
- BMs mouse models were established using human breast, lung, and melanoma cancer cells.
- In vitro and in vivo models were used to assess p28's BBB penetration.
- Therapeutic efficacy was evaluated using p28 combined with radiation and temozolomide.
Main Results:
- p28 demonstrated superior BBB penetration compared to temozolomide.
- p28 localized to brain tumor lesions and activated the p53-p21 axis, enhancing DNA-damaging agent efficacy.
- Combination therapy with p28 and radiation significantly reduced BMs tumor burden in vivo.
Conclusions:
- The cell-cycle inhibitor p28 effectively crosses the BBB and targets brain tumors.
- p28 potentiates the anti-tumor effects of DNA-damaging agents.
- p28 shows significant therapeutic potential for treating brain metastases.
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