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Increased Anticancer Efficacy of Intravesical Mitomycin C Therapy when Combined with a PCNA Targeting Peptide
Odrun A Gederaas1, Caroline D Søgaard1, Trond Viset2
1Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Abstract:
Non-muscle-invasive bladder cancers (NMIBCs) are tumors confined to the mucosa or the mucosa/submucosa. An important challenge in treatment of NMIBC is both high recurrence and high progression rates. Consequently, more efficacious intravesical treatment regimes are in demand. Inhibition of the cell's DNA repair systems is a new promising strategy to improve cancer therapy, and proliferating cell nuclear antigen (PCNA) is a new promising target. PCNA is an essential scaffold protein in multiple cellular processes including DNA replication and repair. More than 200 proteins, many involved in stress responses, interact with PCNA through the AlkB homologue 2 PCNA-interacting motif (APIM), including several proteins directly or indirectly involved in repair of DNA interstrand crosslinks (ICLs). In this study, we targeted PCNA with a novel peptide drug containing the APIM sequence, ATX-101, to inhibit repair of the DNA damage introduced by the chemotherapeutics. A bladder cancer cell panel and two different orthotopic models of bladder cancer in rats, the AY-27 implantation model and the dietary BBN induction model, were applied. ATX-101 increased the anticancer efficacy of the ICL-inducing drug mitomycin C (MMC), as well as bleomycin and gemcitabine in all bladder cancer cell lines tested. Furthermore, we found that ATX-101 given intravesically in combination with MMC penetrated the bladder wall and further reduced the tumor growth in both the slow growing endogenously induced and the rapidly growing transplanted tumors. These results suggest that ATX-101 has the potential to improve the efficacy of current MMC treatment in NMIBC.
Insights
A novel peptide drug, ATX-101, targeting proliferating cell nuclear antigen (PCNA) enhances chemotherapy for non-muscle-invasive bladder cancer (NMIBC). This approach shows promise in reducing tumor growth and recurrence rates for NMIBC patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Non-muscle-invasive bladder cancer (NMIBC) presents high recurrence and progression rates, necessitating improved intravesical treatments.
- Inhibiting DNA repair mechanisms, specifically targeting proliferating cell nuclear antigen (PCNA), is a novel strategy for enhancing cancer therapy.
- PCNA interacts with numerous proteins via the AlkB homologue 2 PCNA-interacting motif (APIM), many involved in DNA repair, including interstrand crosslink repair.
Purpose of the Study:
- To evaluate the efficacy of ATX-101, a novel peptide drug targeting PCNA, in combination with chemotherapy for NMIBC.
- To assess the potential of ATX-101 to improve current intravesical treatment regimens for bladder cancer.
Main Methods:
- Utilized a bladder cancer cell panel and two orthotopic rat models (AY-27 implantation and BBN induction) for preclinical evaluation.
- Administered ATX-101 intravesically in combination with mitomycin C (MMC), bleomycin, and gemcitabine.
- Assessed tumor growth inhibition and drug penetration into the bladder wall.
Main Results:
- ATX-101 significantly enhanced the anticancer efficacy of mitomycin C, bleomycin, and gemcitabine across all tested bladder cancer cell lines.
- Intravesical administration of ATX-101 combined with MMC demonstrated penetration of the bladder wall.
- Combined treatment led to substantial reduction in tumor growth in both slow-growing endogenous and rapidly growing transplanted tumors.
Conclusions:
- ATX-101 shows potential as an adjunct therapy to improve the efficacy of mitomycin C in treating non-muscle-invasive bladder cancer.
- Targeting PCNA with APIM-based peptides offers a promising strategy to overcome treatment resistance and improve outcomes in NMIBC.
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