Jin Yeo

Background: Primary osteosarcoma is cancer that originates in a patient’s bones, most often affecting long tubular bones like the femur. The median age of diagnosis is 20 years old, with patients presenting clinical symptoms such as bone lesions, joint dysfunction, and localized swelling¹. Localized swelling or the pain associated with these clinical presentations may resemble puberty symptoms or growing pains, so it is important to confirm diagnosis via radiography². The most common treatment method is surgical resection and chemotherapy with the MAP regimen, consisting of Methotrexate, Adriamycin, and Platinol¹. With treatment, overall survival rates are around 60-70%, however, survival rates plummet to less than 30% after metastasis or recurrence^1,3. Additionally, these young patients must endure complications such as drug resistance and significant side effects from treatment⁴. Interventions that can mitigate these issues could improve survival rates significantly, and one potential drug target is Proliferating Cell Nuclear Antigen (PCNA) for its role in DNA damage tolerance (DDT) mechanisms, DNA replication, and general cell homeostasis^5,6,7.

Objective: In this literature review, we investigate the potential of PCNA as a feasible drug target for primary osteosarcoma by looking at PCNA’s role within the cell and the mechanisms by which it fulfills its function.

Search Methods: The PubMed database was searched with keywords such as “Osteosarcoma”[Majr], “Osteosarcoma/drug therapy”[Mesh], “Osteosarcoma/radiotherapy”[Mesh], “Proliferating Cell Nuclear Antigen”[Mesh], and “Proliferating Cell Nuclear Antigen/therapeutic use”[Mesh], with the publication dates restricted between 2019 and 2024 (present).

Results: PCNA was originally known for its role in DNA replication, sitting at the replication fork on DNA. Studies indicated that changes in PCNA function via its ability to bind to AlkB homolog 2 PCNA interacting motif (APIM) affected cells’ ability to replicate after polymerase blocking lesions⁵. Recent studies further showed that PCNA is heavily involved in DDT mechanisms, specifically via APIM^5,6. Targeting PCNA via APIM could allow specific targeting of abnormal cells and reduce peripheral effects, due to how ubiquitination of PCNA shifts the affinity of PCNA from replication proteins to DDT proteins such as HLTF^5,7,8. One such drug is ATX-101, a cell-penetrating peptide drug. It has been shown to increase the anti-cancer effects of drugs such as AEE788, a VEGFR inhibitor, when used together in vitro in multiple human cancer cell lines, with a significant decrease in overall survival of cancerous cells and tumor volume⁴. In a clinical study, ATX-101 was shown to be effective in tumor stabilization for a variety of different cancers, with many patients transitioning from progressive to stable disease during treatment and staying stable even after the trial was over, for a median time of 18 weeks after treatment discontinuation⁹.

Conclusions: Studies showed that drugs targeting PCNA via APIM such as ATX-101 can mitigate inhibitor drug resistance in vitro in multiple cancer cell lines and is effective in tumor stabilization in vivo for patients with a variety of advanced solid tumors. While current drugs targeting PCNA have not been tested for primary osteosarcoma yet, if these findings hold, this could lead to a significant improvement in overall survival rates and quality of life for patients.

Works Cited:

1. (a) Nakano K. Challenges of systemic therapy investigations for bone sarcomas. International Journal of Molecular Sciences. 2022;23(7):3540. doi:10.3390/ijms23073540
2. (b) Pekarek L, De la Torre-Escuredo B, Fraile-Martinez O, et al. Towards the search for potential biomarkers in osteosarcoma: state-of-the-art and translational expectations. International Journal of Molecular Sciences. 2022;23(23):14939. doi:10.3390/ijms232314939
3. (c) Sayles LC, Breese MR, Koehne AL, et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discovery. 2019;9(1):46-63. doi:10.1158/2159-8290.CD-17-1152
4. (d) Søgaard CK, Nepal A, Petrovic V, et al. Targeting the non-canonical roles of PCNA modifies and increases the response to targeted anti-cancer therapy. Oncotarget. 2019;10(68):7185-7197. doi:10.18632/oncotarget.27267
5. (e) Seelinger M, Otterlei M. Helicase-Like Transcription Factor HLTF and E3 Ubiquitin Ligase SHPRH Confer DNA Damage Tolerance through Direct Interactions with Proliferating Cell Nuclear Antigen (PCNA). International Journal of Molecular Sciences. 2020;21(3):693. doi:10.3390/ijms21030693
6. (f) Ræder SB, Nepal A, Bjørås KØ, et al. APIM-Mediated REV3L–PCNA Interaction Important for Error Free TLS Over UV-Induced DNA Lesions in Human Cells. International Journal of Molecular Sciences. 2019;20(1):100. doi:10.3390/ijms20010100
7. (g) Røst LM, Ræder SB, Olaisen C, et al. PCNA regulates primary metabolism by scaffolding metabolic enzymes. Oncogene. 2023;42(8):613-624. doi:10.1038/s41388-022-02579-1
8. (h) Takaoka K, Kawazu M, Koya J, et al. A germline HLTF mutation in familial MDS induces DNA damage accumulation through impaired PCNA polyubiquitination. Leukemia. 2019;33(7):1773-1782. doi:10.1038/s41375-019-0385-0
9. (i) Lemech CR, Kichenadasse G, Marschner JP, Alevizopoulos K, Otterlei M, Millward M. ATX-101, a cell-penetrating protein targeting PCNA, can be safely administered as intravenous infusion in patients and shows clinical activity in a Phase 1 study. Oncogene. 2023;42(7):541-544. doi:10.1038/s41388-022-02582-6