Onyx-015

Onyx-015 is an experimental oncolytic virus created by genetically engineering an adenovirus.^[1] It has been trialed as a possible treatment for cancer. The E1B-55kDa gene has been deleted allowing the virus to selectively replicate in and lyse p53-deficient cancer cells.^[2]

Background

Tumours form in cells when mutations in genes involved in cell cycle control and apoptosis accumulate over time.^[3] Most tumours studied, have defects in the p53 tumor suppressor pathway.^[4] p53 is a transcription factor that plays a role in apoptosis, cell cycle and DNA repair. It blocks cell progression in response to cellular stress or DNA damage. Many viruses replicate by altering the cell cycle and exploiting the same pathways that are altered in cancer cells.^[5] E1B proteins produced by adenoviruses protect the infected cell by binding to and degrading the p53 transcription factors,^[6] preventing it from targeting the cell for apoptosis. This allows the virus to replicate, package its genome, lyse the cell and spread to new cells.

This gave rise to the idea that an altered adenovirus could be used to target and eliminate cancer cells. Onyx-015 is a adenovirus that was developed in 1987 with the function of the E1B gene knocked out,^[7] meaning cells infected with Onyx-015 are incapable of blocking p53's function. If Onyx-015 infects a normal cell, with a functioning p53 gene, it will be prevented from multiplying by the action of the p53 transcription factor. However if Onyx-015 infects a p53 deficient cell it should be able to survive and replicate, resulting in selective destruction of cancer cells.

Trials

The patent for ONYX-015 was held by ONYX Pharmaceuticals^[8] and it was used in combination with the standard chemotherapeutic agents cisplatin and 5-fluorouracil to combat head and neck tumours.^[9] Onyx-015 has been extensively tested in clinical trials, with the data indicating that it is safe and selective for cancer.^[10] However, limited therapeutic effect has been demonstrated following injection and systemic spread of the virus was not detected.^[11] Further development of Onyx-015 was abandoned in the early 2000s, the rights being sold to the Chinese company, Shanghai Sunway Biotech. On November 17, 2005, the Chinese State Food and Drug Administration approved H101, an oncolytic adenovirus similar to Onyx-015 (E1B-55K/E3B-deleted), for use in combination with chemotherapy for the treatment of late-stage refractory nasopharyngeal cancer.^[12][13]

References

1. ^ Definition of ONYX-015 - National Cancer Institute Drug Dictionary
2. ^ John Nemunaitis, Ian Ganly, Fadlo Khuri, James Arseneau, Joseph Kuhn, Todd McCarty, Stephen Landers, Phillip Maples, Larry Rome, Britta Randlev, Tony Reid, Sam Kaye and David Kirn (2000). "Selective Replication and Oncolysis in p53 Mutant Tumors with ONYX-015, an E1B-55kD Gene-deleted Adenovirus, in Patients with Advanced Head and Neck Cancer: A Phase II Trial". Cancer Res 60: 6359. PMID 11103798. 
3. ^ Vogelstein, B.; Kinzler, K. (1993). "The multistep nature of cancer". Trends in Genetics 9 (4): 138–141. doi:10.1016/0168-9525(93)90209-Z. PMID 8516849.  edit
4. ^ Levine, A. (1997). "P53, the Cellular Gatekeeper for Growth and Division". Cell 88 (3): 323. doi:10.1016/S0092-8674(00)81871-1. PMID 9039259.  edit
5. ^ Ries, S.; Korn, W. (2002). "ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus". British journal of cancer 86 (1): 5–11. doi:10.1038/sj.bjc.6600006. PMC 2746528. PMID 11857003. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2746528.  edit
6. ^ Yew, P.; Berk, A. (1992). "Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein". Nature 357 (6373): 82–85. Bibcode 1992Natur.357...82Y. doi:10.1038/357082a0. PMID 1533443.  edit
7. ^ Barker DD, Berk AJ. (1987). "Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection". Virology 156 (1): 107–121. doi:10.1016/0042-6822(87)90441-7. PMID 2949421. 
8. ^ Bischoff, J. R.; Kirn, D. H.; Williams, A.; Heise, C.; Horn, S.; Muna, M.; Ng, L.; Nye, J. A. et al. (1996). "An Adenovirus Mutant That Replicates Selectively in p53- Deficient Human Tumor Cells". Science 274 (5286): 373–376. doi:10.1126/science.274.5286.373. PMID 8832876.  edit
9. ^ Khuri, F.; Nemunaitis, J.; Ganly, I.; Arseneau, J.; Tannock, I.; Romel, L.; Gore, M.; Ironside, J. et al. (2000). "A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer". Nature medicine 6 (8): 879–885. doi:10.1038/78638. PMID 10932224.  edit
10. ^ Kirn, D.; Thorne, S. (2009). "Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer". Nature reviews. Cancer 9 (1): 64–71. doi:10.1038/nrc2545. PMID 19104515.  edit
11. ^ Liu, T.; Hwang, T.; Bell, J.; Kirn, D. (2008). "Translation of targeted oncolytic virotherapeutics from the lab into the clinic, and back again: a high-value iterative loop". Molecular therapy : the journal of the American Society of Gene Therapy 16 (6): 1006–1008. doi:10.1038/mt.2008.70. PMID 18500240.  edit
12. ^ Liu, T.; Kirn, D. (2008). "Gene therapy progress and prospects cancer: oncolytic viruses". Gene therapy 15 (12): 877–884. doi:10.1038/gt.2008.72. PMID 18418413.  edit
13. ^ Chinese State FDA approval