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ONYX-015. Onyx Pharmaceuticals
1Section of Hematology/Oncology, University of Chicago Medical Center, IL 60637, USA. crudin@medicine.bsd.uchicago.edu
Abstract:
ONYX-015 (CI-1042), an adenovirus modified selectively to replicate in and kill cells that harbor p53 mutations, is under development by Onyx Pharmaceuticals for the potential treatment of various solid tumors, including head and neck, gastrointestinal and pancreatic tumors. It is a recombinant adenovirus that carries a loss-of-function mutation at the E1B locus, the product of which is a 55 kDa protein that binds to and inactivates the p53 tumor suppressor protein. Wild-type adenoviruses must disable this gene before viral replication can occur. This, the ONYX-015 adenovirus will leave normal cells unaffected. Mutations in the p53 tumor suppressor gene are the most common type of genetic abnormality in cancer, occurring in more than half of all major cancer types. Thus, these cells are susceptible to the virus, which will readily replicate and cause cell death. ONYX-015 is in ongoing phase III trials for the treatment of recurrent head and neck cancer, phase II trials for colorectal, ovary, pancreas and mouth tumors, and phase I trials for digestive disease, esophagus and liver tumors. Onyx Pharmaceuticals was granted US-05677178 covering methods for the treatment of p53-related cancers in October 1997. The patent specifically covers the use of modified adenoviruses and other DNA viruses, which lack viral proteins that bind to p53, for the treatment of cancer patients whose tumors lack p53 function. The USPTO awarded Onyx Pharmaceuticals US-05846945 in December 1998, covering methods for treating cancer using replicating adenoviral therapy in combination with chemotherapy. In April 1999, the company also received EP-094910177.8 covering the technology in Europe.
Insights
ONYX-015 is a novel oncolytic adenovirus designed to target cancer cells with p53 mutations, sparing normal cells. This targeted viral therapy shows promise for treating various solid tumors, including head and neck cancers.
Area of Science:
- Oncolytic virotherapy
- Cancer genetics
- Viral oncology
Background:
- Mutations in the p53 tumor suppressor gene are prevalent in over half of human cancers.
- Wild-type adenoviruses require p53 inactivation for replication, making them ineffective against p53-mutated cancer cells.
- ONYX-015 is a modified adenovirus engineered to selectively replicate in and destroy cancer cells with p53 loss-of-function mutations.
Purpose of the Study:
- To evaluate the therapeutic potential of ONYX-015 (CI-1042) as a targeted cancer treatment.
- To investigate the selective replication and oncolytic activity of ONYX-015 in p53-mutated cancer cells.
- To review the ongoing clinical trial status and patent landscape for ONYX-015.
Main Methods:
- Development of a recombinant adenovirus (ONYX-015) with a loss-of-function mutation in the E1B gene, preventing p53 inactivation.
- Selective viral replication and cell lysis in cancer cells harboring p53 mutations.
- Clinical trials (Phase I, II, and III) across various solid tumor types, including head and neck, gastrointestinal, pancreatic, colorectal, ovarian, and liver cancers.
Main Results:
- ONYX-015 demonstrates selective replication in cancer cells with p53 mutations, leading to cell death.
- Normal cells with functional p53 remain largely unaffected by ONYX-015.
- Ongoing clinical trials are evaluating its efficacy in recurrent head and neck cancer and other solid tumors.
Conclusions:
- ONYX-015 represents a promising targeted therapy for cancers with p53 mutations.
- Its oncolytic mechanism offers a potential treatment strategy with reduced toxicity to normal tissues.
- Onyx Pharmaceuticals holds key patents covering the use of modified adenoviruses for treating p53-deficient cancers.