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Published on: April 15, 2016
Cancer therapy with a replicating oncolytic adenovirus targeting the hypoxic microenvironment of tumors
Dawn E Post1, Narra Sarojini Devi, Zhenchao Li
1Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University, Atlanta, Georgia 30322, USA.
Abstract:
Hypoxia plays a critical role in driving tumor malignancy and is associated with poor patient survival in many human cancers. Novel therapies targeting hypoxic tumor cells are urgently needed, because these cells hinder tumor eradication. Here we demonstrate than an anticancer strategy based on intratumoral delivery of a novel type of oncolytic adenovirus targeting tumor hypoxia is therapeutically efficient and can augment standard chemotherapy. We used a conditionally replicative adenovirus (HYPR-Ad) to specifically kill hypoxic tumor cells. Viral infection and conditional replication occurred efficiently in hypoxic/hypoxia-inducible factor-active cells in culture and in vivo, prevented tumor formation, and reduced the growth of established tumors. Combining HYPR-Ad with chemotherapy effective against normoxic cells resulted in strongly enhanced antitumor efficacy. These studies demonstrate that targeting the hypoxic microenvironment of tumors rather than an intrinsic gene expression defect is a viable and novel antitumor therapeutic strategy that can be used in combination with existing treatment regimens. The replication and oncolytic potential of this virus was made dependent on hypoxic/hypoxia-inducible factor, a transcription factor activated in the tumor hypoxic microenvironment, broadening its therapeutic use to solid tumors of any genetic make-up or tissue of origin.
Insights
Novel oncolytic adenovirus therapy specifically targets tumor hypoxia, enhancing chemotherapy efficacy. This approach offers a new strategy against malignant tumors, improving patient survival by eradicating hard-to-treat hypoxic cells.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Hypoxia is a critical factor in tumor malignancy and poor patient survival.
- Hypoxic tumor cells are resistant to conventional therapies, hindering tumor eradication.
- Targeting the tumor microenvironment presents a novel therapeutic avenue.
Purpose of the Study:
- To develop and evaluate a novel oncolytic adenovirus (HYPR-Ad) for targeting hypoxic tumor cells.
- To assess the therapeutic efficiency of HYPR-Ad in vitro and in vivo.
- To investigate the combination therapy of HYPR-Ad with standard chemotherapy.
Main Methods:
- Development of a conditionally replicative adenovirus (HYPR-Ad) dependent on hypoxia-inducible factor (HIF).
- In vitro and in vivo studies to evaluate viral infection, replication, and oncolytic activity in hypoxic cells.
- Combination therapy studies with standard chemotherapy agents.
Main Results:
- HYPR-Ad efficiently infected and replicated in hypoxic/HIF-active cells in culture and in vivo.
- Intratumoral delivery of HYPR-Ad prevented tumor formation and reduced established tumor growth.
- Combination of HYPR-Ad with chemotherapy demonstrated significantly enhanced antitumor efficacy.
Conclusions:
- Targeting the hypoxic tumor microenvironment with HYPR-Ad is a viable and novel anticancer strategy.
- HYPR-Ad can be effectively combined with standard chemotherapy to augment antitumor effects.
- This approach broadens therapeutic options for solid tumors, irrespective of genetic makeup or origin.
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