Oncolytic adenoviruses as a therapeutic approach for osteosarcoma: A new hope

Abstract

Osteosarcoma is the most common bone cancer among those with non-hematological origin and affects mainly pediatric patients. In the last 50 years, refinements in surgical procedures, as well as the introduction of aggressive neoadjuvant and adjuvant chemotherapeutic cocktails, have increased to nearly 70% the survival rate of these patients. Despite the initial therapeutic progress the fight against osteosarcoma has not substantially improved during the last three decades, and almost 30% of the patients do not respond or recur after the standard treatment. For this group there is an urgent need to implement new therapeutic approaches. Oncolytic adenoviruses are conditionally replicative viruses engineered to selectively replicate in and kill tumor cells, while remaining quiescent in healthy cells. In the last years there have been multiple preclinical and clinical studies using these viruses as therapeutic agents in the treatment of a broad range of cancers, including osteosarcoma. In this review, we summarize some of the most relevant published literature about the use of oncolytic adenoviruses to treat human osteosarcoma tumors in subcutaneous, orthotopic and metastatic mouse models. In conclusion, up to date the preclinical studies with oncolytic adenoviruses have demonstrated that are safe and efficacious against local and metastatic osteosarcoma. Knowledge arising from phase I/II clinical trials with oncolytic adenoviruses in other tumors have shown the potential of viruses to awake the patient´s own immune system generating a response against the tumor. Generating osteosarcoma immune-competent adenoviruses friendly models will allow to better understand this potential. Future clinical trials with oncolytic adenoviruses for osteosarcoma tumors are warranted.

Keywords: Bones; Cancer; Oncolytic adenovirus; Osteosarcoma; Tumor; Virotherapy.

Fig. 1

A) Illustration showing the location of the fiber protein on the adenovirus capsid, as well as the three structural domains of the fiber. B) Schematic adenovirus viral cycle. The adenovirus recognizes its specific receptor (1) triggering its internalization inside the cell (2). Then the virus migrates through the microtubules (3) and introduces the viral genome inside the nucleus (4). The E1A gene is expressed immediately (5) the E1A protein binds pRB releasing the transcription factor E2F and thus the cell cycle arrest (6), which in turn will promote the expression of viral proteins and the genome replication, obtaining the viral progeny (7).

Fig. 2

Schematic diagram representing the progression of the oncolytic adenovirus cycle following the infection of a tumor cell versus a healthy cell. Although the virus is able to infect normal healthy cells its replication is impaired, thus the cell remains undamaged. On the contrary, the virus replicates in a tumor cell and generates new viral particles, which in turn leads to the lysis of the cell and the spread of these particles to nearby cells.

Fig. 3

Examples of strategies to obtain oncolytic adenoviruses with tumor selective replication (A) or an enhanced tumor tropism (B and C). A) By mutating the E1A or E1B genes the replication is restricted to pRB or p53 deficient cells, respectively. The expression of E1A under tumor specific promoters, like human telomerase promoter (hTERT), allows viral replication only in tumor cells. B) Generation of chimeric Ad5 viruses by fiber replacement from another serotype (AdX), thus obtaining an Ad5 with the tropism of the AdX. C) Addition of the integrin binding motif CDCRGDCDC within the knob domain of the fiber.

Fig. 4

Schematic illustration showing an enhancement of the viral spread in the presence of a porous extracellular matrix (ECM). An infected tumor cell (1) will eventually produce new infectious viral particles. The spread of a normal oncolytic adenovirus is hindered by a dense hyaluronic acid ECM (2). The VCN-01 adenovirus encodes the human hyaluronidase PH20, which is secreted by the infected cell and, in turn, the hyaluronidase degrades the hyaluronic acid, facilitating the spread of the viral progeny through the ECM to new tumor cells (3).