RESUMEN
The PAX3-FOXO1 fusion gene functions as a transactivator and increases expression of many cancer-related genes. These lead to metastases and other unfavorable outcomes for alveolar rhabdomyosarcoma (ARMS) patients. In order to target ARMS with the PAX3-FOXO1 transactivator, we developed an Oncolytic Adenovirus (OAd) regulated by the myogenin (pMYOG) promoter with a mutation in the Myocyte Enhancer Factor-2 binding site (mMEF2) in this study. The expression of MYOG in the two RMS cell lines (Rh30; PAX3-FOXO1-positive, RD; PAX3-FOXO1-negative) is about 1,000 times higher than normal skeletal muscle cell (SkMC). Ad5/3-pMYOG(S)-mMEF2 (short-length pMYOG-controlled OAd with mMEF2) showed strong replication and cytocidal effect in Rh30, but to a much lesser extent in RD. Ad5/3-pMYOG(S) (pMYOG-controlled OAd with native pMYOG) showed similar effects in RD and Rh30. Neither virus killed SkMC, indicating that Ad5/3-pMYOG(S)-mMEF2 selectively replicates and kills cells with PAX3-FOXO1. Additionally, Ad5/3-pMYOG(S)-mMEF2 showed replication and spread in vitro as well as tumor growth suppression and intratumoral viral spread in vivo, selectively in Rh30 not in RD. Our findings revealed that Ad5/3-pMYOG(S)-mMEF2 shows a promise as a safe and potent therapy to improve treatment in PAX3-FOXO1-positive ARMSs.
RESUMEN
Gene therapy with viral vectors has significantly advanced in the past few decades, with adenovirus being one of the most commonly employed vectors for cancer gene therapy. Adenovirus vectors can be divided into 2 groups: (1) replication-deficient viruses; and (2) replication-competent, oncolytic (OVs) viruses. Replication-deficient adenoviruses have been explored as vaccine carriers and gene therapy vectors. Oncolytic adenoviruses are designed to selectively target, replicate, and directly destroy cancer cells. Additionally, virus-mediated cell lysis releases tumor antigens and induces local inflammation (e.g., immunogenic cell death), which contributes significantly to the reversal of local immune suppression and development of antitumor immune responses ("cold" tumor into "hot" tumor). There is a growing body of evidence suggesting that the host immune response may provide a critical boost for the efficacy of oncolytic virotherapy. Additionally, genetic engineering of oncolytic viruses allows local expression of immune therapeutics, thereby reducing related toxicities. Therefore, the combination of oncolytic virus and immunotherapy is an attractive therapeutic strategy for cancer treatment. In this review, we focus on adenovirus-based vectors and discuss recent progress in combination therapy of adenoviruses with immunotherapy in preclinical and clinical studies.