Combination of cabazitaxel and p53 gene therapy abolishes prostate carcinoma tumor growth.,Gene Therapy

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Combination of cabazitaxel and p53 gene therapy abolishes prostate carcinoma tumor growth.
Gene Therapy ( IF 4.6 ) Pub Date : 2019-03-29 , DOI: 10.1038/s41434-019-0071-x
Rodrigo Esaki Tamura _{1,

2} , Marlous G Lana ₁ , Eugenia Costanzi-Strauss ₃ , Bryan E Strauss ₁

Affiliation

For patients with metastatic prostate cancer, the 5-year survival rate of 31% points to a need for novel therapies and improvement of existing modalities. We propose that p53 gene therapy and chemotherapy, when combined, will provide superior tumor cell killing for the treatment of prostate carcinoma. To this end, we have developed the AdRGD-PGp53 vector which offers autoregulated expression of p53, resulting in enhanced tumor cell killing in vitro and in vivo. Here, we combined AdRGD-PGp53 along with the chemotherapy drugs used in the clinical treatment of prostate carcinoma, mitoxantrone, docetaxel, or cabazitaxel. Our results indicate that all drugs increase phosphorylation of p53, leading to improved induction of p53 targets. In vitro experiments reveal that AdRGD-PGp53 sensitizes prostate cancer cells to each of the drugs tested, conferring increased levels of cell death. In a xenograft mouse model of in situ gene therapy, AdRGD-PGp53 treatment, when combined with cabazitaxel, drastically reduced tumor progression and increased survival rates to 100%. Strikingly, we used a sub-therapeutic dose of cabazitaxel thus avoiding leukopenia, yet still showed potent anti-tumor effects when combined with AdRGD-PGp53 in this mouse model. The AdRGD-PGp53 approach warrants further development for its application in gene therapy of prostate carcinoma.

中文翻译：

卡巴他赛与p53基因疗法的结合消除了前列腺癌的肿瘤生长。

对于转移性前列腺癌患者，其5年生存率31％表示需要新疗法和改善现有治疗方法。我们建议，将p53基因疗法和化学疗法结合使用时，将为杀死前列腺癌提供优异的肿瘤细胞杀伤力。为此，我们开发了AdRGD-PGp53载体，该载体可自动调节p53的表达，从而增强了体内外肿瘤细胞的杀伤力。在这里，我们将AdRGD-PGp53与用于临床治疗前列腺癌，米托蒽醌，多西他赛或卡巴他赛的化学疗法药物联合使用。我们的结果表明，所有药物均会增加p53的磷酸化，从而改善对p53靶标的诱导。体外实验表明，AdRGD-PGp53使前列腺癌细胞对每种测试药物敏感，赋予增加的细胞死亡水平。在原位基因治疗的异种移植小鼠模型中，AdRGD-PGp53治疗与卡巴他赛联合使用可显着降低肿瘤进展并将生存率提高至100％。令人惊讶的是，我们在该小鼠模型中使用亚治疗剂量的卡巴他赛避免了白细胞减少症，但仍显示出与AdRGD-PGp53结合时有效的抗肿瘤作用。AdRGD-PGp53方法在前列腺癌的基因治疗中的应用值得进一步开发。在该小鼠模型中与AdRGD-PGp53结合使用时仍显示出强大的抗肿瘤作用。AdRGD-PGp53方法在前列腺癌的基因治疗中的应用值得进一步开发。在该小鼠模型中与AdRGD-PGp53结合使用时仍显示出强大的抗肿瘤作用。AdRGD-PGp53方法在前列腺癌的基因治疗中的应用值得进一步开发。

更新日期：2019-11-18

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