Genetically Engineered Viruses for Prostate Cancer Therapy

描述(申请人提供)：基因设计的病毒载体仅限于癌细胞复制，是前列腺癌治疗的一种有吸引力的策略，因为这些病毒可以在肿瘤中复制和传播，但对正常前列腺和周围神经无毒。这克服了目前常规治疗的挑战，如手术和放射治疗，并为癌症治疗开辟了一条新的途径-病毒溶瘤-允许使用在癌症治疗领域独一无二的肿瘤细胞杀灭方法。由于病毒治疗的机制和潜在的毒性不同于标准激素或化疗，协同作用的可能性值得探索。我们提供的数据导致了人们对药物和/或小分子与癌细胞途径和特定的溶瘤单纯疱疹病毒(OHSV)基因突变相互作用的思维方式的转变。我们的主要假设是，我们可以识别特定的药物和/或调节重要前列腺癌细胞通路的小分子，当与适当的OHSV载体配对时，可以增加溶瘤癌细胞的破坏。我们计划研究以下目标：目的1：我们假设我们的高通量筛选发现的促进OHSV在人前列腺癌细胞中传播的小分子，在体内外将协同作用杀死前列腺癌；目的2：我们假设组蛋白脱乙酰酶抑制剂将通过影响致癌信号通路使前列腺癌细胞对携带适当突变的OHSV敏感；目的3：我们假设OHSV通过抑制缺氧诱导的促血管生成因子的表达而发挥抗血管生成载体的作用，微管纺锤体毒素可进一步增强这一作用。 公共卫生相关性：目前局限性前列腺癌的治疗方式包括手术和放射治疗，两者都与神经损伤、性和/或膀胱功能障碍以及其他并发症的风险有关。转移性前列腺癌也有糟糕的治疗选择。在这项提案中，我们正在开发针对局部和转移性疾病的治疗方式。这一点和缺乏良好的化疗反应强调了公共卫生的相关性和发展我们提议的策略作为前列腺癌治疗关键问题的新方法的重要性。

DESCRIPTION (provided by applicant):: Viral vectors genetically-engineered for replication restricted to cancer cells represent an attractive strategy for prostate cancer therapy because these viruses can replicate and spread in the tumor yet be non-toxic to normal prostate and the surrounding nerves. This overcomes a current challenge of conventional treatments, such as surgery and radiation therapy, and has opened a new avenue for cancer therapy - viral oncolysis- which allows for methods of tumor cell killing that are unique in the field of cancer therapy. Since the mechanisms of viral therapy and the potential toxicities differ from those of standard hormonal or chemotherapy, the possibilities of synergy are worthy of exploration. We have provided data leading to a paradigm shift in thinking about the interactions of pharmaceuticals and/or small molecules with cancer cell pathways and specific oncolytic herpes simplex virus (oHSV) gene mutations. Our overarching hypothesis is that we can identify specific pharmaceuticals and/or small molecules that modulate important prostate cancer cell pathways and, when paired with appropriate oHSV vectors can increase oncolytic cancer cell destruction. We plan to study the following aims: AIM 1: We hypothesize that the small molecules identified by our high throughput screen to enhance oHSV spread in human prostate cancer cells, will synergize in vitro and in vivo to kill prostate cancer; AIM 2: We hypothesize that histone deacetylase inhibitors will sensitize prostate cancer cells to oHSV bearing appropriate mutations through effects on oncogenic signaling pathways; AIM 3: We hypothesize that oHSV's can act as antiangiogenic vectors by attenuating the expression of proangiogenic factors induced by hypoxia and that this effect can be further enhanced by microtubule-spindle poisons. PUBLIC HEALTH RELEVANCE: Current treatment modalities for localized prostate cancer include surgery and radiation therapy, both of which are associated with risks of nerve damage and sexual and/or bladder dysfunction, and other complications. Metastatic prostate cancer also has poor treatment options. In this proposal, we are developing therapeutic modalities to target both local and metastatic disease. This and the lack of good chemotherapeutic responses underscores the public health relevance and importance of developing our proposed strategy as a novel approach to the critical problem of prostate cancer therapy.