Genetically Engineered Viruses for Prostate Cancer Therapy

描述（由申请人提供）：对癌细胞进行基因工程复制的病毒载体代表了一种有吸引力的前列腺癌治疗策略，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。这克服了传统治疗的挑战，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——它允许肿瘤细胞杀死的方法在癌症治疗领域是独一无二的。由于病毒治疗的机制和潜在的毒性不同于标准的激素或化疗，因此协同作用的可能性值得探索。我们提供的数据导致了思考药物和/或小分子与癌细胞途径和特异性溶瘤性单纯疱疹病毒（oHSV）基因突变的相互作用的范式转变。我们的首要假设是，我们可以确定特定的药物和/或小分子，调节重要的前列腺癌细胞通路，当与适当的oHSV载体配对时，可以增加溶瘤性癌细胞的破坏。我们的研究计划有以下目的：目的1：我们的高通量筛选发现的小分子可以增强oHSV在人前列腺癌细胞中的传播，我们假设这些小分子可以在体外和体内协同杀死前列腺癌；目的2：我们假设组蛋白去乙酰化酶抑制剂会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；AIM 3：我们假设oHSV可以通过减弱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，而微管纺锤体毒物可以进一步增强这种作用。

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.