Inhibitors of Heat Shock Response

描述（由申请人提供）：最近抗癌药物的发展导致了几种有效的组成性热休克反应（HSR）阻滞剂的分离，例如HSP90抑制剂格尔达霉素（DMAG）和蛋白酶体抑制剂Velcade（硼替佐米），这对多种癌症细胞类型的存活至关重要。我们在动物模型中的初步研究结果表明，不幸的是，这些药物本身的治疗并不能诱导肿瘤中特异性和有效的细胞死亡，因为它们诱导了额外的hsf -1依赖性信号通路。然而，PTS诱导剂DMAG和硼替佐米与抑制hsf -1介导的转录的化合物协同作用，可诱导高达50倍的肿瘤细胞死亡。

DESCRIPTION (provided by applicant): The recent development of anti-cancer pharmaceuticals has resulted in the isolation of several effective blockers of constitutive heat shock response (HSR), such as the HSP90 inhibitor Geldanamycin (DMAG) and the proteasome inhibitor Velcade (Bortezomib), which is critical to the survival of a wide range of cancer cell types. The results of our preliminary studies in an animal model show that unfortunately, treatment involving these drugs by themselves does not induce specific and efficient cell death in tumors, because they induce an additional HSF-1-dependent signaling pathway. However, the PTS inducers DMAG and Bortezomib act synergistically with chemical compounds that suppress HSF-1-mediated transcription to induce up to a 50-fold more tumor cell death. The ultimate goal of the proposed program is to develop a novel class of highly potential anti-cancer drugs that target both basal and inducible HSR. Phase I studies will initiate the drug development pipeline by high-throughput screening (HTS) of a small library of known pharmaceuticals and prove the value of the proposed anti-cancer therapy. The main goal of Phase II studies will be to develop and initiate preclinical studies of several lead compounds targeting inducible HSR. We aim to isolate a novel class of anti-cancer drugs that has unique properties and that has not been described in the literature or applied in clinical trials. In this way, our approach may identify drugs with tremendous therapeutic potential that could significantly improve the efficiency of anti-cancer chemotherapy. PUBLIC HEALTH RELEVANCE: The goal of this project is to isolate chemical compounds capable of suppressing cancerspecific heat shock response pathways leading to establishment of novel approaches to anti-tumor therapies. Inhibitors of heat shock response will be isolated from a library of pharmaceutically characterized compounds by using a panel of cancer cell lines containing a specific heat shock reporter gene, allowing for the development of cellbased readout drug screening protocols and isolation of new potent anti-tumor drugs.