Targeting MYC in pancreatic cancer

MYC蛋白是促成大多数人类肿瘤发生的癌蛋白。该项目旨在了解MYC抑制在胰腺肿瘤模型中的后果，并验证基于小分子的策略，以干扰MYC在体内的致癌功能。它有两个主要方面：首先，我们发现，正如预期的那样，使用显性负等位基因OmoMYC或shRNA介导的MYC耗竭抑制MYC强烈抑制KRAS/p53突变小鼠胰腺肿瘤细胞的生长。然而，令人惊讶的是，当我们在同基因原位移植模型中分析这一点时，这种依赖性在体内大大减轻。虽然MYC抑制对基因表达的影响在培养和体内非常相似，但体内肿瘤生长似乎基本上不受干扰，挑战了在已建立的PDAC肿瘤中靶向MYC是有效治疗策略的概念。MYC在培养物和体内的作用的转录组学分析还显示，MYC抑制促进胰腺癌发生并控制肿瘤细胞与免疫细胞和微环境的相互作用的几种信号传导途径，并且我们的目标是了解这些中的哪些对于支持MYC抑制的胰腺肿瘤细胞的生长至关重要。我们描述了一类新的USP 28泛素特异性蛋白酶的小分子抑制剂，因为我们先前已经表明USP 28稳定肿瘤细胞中的MYC。这些抑制剂消耗我们已经尝试过的多个细胞中的MYC，并对全局转录谱具有MYC特异性影响。对它们在不同浓度下的作用进行更详细的分析提出了这样的希望，即它们可能能够特异性地干扰我们在这些肿瘤中观察到的MYC依赖性逃避T细胞介导的免疫逃逸。我们建议探讨这种可能性。

MYC proteins are onco-proteins that contribute to the genesis of the majority of all human tumors. The project aims at understanding the consequences of MYC inhibition in models of pancreatic tumors and at validating small molecule-based strategies to interfere with the oncogenic functions of MYC in vivo. It has two main aspects:First, we have found, as expected, that inhibition of MYC using a dominant-negative allele, OmoMYC, or shRNA-mediated depletion of MYC strongly suppresses growth of KRAS/p53-mutant mouse pancreatic tumor cells. Surprisingly, however, this dependence is much alleviated in vivo when we analyze this in a syngeneic orthotopic transplant model. Although effects of MYC inhibition on gene expression are very similar in culture and in vivo, tumor growth in vivo appears largely unperturbed, challenging the concept that targeting MYC in established PDAC tumors is a valid therapeutic strategy. Transcriptomic analyses of the effects of MYC in culture and in vivo also shows that MYC suppresses several signaling pathways that promote pancreatic carcinogenesis and control the interaction of tumor cells with immune cells and the microenvironment and we aim to understand which of these are critical to support the growth of MYC-inhibited pancreatic tumor cells.Second, we characterize a new class of small molecule inhibitors of the USP28 ubiquitin-specific protease, since we have shown previously that USP28 stabilizes MYC in tumor cells. These inhibitors deplete MYC in multiple cells we have tried and have MYC-specific effects on global transcriptional profiles. A more detailed analysis of their effects at different concentrations raise the hope that they may be able to specifically interfere with the MYC-dependent evasion from T-cell mediated immune escape that we observe in these tumors. We propose to explore this possibility.