Targeting MYC in pancreatic cancer

MYC蛋白是一种癌蛋白，与大多数人类肿瘤的发生有关。该项目旨在了解抑制MYC在胰腺肿瘤模型中的后果，并验证基于小分子的策略在体内干扰MYC的致癌功能。它有两个主要方面：第一，我们发现，正如预期的那样，使用显性负向等位基因OmoMYC或shRNA介导的MYC缺失抑制MYC会强烈抑制KRAS/P53突变的小鼠胰腺癌细胞的生长。然而，令人惊讶的是，当我们在同种异体原位移植模型中分析这种依赖时，这种依赖在体内得到了很大程度的缓解。尽管抑制MYC对基因表达的影响在培养和体内非常相似，但体内肿瘤的生长似乎基本没有受到干扰，挑战了在已建立的PDAC肿瘤中靶向MYC是一种有效的治疗策略的概念。对MYC在培养和体内作用的转录分析也表明，MYC抑制了几个促进胰腺癌发生的信号通路，并控制了肿瘤细胞与免疫细胞和微环境的相互作用，我们的目标是了解其中哪些是支持MYC抑制的胰腺肿瘤细胞生长的关键。第二，我们表征了一类新的USP28泛素特异性蛋白水解酶的小分子抑制剂，因为我们之前已经证明USP28稳定肿瘤细胞中的MYC。这些抑制剂耗尽了我们已经尝试过的多个细胞中的MYC，并在全球转录谱上具有MYC特异性的效果。对它们在不同浓度下的作用进行更详细的分析后，人们希望它们能够特异性地干扰我们在这些肿瘤中观察到的依赖MYC的逃避T细胞介导的免疫逃避。我们建议探索这种可能性。

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.