Project Details
Projekt
Targeting MYC in pancreatic cancer
Applicant
Professor Dr. Martin Eilers
Subject Area
Hematology, Oncology
Biochemistry
Biochemistry
Term
from 2015 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 267467939
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.
DFG Programme
Research Units
