Periodic Reporting for period 3 - TarMyc (Targeting the Oncogenic Function of Myc in vivo)
Periodo di rendicontazione: 2021-03-01 al 2022-08-31
Transcription factors of the Myc oncoprotein family are key factors for the development of most human tumours. Proof-of-principle studies using a dominant negative allele of Myc in mice demonstrated the dependency of established tumours on Myc function. However, these experiments are not transferable to human medicine and did not identify crucial Myc target genes.
The central goal of TarMyc is to develop strategies to target Myc function for cancer therapy. Our previous work has shown that Myc regulates different genes, participating in different cellular processes, depending on its nuclear concentration and the gene promoter’s affinity for Myc. At low, physiological levels, Myc regulates genes involved in growth (e.g. ribosome formation), but at high, oncogenic levels, Myc regulates genes involved in signalling and angiogenesis. We have also found that Myc-mediated gene repression, which depends on complexing with Miz1, requires higher Myc levels than gene activation, and that tumours—but not non-transformed tissues—depend on Myc–Miz1-mediated repression. The concept that Myc regulates distinct sets of genes at physiological and oncogenic levels opens the compelling possibility to target specifically the oncogenic functions of Myc.
Here, we explore this concept in vivo and identify crucial Myc target genes: First, we deplete Myc function by expressing shRNA in mice with established solid tumours, to estimate the therapeutic window of Myc inhibition and identify the primary targets of oncogenic Myc in vivo. Second, we will analyse non-transformed settings where Myc’s regulation of low-affinity genes is beneficial for organisms. I speculate that this happens during regeneration after tissue damage. Third, we will develop strategies to interfere specifically with the oncogenic function of Myc by (i) identifying genes in tumours targeted by Myc that could be new drug targets, and (ii) developing a novel class of drugs that reduce Myc cellular concentrations.
The central goal of TarMyc is to develop strategies to target Myc function for cancer therapy. Our previous work has shown that Myc regulates different genes, participating in different cellular processes, depending on its nuclear concentration and the gene promoter’s affinity for Myc. At low, physiological levels, Myc regulates genes involved in growth (e.g. ribosome formation), but at high, oncogenic levels, Myc regulates genes involved in signalling and angiogenesis. We have also found that Myc-mediated gene repression, which depends on complexing with Miz1, requires higher Myc levels than gene activation, and that tumours—but not non-transformed tissues—depend on Myc–Miz1-mediated repression. The concept that Myc regulates distinct sets of genes at physiological and oncogenic levels opens the compelling possibility to target specifically the oncogenic functions of Myc.
Here, we explore this concept in vivo and identify crucial Myc target genes: First, we deplete Myc function by expressing shRNA in mice with established solid tumours, to estimate the therapeutic window of Myc inhibition and identify the primary targets of oncogenic Myc in vivo. Second, we will analyse non-transformed settings where Myc’s regulation of low-affinity genes is beneficial for organisms. I speculate that this happens during regeneration after tissue damage. Third, we will develop strategies to interfere specifically with the oncogenic function of Myc by (i) identifying genes in tumours targeted by Myc that could be new drug targets, and (ii) developing a novel class of drugs that reduce Myc cellular concentrations.
In the first half of TarMyc, we have obtained genetically modified mice in which we can lower the levels of expressed Myc and MIZ1 in the complete organism. We are currently exploring the phenotype of these animals and crossing them with other genetic stains to obtain tumor prone mice. We have also analyzed which genes are regulated by Myc in vivo in a model of pancreas cancer and compared them to Myc target genes in vitro. Intriguingly, the target profile differs drastically. We are now cloning pooled sh-libraries for the Myc target genes identified in vivo. Finally, we have identified small molecules which lower the concentration of the Myc-interacting protein AURORA-A and thus can now block a crucial effector function of Myc.
We expect that the project will identify crucial Myc target genes which are essential for oncogenic growth but dispensable for physiological growth and find novel strategies for pharmaceutical targeting.