The Myc family of oncogenic transcription factors is activated in ~70% of human cancers and they regulate the transcription of a large cast (10-15%) of the genome to coordinate metabolism, cell growth and division, differentiation, and development. Further, Myc lies downstream of activated Ras oncoproteins that are frequently mutated in human cancers, where Ras signaling impairs turnover of Myc protein and augments its transcriptional activity. Over the past funding cycle we demonstrated that Myc's proliferative response is rate limiting for tumor development. Remarkably, this pathway strictly relies on a single Myc transcription target, ornithine decarboxylase (Odc), the rate limiting enzyme of polyamine biosynthesis. Here we demonstrated that treatment with the Odc suicide inhibitor DFMO, or simply halving the levels of Odc (in Odc+/- mice), triples the lifespan of tumor-prone, Myc transgenic mice and that it also impairs epidermal carcinogenesis, which is associated with activating mutations in Ras. Collectively, these findings suggest that targeting Odc will have widespread benefit in cancer prevention, a fact now validated in ongoing human cancer chemoprevention trials. Further, we established that targeting Odc disables Myc's proliferative response by selectively affecting Myc's ability to provoke the degradation of the cyclin- dependent kinase inhibitor p27Kip1, a tumor suppressor that inhibits entry and progression through S-phase. Here we first demonstrated that Myc triggers p27Kip1 degradation by activating the transcription of Cks1, a component of the SCFSkp2 E3 ubiquitin ligase complex that directs p27Kip1 destruction. Surprisingly, we have now shown that Odc is required for Myc to induce Cks1 transcription. Collectively, these findings suggest a Myc>Odc>Cks1-to-p27Kip1 pathway drives Myc-induced proliferation and tumorigenesis. Using validated Myc-driven mouse models of B cell lymphoma and mammary adenocarcinoma, and of K-Ras-directed lung adenocarcinoma, we will test the roles of Odc in oncogene-driven proliferation and tumor development, the maintenance of the malignant state, and its interplay with tumor suppressor pathways. These studies include those that evaluate potential therapeutic index, where the intrinsic effects of Odc loss on pre- existing tumor cells versus its effects in normal cells will be determined. We will also critically assess the roles of p27Kip1 and Cks1 as downstream targets of Odc in cancer development and tumor maintenance, and will define the mechanism by which Odc regulates Cks1 and p27Kip1 expression. Given the pervasive and aggressive nature of Myc- and Ras-associated malignancies in human cancer, especially in the three malignancies interrogated herein, and clinical trials establishing the efficacy of targeting Odc in human cancer chemoprevention, the proposed studies are clearly highly relevant to the mission of the NCI.
The research supported by this revised, competitive renewal application (R01 CA100603A1) is directly, clinically relevant to chemoprevention and perhaps therapy for three refractory, devastating human malignancies, lymphoma, breast cancer, and lung adenocarcinoma. Our studies have focused on the clinically validated target ornithine decarboxylase (Odc), a metabolic enzyme whose expression is directly induced by Myc oncoproteins, and also by mutated Ras oncogenes, which together are activated in >75% of human tumors. Importantly, we have shown that targeting Odc impairs Myc's proliferative response and triples the lifespan of tumor-prone, Myc transgenic mice, and that this also compromises the development of skin tumors having Ras oncogene involvement. The proposed studies will define the roles of Odc in regulating the development and maintenance of lymphoma and lung and breast cancer, and will resolve how Odc regulates the proliferative response provoked by oncogenes, with the expectation that these studies will reveal new targets for cancer prevention and treatment.
|Amelio, Antonio L; Fallahi, Mohammad; Schaub, Franz X et al. (2014) CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement. Proc Natl Acad Sci U S A 111:E3260-8|
|Hoellein, Alexander; Fallahi, Mohammad; Schoeffmann, Stephanie et al. (2014) Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma. Blood 124:2081-90|
|Doherty, Joanne R; Cleveland, John L (2013) Targeting lactate metabolism for cancer therapeutics. J Clin Invest 123:3685-92|
|den Hollander, Jurgen; Rimpi, Sara; Doherty, Joanne R et al. (2010) Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116:1498-505|
|Rounbehler, Robert J; Li, Weimin; Hall, Mark A et al. (2009) Targeting ornithine decarboxylase impairs development of MYCN-amplified neuroblastoma. Cancer Res 69:547-53|
|Carew, Jennifer S; Nawrocki, Steffan T; Reddy, Venudhar K et al. (2008) The novel polyamine analogue CGC-11093 enhances the antimyeloma activity of bortezomib. Cancer Res 68:4783-90|
|Rodrigues, Claudia O; Nerlick, Steve T; White, Elsie L et al. (2008) A Myc-Slug (Snail2)/Twist regulatory circuit directs vascular development. Development 135:1903-11|
|Guo, Yongjun; Cleveland, John L; O'Brien, Thomas G (2005) Haploinsufficiency for odc modifies mouse skin tumor susceptibility. Cancer Res 65:1146-9|
|Nilsson, Jonas A; Cleveland, John L (2004) Mnt: master regulator of the Max network. Cell Cycle 3:588-90|
|Nilsson, Jonas A; Maclean, Kirsteen H; Keller, Ulrich B et al. (2004) Mnt loss triggers Myc transcription targets, proliferation, apoptosis, and transformation. Mol Cell Biol 24:1560-9|