Our Science – Young Website
Matthew R. Young, Ph.D.
Molecular Targets for Cancer Prevention
Dr. Young has shown that mitogen-activated protein kinases (MAPKs) are responsible for activating the transcription factor AP-1, leading to neoplastic transformation of mouse JB6 cells (Huang et al., PNAS, 1998 and Watts et al., Oncogene, 1998) and that the Fos family member Fra-1 is a target for MAPK phosphorylation (Young et al., Mol Cell Biol, 2002). Dr. Young has also shown that p65/nuclear factor-kappaB (NFkB) activation is required for transformation of JB6 cells (Hsu et al., Cancer Res, 2001). Similarly, both AP-1 and NFkB can be targeted to suppress tumorigenesis in human keratinocytes (Li et al., Mol Carcinog, 2000). Other AP-1 regulated genes that are targets for cancer prevention include cyclooxygenase-2 (Cox-2), osteopontin and sulfiredoxin (Matthews et al., Cancer Res, 2007, Wei et al., PNAS, 2011). Current projects include identifying translational targets of tumor suppressor programmed cell death 4 (PDCD4) (Young et al., Trends Mol Med, 2003).
Mouse Models for Cancer Prevention
In 1999, Dr. Young showed that activation of the transcription factor AP-1 is required for skin tumor promotion in vivo and that AP-1 can be specifically targeted by dominant negative AP-1 in a transgenic mouse model (Young et al., PNAS, 1999). Dr. Young set up a collaboration with multiple extramural labs to extend these studies to show that AP-1 can be targeted for prevention of human-relevant tumor promoters such as the human papilloma virus (Young et al., Molec Carc, 2002) and UVB (Cooper et al., Molec Can Res, 2003). Other collaborations have shown that AP-1 can be targeted for prevention of estrogen receptor-negative mammary tumors, (Shen et al., Cancer Prev Res, 2008) and carcinogen-induced lung tumors (Tichelaar et al., Cancer Prev Res, 2010). Recently, Dr. Young has established a mouse models for colon cancer. In collaboration with the Small Animal Imaging Program he has detected tumors as small as 1.2 mm3 in the mouse colon by MRI (Young et al., Neoplasia, 2009). Current mouse models in use include the model of colitis-associated colon tumorigenesis (AOM/DSS) and the colon specific knock out of the APC gene.
Dr. Young began his translational research in 2004 with the recruitment of Johns Hopkins Molecular Targets and Drug Discovery Technologies Master student Katie Ruocco. In collaboration with the NCI's Molecular Targets Laboratory, Dr. Young designed a high through-put assay to identify small molecule inhibitors that mimic the tumor suppressor phenotype of the dominant negative AP-1, which blocks tumorigenesis in vitro and in vivo without any detectable undesirable affects (Young et al., PNAS, 1999). A number of chemically diverse compounds were discovered by screening the NCI synthetic and natural product libraries (Ruocco et al., J Biomol Screen, 2007). Of particular interest was NSC 676914, a small-molecule that selectively targets NFkB activity (Kang et al., Mol Cancer Ther, 2009). Currently, analogs of NSC 676914 generated by the Peptide Design and Materials Section are being tested to find compounds with a higher specificity.
With the recruitment of Dr. Elaine Lanza, head of the Human Colon Cancer Prevention Section and cancer prevention fellows Drs. Gerd Bobe and Roycelynn Mentor-Marcel, the LCP began translational research on colon cancer. Dr. Young's experience in mouse models allowed the LCP to translate data from human clinical studies into better designed mouse models and, conversely, to employ the information learned from these mouse models in new clinical studies. Working as a team, the LCP was able to recapitulate in mice the results from the Polyp Prevention Trial (PPT), which showed that men who consumed a high dry bean diet had reduced risk of advanced colorectal adenoma recurrence (Lanza et al., J Nutr, 2006). In obese mice, dry beans altered chemically induced inflammation-associated serum and colon markers and attenuated colon carcinogenesis (Bobe et al., Nutr Cancer, 2008; Mentor-Marcel et al., Cancer Prev Res, 2009). Currently, Dr. Young is collaborating with Dr. Young Kim, from the Division of Cancer Prevention, and with Dr. Bobe, now at Oregon State University, to determine the effects of bean extracts, dietary supplemented flavonols, resveratrol and other dietary compounds on colitis-associated cancer (CAC). They are also characterizing bean-induced changes in the metabolic pathways by analyzing serum metabolomics from both the mouse model of CAC and the human samples from the PPT. Drs. Young and Kim are also generating a metabolic analysis of the preventive effects of resveratrol on CAC.
This page was last updated on 4/17/2014.