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Jaseok Peter Koo PhD

Associate Professor of Medicine (Medical Oncology)

Research Interests

Cancer prevention and therapy; Lung carcinogenesis; Epithelial cell biology; Personalized medicine; Molecular targets; Drug development; Transcription Factor CREB; Inflammation; Cytokines and chemokines and receptors; Biomarkers for early detection and therapy

Current Projects

1. Targeting Transcription Factors: CREB as a Novel Target for Cancer Treatment.

We are focusing on to identify methods and novel drugs to target CREB transcription system for preventive and/or therapeutic strategies in patients with NSCLC.

2. Inflammation and Cancer: Targeting Signal Transduction Networks from Chemokine Receptor to Transcription Factors (CREB and NF-kB) for Cancer Prevention and Treatment.

CXCR2 expression in NSCLC tumor cells is frequent and associated with an adverse outcome. The receptor system is associated with an activation of the KRAS and NF-kB pathways. We are developing new methods and drugs targeting this chemokine system.

3. Cancer Prevention: Characterization of Epithelial Preneoplasia, and Identification of Novel Targets for Cancer Prevention and Biomarkers for Early Detection of Lung Cancer.

We are working on the identification of new biomarkers (molecules and genetic mutations) detecting lung cancers at its early stage.

4. Normal Physiologic Differentiation of Bronchial Epithelial Cells

The goal of this study is to elucidate the precise mechanism of normal differentiation of bronchial epithelial cells. Abnormally differentiated bronchial epithelial cells contribute to the pathogenesis of several lung diseases, including COPD, asthma, emphysema, and lung cancer.


Research Summary

Comprehensive understanding of carcinogenesis provides critical knowledge useful for the development of efficient targets and methods for treatment and prevention of cancer. My research interests focus on the identification of novel targets and development of new drugs for treatment and prevention of cancer. In particular, targeting signaling networks linking membrane receptors to transcription factor CREB (cAMP-responsive element-binding protein) using small molecule inhibitors is my laboratory’s immediate research objective. I am also interested in identifying novel drugs (single or combination) targeting resistant and refractory cancers.

Extensive Research Description

1. Targeting Transcription Factors: CREB as a Novel Target for Cancer Treatment.

CREB and NF-kB transcription factors have been implicated as linkers of inflammation and cancer. We tested our hypothesis that CREB is a master regulator and critical linker of inflammation and cancer and found that: 1) CREB is important for normal differentiation of bronchial epithelial cells (Mol Biol Cell 2006; Mol Cell Biol 2007); 2) CREB is involved in overexpression of numerous proinflammatory cytokines and proangiogenic chemokines (Cancer Prev Res 2008); 3) CREB is overexpressed in various human cancers, such as lung, head and neck, breast, brain, prostate, ovarian, and pancreatic cancer (unpublished data); 4) overexpression of CREB is associated with negative prognosis of non-small cell lung cancer (NSCLC) (Cancer Res 2008a); 5) suppression of CREB expression and activity inhibits growth and survival of NSCLC cells (Cancer Res 2008b); and 6) inflammatory mediators such as prostaglandin (PG)E2 and PGF2a activate CREB via the PKA and PKC pathways (J Immunol 2009).

These findings suggest that CREB plays a crucial role in both normal physiologic function (normal mucous cell differentiation) and pathologic progression of lung disease (inflammatory lung response and lung tumorigenesis/carcinogenesis). Our findings have demonstrated that overexpression and activation of CREB can result in prolonged overexpression of mediators that sustain chronic lung inflammation and cause abnormal survival and proliferation of metaplastic and/or premalignant bronchial epithelial cells, and ultimately promote lung cancer development. These results warrant further studies testing CREB as a potential novel target for prevention of and therapy for cancers.

2. Inflammation and Cancer: Targeting Signal Transduction Networks from Chemokine Receptor to Transcription Factors (CREB and NF-kB) for Cancer Prevention and Treatment.

We recently reported that pro-inflammatory cytokine interleukin (IL)-1b induces overexpression of pro-angiogenic CXCL5 and IL-8 (CXCL8) chemokines via CREB and NF-kB transactivation. Blocking these chemokines’ cognate receptor, CXCR2, using a neutralizing antibody or small molecule inhibitor targeting CREB activity completely blocked migration of endothelial cells (Cancer Prev Res 2008).

CXCR2 plays an important role in inflammation, and stimulation of CXCR2-expressing endothelial cells by CXC family chemokines promotes angiogenesis. Our recent study aimed to elucidate the expression of CXCR2 by tumor cells and its impact on prognosis in NSCLC, in order to further determine the role of CXCR2 in lung carcinogenesis. We determined CXCR2 expression using immunohistochemistry in a large tissue microarray that included 458 NSCLC samples. We found that high CXCR2 expression was associated with overall survival (HR 1.465; CI=1.088-1.972, p-value=0.012) and that a trend was observed between high CXCR2 expression and recurrence-free survival (HR 1.261; CI=0.973-1.633, p-value=0.080) in a multicovariate Cox proportional hazards model after adjusting for age, gender, histologic type, stage, and use of neoadjuvant chemotherapy. In addition, in a separate study gene expression distributions of CXCR2 and its chemokine ligands were strikingly similar in NSCLC cell lines and lung adenocarcinoma tissue (442 patients’ samples). In both cases, hierarchical clustering showed a cluster mostly driven by CXCR2, CXCL5, and CXCL7, representing 20% of the samples. Principal component analysis showed that KRAS and NF-kB oncogenic pathways were the top two gene sets associated with those 20% of patients. Interestingly, those patients turned out to be associated with a poor overall survival in 442 lung adenocarcinoma.

In conclusion, CXCR2 expression in NSCLC tumor cells is frequent and associated with an adverse outcome. The CXCR2/CXCL ligands biological axis may be associated with an activation of the KRAS and NF-kB pathways and could lead to a new therapeutic and preventive method for lung adenocarcinoma. These studies may lead to a new therapeutic option to target angiogenesis (particularly, VEGF/VEGFR-independent angiogenesis) using antibodies and/or small molecule inhibitors that block CXCR2 and/or CREB activity, respectively (Manuscript in Review).

3. Cancer Prevention: Characterization of Epithelial Preneoplasia, and Identification of Novel Targets for Cancer Prevention and Biomarkers for Early Detection of Lung Cancer.

Bronchial epithelial cells are the front line of defense in protecting vulnerable lung tissue from airborne pathogens, and they are also the origin of lung cancer. However, epithelial cells under chronic inflammation develop abnormally differentiated epithelium including mucous cell metaplasia, squamous metaplasia, hyperplasia, and dysplasia, and eventually carcinoma in situ. Mucous cell metaplasia in the airway mucosa is known to be the production source of uncontrollable amounts of mucus. Severe mucus hypersecretion can cause death by obstructing airways. Our studies showed that CREB is involved in the regulation of mucin expression and normal mucous cell differentiation (Mol Biol Cell 2006; Mol Cell Biol 2007).

Using primary normal human tracheobronchial epithelial (NHTBE) cells cultured by the 3-dimensional organotypic method, we found that the EGFR ligands EGF, TGF-a, and amphiregulin induce hyperplasia, as determined by cell proliferation and formation of multilayered epithelium. We also found that EGF induced the increased expression of cyclin D1, which plays a critical role in bronchial hyperplasia, and the overexpression was mediated by activating the MAPK pathway. Erlotinib, an EGFR tyrosine kinase inhibitor, and U0126, a MEK inhibitor, completely inhibited EGF-induced hyperplasia. In conclusion, we demonstrated that bronchial hyperplasia can be modeled in vitro using primary NHTBE cells maintained in a 3D organotypic culture. Inhibitors of EGFR and MEK completely blocked EGF-induced bronchial hyperplasia, suggesting chemopreventive roles of these inhibitors (Cancer Res 2007, cover highlight; Cancer Prev Res, 2011).

I am also focusing on elucidation of the differential roles of CREB throughout the spectrum from normal epithelial differentiation to inflammatory changes and then to carcinogenesis. Findings from this work will delineate CREB’s crucial role in linking physiologic functions of CREB to pathophysiological progression in the lung, including perturbed inflammatory responses and lung tumorigenesis.

Taken all together, our findings unequivocally demonstrate that CREB plays a crucial role in the physiology and pathobiology of airway epithelial cells. Our studies have provided the first significant evidence that CREB has potential as a new molecular target for the prevention and treatment of inflammatory lung diseases and lung cancer, diseases that have had few breakthroughs or improvements in treatment options or outcomes over the last few decades. This is a new paradigm in that CREB is seen as a critical link between normal differentiation, inflammation, and lung cancer development. Identification of the role of CREB throughout the spectrum of normal epithelial differentiation, inflammation, and carcinogenesis in the lung is a unique aspect of my laboratory’s research program. In the future, I will continue to comprehensively investigate this new paradigm, which may lead to development of novel therapeutic methods for chronic lung inflammation and lung carcinogenesis.

  1. 4. Normal Physiologic Differentiation of Bronchial Epithelial Cells

Physiologic function of bronchial epithelial cells present in the lung with inflammatory diseases, such as COPD, asthma, chronic bronchitis, emphysema, and lung cancer, is often compromised. Mechanisms by which normal mucociliary differentiated bronchial epithelium is maintained and by which aberrant differentiation of bronchial epithelium develops are not known (Mol Biol Cell 2006; Mol Cell Biol 2007). Understanding the differentiation mechanism of bronchial epithelial cells would provide important knowledge and novel targets for prevention and treatment of lung diseases.

We showed that CREB has a novel role in airway epithelial cells under both physiologic and pathobiologic conditions. Specifically,under physiologic conditions,CREB plays a critical role in the expression of the MUC5AC mucous cell-specific marker gene and in normal differentiation of airway epithelial cells. Under pathobiologic conditions, persistent activation of CREB by inflammatory mediators such as the proinflammatory cytokine IL-1b and prostaglandins plays a critical role in the overexpression of MUC5AC, mucous cell metaplasia, and resulting mucus hypersecretion (J Immunol 2009). Further studies showed that the PKC/MEK/ERK/p90RSK/CREB pathway is the major signaling cascade in which these stimuli activate CREB. On the other hand, squamous metaplasia in the bronchial epithelium lacks expression of CREB. Thus, it is apparent that CREB is playing dual roles in physiology and pathobiology in the lung. In addition, altered expression and activation of molecules in the signaling pathway have been implicated in carcinogenesis.

The overall goal of the proposed research is to elucidate the precise mechanism by which the CREB signaling pathway system regulates normal differentiation mechanisms of bronchial epithelial cells. Abnormally differentiated bronchial epithelial cells contribute to the pathogenesis of several lung diseases, including COPD, asthma, emphysema, and lung cancer.


Selected Publications

  • Targeting vascular endothelial growth factor in patients with squamous cell lung cancer. Koo PJ, Morgensztern D, Boyer JL, Herbst RS. J Clin Oncol. 2012 Apr 1;30(10):1137-9
  • Lee JS, Ryu SH, Kang SM, Chung WC, Gold KA, Kim ES, Hittelman WH, Hong WK, Koo JS. Prevention of Bronchial Hyperplasia by EGFR Pathway Inhibitors in an Organotypic Culture Model. Cancer Prev Res, 2011, Aug;4(8):1306-1315.
  • Chung WC, Ryu SH, Sun H, Zeldin DC, Koo JS. CREB mediates prostaglandin F2alpha-induced MUC5AC overexpression. J Immunol 2009;182(4):2349-2356.
  • Aggarwal S, Kim SW, Ryu SH, Chung WC, Koo JS. Growth suppression of lung cancer cells by targeting cyclic AMP response element-binding protein. Cancer Res 2008;68(4):981-988.
  • Seo HS, Liu DD, Bekele BN, Kim MK, Pisters K, Lippman SM, Wistuba II, Koo JS. Cyclic AMP response element-binding protein overexpression: A feature associated with negative prognosis in never smokers with non-small cell lung cancer. Cancer Res 2008;68(15):6065-6073.
  • Kim SW, Cheon K, Kim CH, Yoon JH, Hawke DH, Kobayashi R, Prudkin L, Wistuba II, Lotan R, Hong WK, Koo JS. Proteomics-based identification of proteins secreted in apical surface fluid of squamous metaplastic human tracheobronchial epithelial cells cultured by three-dimensional organotypic air-liquid interface method. Cancer Res 2007;67(14):6565-6573.

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