Carter Van Waes, M.D., Ph.D.

Chief
Head and Neck Surgery Branch

Clinical Director
NIDCD

Research Statement

The Tumor Biology Section, Head and Neck Surgery Branch of the NIDCD conducts clinical studies and trials concerning the pathogenesis, prevention, diagnosis, and treatment of neoplasms of the head and neck region that affect human communication. Squamous cell carcinoma is the most prevalent malignancy involving the upper aerodigestive tract which affects voice, speech, taste, smell, hearing, and balance as well as survival. Over 42,000 Americans develop neoplasms of the upper aerodigestive tract each year, and approximately 320,000 Americans currently alive suffer significant impairment of communication and other disability as a result of tumor destruction or ablative surgical and radiation therapy. Despite therapy, over 12,000 of these patients in the U.S. die of disease annually. New modalities for prevention and therapy are needed in order to improve preservation of function and survival.

Accomplishments

Signal transcription factors in head and neck cancer

A major focus of the Tumor Biology Section (TBS) has been to identify and determine the mechanisms of activation of key signal activated transcription factors responsible for altered gene and protein expression and molecular pathogenesis, that may serve as molecular targets for prevention and therapy of HNSCC. Our laboratory discovered that transcription factor Nuclear Factor-kappaB, initially identified as a transient activator of genes in response to injury and infection, is aberrantly turned on in HNSCC (Ondrey, Mol Carcinogenesis, 1999). NF-kappaB was found to be a key regulator of cancer cell survival and the multiple cytokines and factors that promote inflammation, angiogenesis and tumorigenesis (Duffey, Cancer Res, 1999; Dong, Cancer Res, 1999). Using microarray gene expression profiling, we further showed that as many as ~60 percent of the genes abnormally expressed in murine and human SCC are NF-kappaB regulated genes, and their expression and the malignant phenotype may be reverted by inhibition of NF-kappaB (Dong Cancer Res, 2001; Loercher, Cancer Res, 2004; Yan, Genome Biology, 2007; Lee, Clin Cancer Res, 2007). We have further demonstrated that NF-kappaB is part of a network of injury signal transcription factors altered in HNSCC. NF-kappaB contributes to activation of other prosurvival pathways and genes, such as IL-6-mediated STAT3 activation, and inhibition of pro-death pathways, notably tumor suppressor p53 (Hong, FASEB J. 2000; Friedman, Clin Cancer Res, 2007; Lee, Int J Cancer, 2008). Using a systems biology approach, we have recently shown important links between NF-kappaB, other pathways and gene expression patterns in HNSCC (Yan, Genome Biol, 2008). Through a collaboration with Dr. Wendy Weinberg of the FDA, a novel interaction between subunits of the NF-kappaB cREL and p63 deltaNp63 family subunits in regulating p21 and cell growth of normal keratinocytes, and their aberrant activation in HNSCC was demonstrated (King, Cancer Res, 2008).

Signal cytokines in molecular pathogenesis and as biomarkers

Clinical studies showed that NF-kappaB related and other signal cytokines and growth factors that promote inflammation and blood vessel formation such as IL-1, IL-6, IL-8, GRO-1, GM-CSF, HGF and VEGF are constitutively expressed by human HNSCC (Chen, Clin Cancer Res, 1999; Dong, Cancer Res, 2001, Druzgal, Head Neck, 2005). Constitutive IL-1 expression was shown to be an autocrine activator of NF-kappaB and proliferation (Chen, Cancer Res, 1999; Wolf Clin Cancer Res, 2001). Autocrine and paracrine IL-6 was shown to promote STAT3 activation and proliferation (Hong, FASEB J, 2000). GRO-1 and its receptor CXCR2 were shown to be key factors in inflammation, angiogenesis and tumorigenesis in syngeneic and transgenic mice (Loukinova, Oncogene (Nature), 2000). HGF and its receptor c-MET were shown to be important in spread and metastasis (Dong, Cancer Res, 2001; Dong, Oncogene (Nature), 2004; Worden Cancer Res, 2005) Among these cytokines and factors, IL-6, IL-8, GRO-1, HGF, and VEGF were detected in the serum of patients with newly developed or recurrent head and squamous cell carcinoma (Chen, Clin Cancer Res, 1999; Dong, Cancer Res, 2004; Druzgal, Head Neck, 2005). The potential use of multiplex assay of these cytokines as serum proteomic biomarkers of response, recurrence and survival was demonstrated in a collaborative study with the NCI Specialized Program of Research Excellence (SPORE) at University of Michigan (Allen, Clin Cancer Res, 2007).

Molecular targeted therapy

After discovery of the role of NF-kappaB in molecular pathogenesis of HNSCC, we demonstrated that a novel first generation proteasome inhibitor (bortezomib, PS-341), was a potent inhibitor of NF-kappaB, cell proliferation, survival, cytokine expression, angiogenesis and tumorigenesis in preclinical studies (Sunwoo, Clin Cancer Res, 2001). The inhibition of NF-kappaB and the proteasome was shown to sensitize HNSCC to radiation, one of the major treatment modalities for HNSCC (Kato, Head Neck, 2000; Van Waes, Proteasome Inhibitors in Cancer Therapy, 2004). The NIDCD HNSB together with the NCI Radiation and Medical Oncology Branches conducted the first in human phase I study of a proteasome inhibitor with re-irradiation in patients with recurrent HNSCC (Van Waes, Int J Rad Oncol Biol Phys, 2005; Allen, Clin Cancer Res, 2008). With altered scheduling, we demonstrated the feasibility of this combination, as well as activity of bortezomib in inhibiting NF-kappaB, target genes, proliferation and survival, and serum cytokine biomarkers. This work has been translated to an NCI Eastern Oncology Cooperative Group Phase II two arm trial of bortezomib or bortezomib and irinotecan in recurrent HNSCC (ECOG 1304), which is nearing completion of accrual. The clinical activity of bortezomib alone and the combination, together with NF-kappaB serum cytokines as early pharmacodynamic proteomic markers is being investigated. Newly underway at NIH in Bethesda in collaboration with the NCI SPORE and Cancer Center at University of Pittsburgh is a phase I trial of bortezomib, cetuximab without or with cisplatin and radiation, as a possible next generation combination for advanced HNSCC. Preclinical studies of other molecular targeted combinations such as bortezomib with histone deacetylase inhibitors (Duan, Mol Cancer Ther, 2007) are also being translated in extramural phase I studies. Recently, the antimalarial and anti-inflammatory drug quinacrine and HSP90 inhibitors were shown to inhibit NF-kB, and to reactivate p53 in a subset of HNSCC (Friedman, Clin Cancer Res, 2007; Nottingham, Keystone Proceedings, 2008). Further studies to evaluate clinical potential of such agents are underway.

Molecular Prevention and Therapy

Premalignant precursors of HNSCC and other cancers may provide a window for molecular prevention. Such lesions commonly progress to invasive HNSCC in hereditary Fanconi Anemia, in which there are defects in the FA DNA repair pathway (Van Waes, Arch Otolaryngol Head Neck Surg, 2005). We demonstrated that a synthetic anti-oxidant, Tempol, could reduce oxidative DNA damage in FA fibroblasts, thereby raising the potential of Tempol to delay the onset of HNSCC and other cancers. These findings were reported together with the demonstration that Tempol delays the onset of epithelial malignancies and prolongs survival of transgenic Fancd2(-/-) p53 (+/-) mice with collaborators at Oregon Health Sciences University (Zhang, Cancer Res, 2008). Studies of natural and synthetic inhibitors of NF-kappaB activation have been of interest for chemoprevention of cancer (Van Waes, Clin Cancer Res, 2007). Inhibition of protein kinase CK2 and both Inhibitor Kappa B Kinases alpha and beta inhibit activation of NF-kappaB in HNSCC (Yu, Cancer Res, 2006), identifying these as potential targets for natural and synthetic agents.

Lab Personnel

Zhong Chen, M.D., Ph.D., Staff Scientist (Send e-mail)
Reza Ehsanian, B.S., Graduate Partnership Program Fellow (Send e-mail)
Jay Friedman, Ph.D. Research Fellow (Send e-mail)
Hai Lu, MD, PhD, Visiting Fellow (Send e-mail)
Liesl Nottingham, M.D., Staff Clinician (Send e-mail)
Bin Yan, Ph.D., Visiting Fellow (Send e-mail)
Xing Ping Yang, Ph.D., Biologist (Send e-mail)
Ning Yeh, M.D., Biomedical Technician (Send e-mail)

Clinical Trials Recruitment

Patients with Recurrent Head and Neck Cancer

Phase I study of concomitant therapy with proteasome inhibitor PS-341 and radiation in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (Protocol 01-C-0104).

Phase I study of bortezomib and cetuximabwithout or with cisplatin in combination with radiation for patients with advanced head and neck cancer (Protocol 08-C-0071)

For more information about possible eligibility contact:
Susan Rudy, RN, MSN, CRNP, Research Nurse Practitioner
Phone: 301-496-4887
Email: rudys@nidcd.nih.gov

Employment Opportunities

Cuurently open for applications for Intramural Research Training and Otolaryngology Clinical Research Fellowships for summer/fall 2009.

For additional information, contact:
Carter Van Waes
Chief, Head and Neck Surgery Branch
Clinical Director, NIDCD
Building 10, CRC Rm 4-2732
Bethesda, MD 20892
Phone: (301) 402-4216
Fax: (301) 402-1140
E-mail: vanwaesc@nidcd.nih.gov

Selected Publications

• Allen C, Saigal K, Nottingham L, Arun P, Chen Z, Van Waes C. Bortezomib-induced apoptosis with limited clinical response is accompanied by inhibition of canonical but not alternative nuclear factor-{kappa}B subunits in head and neck cancer. Clin Cancer Res. 2008 Jul 1;14(13):4175-85.
• King KE, Ponnamperuma RM, Allen C, Lu H, Duggal P, Chen Z, Van Waes C, Weinberg WC. The p53 homologue DeltaNp63alpha interacts with the nuclear factor-kappaB pathway to modulate epithelial cell growth. Cancer Res. 2008 Jul 1;68(13):5122-31.
• Wang J, Seethala RR, Zhang Q, Gooding W, van Waes C, Hasegawa H, Ferris RL. Zhang Q, Gooding W, van Waes C, Hasegawa H, Ferris RL. Autocrine and paracrine chemokine receptor 7 activation in head and neck cancer: implications for therapy. J Natl Cancer Inst. 2008 Apr 2;100(7):502-12.
• Yan B, Chen G, Saigal K, Yang X, Jensen ST, Van Waes C, Stoeckert CJ, Chen Z. Systems biology-defined NF-kappaB regulons, interacting signal pathways and networks are implicated in the malignant phenotype of head and neck cancer cell lines differing in p53 status. Genome Biol. 2008;9(3):R53.
• Lee TL, Friedman J, Van Waes C, Chen Z. A signal network involving co-activated NF-kB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas. International Journal of Cancer 122(9):1987–98, 2008.
• Zhang Q-S, Eaton L, Snyder ER, Houghtaling S, Mitchell JB, Finegold M, Van Waes C, Grompe G. Tempol protects against oxidative DNA damage and delays the onset of epithelial tumors in Fanconi Anemia Fancd2-/-Trp53+/- mice. Cancer Research 68(5):1601–8, 2008.
• Chen Z, Lee TL, Yang XP, Dong G, Loercher A, Van Waes C. cDNA Microarray and Bioinformatic Analysis of Nuclear Factor-kappaB Related Genes in Squamous Cell Carcinoma. Methods in Molecular Biology (Clifton,N.J.) 383:81–99, 2007.
• Friedman J, Nottingham L, Duggal P, Pernas F, Yan B, Yang XP, Chen Z, Van Waes C. Deficient TP53 Expression, Function and Cisplatin Sensitivity are Restored by Quinacrine in Head and Neck Cancer. Clinical Cancer Research, 13(22 Pt 1):6568–78, 2007.
• Lee TL, Yang XP, Yan B, Friedman J, Duggal P, Bagain L, Dong G, Yeh NT, Wang J, Zhou J Elkahloun A, Chen Z, Van Waes C. A Novel NF-kB Gene Signature is Differentially Expressed in Head and Neck Squamous Cell Carcinomas in Association with TP53 Status. Featured Cover article—Clinical Cancer Research 13(19):5680–91, 2007.
• Yan B, Yang XP, Lee TL, Friedman J, Tang J, Van Waes C, Chen Z. Genome-wide identification of novel expression signatures reveal distinct patterns and prevalence of binding motifs for p53, NF-kB and other signal transcription factors in head and neck squamous cell carcinoma. Genome Biology 8(5):R78, 2007.
• Allen C, Duffy S, Teknos T, Islam M, Chen Z, Albert P, Wolf GT, Van Waes C. Nuclear Factor-kappaB-related serum factors as longitudinal biomarkers of response and survival in advanced oropharyngeal carcinoma. Featured cover article Clinical Cancer Research 13(11):3182–90, 2007.
• Van Waes C, Yu M, Nottingham L, Karin M. Novel functions of Inhibitor-kappaB Kinases as tumor promoter and suppressors during development and progression of squamous cell carcinoma. Clinical Cancer Research 13(17):4956–9, 2007.
• Allen CT, Ricker JL, Chen Z, Van Waes C. Role of activated nuclear factor-kappaB in the pathogenesis and therapy of squamous cell carcinoma of the head and neck. Head & Neck 29(10):959–71, 2007.
• Van Waes C. Nuclear factor-kappaB in development, prevention, and therapy of cancer. Clinical Cancer Research 13(4):1076–82, 2007.
• Duan J, Chen Z, Van Waes C. Nuclear factor-kappaB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101. Molecular Cancer Therapeutics 6(1):37–50, 2007.
• Snyder E R, Ricker JL, Chen Z, Van Waes C. Variation in cisplatinum sensitivity is not associated with Fanconi’s Anemia/BRCA pathway inactivation in head and neck squamous cell carcinoma cell lines. Cancer Letters 245:75–80, 2007.
• Yu M, Yeh J, Van Waes C. Protein Kinase CK2 Mediates Inhibitor-Kappa B Kinase and Aberrrant Nuclear Factor-kB Activation by Serum Factors in Head and Neck Squamous Carcinoma Cells. Cancer Research 66(13):6722–31, 2006.
• Lee TL, Yeh J, Van Waes C, Chen Z. Epigenetic Modification of Suppressor Of Cytokine Signaling-1 Can Affect Activation of STAT3 by EGFR or IL-6R and JAK and MEK Signaling in Head and Neck Squamous Cell Carcinomas. Molecular Cancer Therapeutics 5(1):8–19, 2006.
• Worden B, Yang XP, Lee TL, Bagain L, Yeh NT, Cohen JG, Van Waes C, Chen Z. Hepatocyte growth factor/scatter factor differentially regulates expression of proangiogenic factors through Egr-1 in head and neck squamous cell carcinoma. Cancer Research 65(16):7071–80, 2005.
• Van Waes C. Head and neck squamous cell carcinoma in patients with Fanconi anemia. Archives of Otolaryngology—Head & Neck Surgery 131(7):640–1, 2005.
• Van Waes C, Chang AA, Lebowitz PF, Druzgal CH, Chen Z, Elsayed YA, Sunwoo JB, Rudy SF, Morris JC, Mitchell JB, Camphausen K, Gius D, Adams J, Sausville EA, Conley BA. Inhibition of nuclear factor-kappaB and target genes during combined therapy with proteasome inhibitor bortezomib and reirradiation in patients with recurrent head-and-neck squamous cell carcinoma. International Journal of Radiation Oncology, Biology, Physics 63(5):1400–12, 2005.
• Loercher A, Lee TL, Ricker JL, Howard A, Geoghegen J, Chen Z, Sunwoo JB, Sitcheran R, Chuang EY, Mitchell JB, Baldwin AS Jr, Van Waes C. Nuclear factor-kappaB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Cancer Res. 2004 Sep 15;64(18):6511-23. Erratum in: Cancer Res. 2004 Nov 1;64(21):8130-2.

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