Kevin Joseph Cullen, MD

1. The Role of Insulin-Like Growth Factor II (IGF-II) in Breast Cancer

After completing clinical training at NCI, Dr. Cullen began lab studies on the role of IGFs in the breast cancer section of Dr. Marc Lippman’s lab. Dr. Cullen moved with Dr. Lippman to Georgetown in 1988, where he established his own lab to continue studies on peptide growth factors in breast cancer. Dr. Cullen has been continuously funded through NIH and other sources since 1989. His lab characterized important genotypic and phenotypic differences in the stroma of normal and malignant breast and demonstrated that expression of potent mitogens, including IGF-II, could be induced in tumor stroma following exposure to malignant breast epithelium. He also demonstrated that IGF-II exerts its mitogenic signal in breast cancer by binding the IGF-I receptor. Additionally, Dr. Cullen showed autocrine IGF-II expression results in an aggressive, hormone-independent phenotype.

1. Cullen KJ, Yee D, Sly WS, Perdue J, Hampton B, et al. Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res. 1990 Jan 1;50(1):48–53. PubMed PMID: 2152773.
2. Cullen KJ, Smith HS, Hill S, Rosen N, Lippman ME. Growth factor messenger RNA expression by human breast fibroblasts from benign and malignant lesions. Cancer Res. 1991 Sep 15;51(18):4978–85. PubMed PMID: 1893385.
3. Cullen KJ, Lippman ME, Chow D, Hill S, Rosen N, et al. Insulin-like growth factor-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression. Mol Endocrinol. 1992 Jan;6(1):91–100. PubMed PMID: 1310798.

2. Cisplatin Action and Resistance in Head and Neck Cancer

After moving to Georgetown University in 1988, as an extension of his clinical care of patients with head and neck cancer, his lab began a series of collaborations with the Department of Otolaryngology. For the past 20 years, his research efforts have shifted to molecular studies in head and neck cancer. Specifically, his lab has focused on the development of predictive and prognostic indicators in squamous cell carcinoma of the head and neck (SCCHN). Dr. Cullen’s group has also analyzed molecular targets and mechanisms of resistance for cisplatin and related drugs in SCCHN. We have demonstrated that overexpression of enzymes in the glutathione pathway, specifically glutathione s-transferase-p (GST-p), is associated with resistance to platinum-based chemotherapy and poor prognosis. Furthermore, his group was the first to demonstrate that overexpression of GST-p in head and neck cancers is frequently the result of gene amplification. As part of his lab’s studies of cisplatin resistance in head and neck cancer, we showed that a significant portion of the antitumor activity of cisplatin in the head and neck may be due to direct interactions of this class of chemotherapy drugs with mitochondrial membrane proteins, specifically isoforms of the voltage-dependent anion channel. Although the preponderance of literature has studied the effects of platinum adducts with nuclear DNA, we demonstrated that cisplatin can induce tumor cell apoptosis by direct action on mitochondrial membrane proteins.

1. Nishimura T, Newkirk K, Sessions RB, Andrews PA, Cullen KJ, et al. Immunohistochemical staining for glutathione S-transferase predicts response to platinum-based chemotherapy in head and neck cancer. Clin Cancer Res. 1996 Nov;2(11):1859–65. PubMed PMID: 9816141.
2. Cullen KJ, Newkirk KA, Schumaker LM, Aldosari N, Rone JD, et al. Glutathione S-transferase pi amplification is associated with cisplatin resistance in head and neck squamous cell carcinoma cell lines and primary tumors. Cancer Res. 2003 Dec 1;63(23):8097–102. PubMed PMID: 14678959.
3. Yang Z, Schumaker LM, Egorin MJ, Zuhowski EG, Cullen KJ, et al. Cisplatin preferentially binds mitochondrial DNA and voltage-dependent anion channel protein in the mitochondrial membrane of head and neck squamous cell carcinoma: possible role in apoptosis. Clin Cancer Res. 2006 Oct 1;12(19):5817–25. PubMed PMID: 17020989.

3. Prognostic and Predictive Biomarkers in Head and Neck Cancer

Our group has extended its work in predictive and prognostic markers to a number of cooperative group-sponsored (Radiation Therapy Oncology Group) and industry-sponsored (TAX-324) trials in head and neck cancer, again demonstrating that important predictive and prognostic information can guide treatment selection for patients with head and neck cancer. In our analysis of the TAX-324 trial, we developed a prognostic marker model that differentiates patients into three risk groups: high risk (24-month survival: 29 percent survival), intermediate risk (24-month survival: 67 percent survival), and low risk (24-month survival: 89 percent) (p<0.0001).

1. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Cullen K, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007 Oct 25;357(17):1705–15. PubMed PMID: 17960013.
2. Schumaker L, Nikitakis N, Goloubeva O, Tan M, Cullen KJ, et al. Elevated expression of glutathione S-transferase pi and p53 confers poor prognosis in head and neck cancer patients treated with chemoradiotherapy but not radiotherapy alone. Clin Cancer Res. 2008 Sep 15;14(18):5877–83. PubMed PMID: 18794100.
3. Cullen KJ, Schumaker L, Nikitakis N, Goloubeva O, Tan M, et al. beta-Tubulin-II expression strongly predicts outcome in patients receiving induction chemotherapy for locally advanced squamous carcinoma of the head and neck: a companion analysis of the TAX 324 trial. J Clin Oncol. 2009 Dec 20;27(36):6222–8. PubMed PMID: 19917838.
4. Wu Y, Posner MR, Schumaker LM, Nikitakis N, Cullen KJ, et al. Novel biomarker panel predicts prognosis in human papillomavirus-negative oropharyngeal cancer: an analysis of the TAX 324 trial. Cancer. 2012 Apr 1;118(7):1811–7. PubMed PMID: 22009819; PubMed Central PMCID: PMC4358790.

4. Disparities in Head and Neck Cancer

Since his move to the University of Maryland in 2004, Dr. Cullen has focused increasingly on the issue of health disparities, specifically survival disparities in head and neck cancer associated with race and ethnicity. Compared with Whites, Blacks have poor survival of head and neck cancer. We demonstrated that this survival disparity is not generalized among all head and neck cancers but arises in large part from a significant survival disparity in the subset of patients with oropharyngeal cancer. Further investigation demonstrated that this difference in survival among patients with oropharyngeal cancer is attributable to a large but unexpected difference in the rate of HPV-positive tumors by race. Whites are four to nine times more likely to have favorable prognosis of HPV tumors compared with Blacks. This finding was cited as one of the most important cancer research discoveries of 2009 by the Journal of Clinical Oncology (Petrelli et al., J Clin Oncol, 2009) and received significant coverage in the national lay and scientific press. We have demonstrated that the prevalence of HPV-positive oropharyngeal cancer is increasing rapidly in Whites. Although it has emerged more recently in Blacks, it is now increasing rapidly in that population as well. His most recent work has extended these observations on disparities in head and neck cancer and has helped to characterize an emerging disparity due to a recent, unexplained increase in the incidence of oral tongue cancer among young White females.

1. Settle K, Posner MR, Schumaker LM, Tan M, Cullen KJ, et al. Racial survival disparity in head and neck cancer results from low prevalence of human papillomavirus infection in black oropharyngeal cancer patients. Cancer Prev Res (Phila). 2009 Sep;2(9):776–81. PubMed PMID: 19641042; PubMed Central PMCID: PMC4459126.
2. Zandberg DP, Liu S, Goloubeva O, Ord R, Cullen KJ, et al. Oropharyngeal cancer (OPC) drives racial outcome disparities in squamous cell carcinoma of the head and neck (HNSCC): ten year experience at the University of Maryland Greenebaum Cancer Center (UMGCC). Head Neck. 2014 Dec 9. PMID: 25488341.
3. Zandberg DP, Liu S, Goloubeva OG, Schumaker LM, Cullen KJ. Emergence of HPV16-positive oropharyngeal cancer in Black patients over time: University of Maryland 1992-2007. Cancer Prev Res (Phila). 2015 Jan;8(1):12–9. PubMed PMID: 24916537; PubMed Central PMCID: PMC4429293.

UM Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC)

• Director, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
• Interim Director, Lombardi Cancer Center, Georgetown University, Washington, DC, October 2000-September 2002
• Professor of Medicine, Oncology and Otolaryngology (Tenured), Georgetown University, Washington, DC, July 2002-January 2004
• Associate Professor of Medicine and Otolaryngology (Tenured), July 1995-June 2002