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| David Carbone, M.D., Ph.D.. | |
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| Wendell Yarbrough, M.D. |
Thoracic/Head and Neck Cancer Research Program
Overview
Substantial growth and development of the thoracic and head and neck oncology research activities at Vanderbilt-Ingram Cancer Center led center leadership to create this new clinical science program in 2009. This program brings together a group of closely aligned basic and clinical investigators dedicated to the understanding, treatment and prevention of these all-too-common malignancies.
Co-Leaders: David Carbone, M.D., Ph.D., and Wendell Yarbrough, M.D.
Scientific Goals
- To support patient-focused translational thoracic and head and neck cancer research.
- To develop and implement strategies for personalized medicine in thoracic and head and neck cancer, including:
a. Appropriate selection of patients for current therapies.
b. Development, testing, and selection of appropriate novel therapies for individual patients. - To promote research focused on thoracic and head and neck cancer within the Cancer Center.
- To support intra- and inter-programmatic and external collaborations to develop new biological insights and treatment strategies for thoracic and head and neck cancer.
- To develop new investigators and leaders who focus on thoracic and head and neck cancers through mentoring and training activities as well as research support.
Program Focus to Meet Scientific Goals
History and Overview of Progress Leading to Creation of the Thoracic/Head & Neck Cancer Program
Thoracic Oncology
The VICC Thoracic Oncology Group has a distinguished record of major contributions in both clinical and translational research in lung cancer. In the clinical arena, our group has made major contributions to the care of patients with both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). For example, VICC investigators were among the first to demonstrate that etoposide and cisplatin (EP) had excellent activity in “refractory” SCLC (Porter et al., 1985). This observation served as an impetus to test EP as induction therapy in SCLC patients with extensive-stage (ES) disease. The pivotal phase III study, conducted within the Southeastern Cancer Study Group, compared four cycles of EP to six cycles of cyclophosphamide, doxorubicin, and vincristine (CAV), the previous “standard” treatment for SCLC. The results conclusively demonstrated that EP was equivalent to CAV but engendered far less toxicity in the patients (Roth et al., 1992). As a result EP became the new standard regimen for ES SCLC in most cooperative group trials. VICC investigators also helped dispel the notion that "more is better" in ES SCLC with one of the first randomized trials conducted testing this concept (Johnson et al., 1987a; Johnson et al., 1987b; Johnson et al., 1985). VICC investigators also played a pivotal role in identifying the activity of new agents such as topotecan and paclitaxel against SCLC (Ettinger et al., 1993; Schiller et al., 1996). In limited stage SCLC, our group was among the first to demonstrate the utility of concurrent chemotherapy and thoracic radiotherapy (TRT) and the resultant survival benefit (Johnson et al., 1993a). From this work we went on test the feasibility and effectiveness of multiple daily fractions of radiation therapy (Johnson et al., 1994; Johnson et al., 1993b). The latter work was the impetus for a pivotal randomized trial that demonstrated the survival advantage achieved with twice daily TRT as compared to standard daily fraction. The results of this study were published in The New England Journal of Medicine (Turrisi et al., 1999).
VICC investigators were also among the first to champion multi-modality therapy in locally advanced NSCLC (Johnson et al., 1990; Johnson et al., 1991). Although much of our work exploring the utility of multi-modality treatment was conducted within the cooperative group setting, our investigators played key roles, including serving as PIs or co-PIs of many of the pivotal studies ( Sause et al., 2000; Sause et al., 1995). We also have helped to define the potential of various radiation enhancing agents with investigations ranging from the preclinical arena through phase I, II, and ultimately III clinical trials. For example, we conducted the original phase I studies with paclitaxel as a radiation enhancer (Choy et al., 1994; Glantz et al., 1996; Safran et al., 1997). Our subsequent phase II studies became the basis for phase III studies in NSCLC in several cooperative groups in the United States, including the Radiation Therapy Oncology Group (RTOG), the Cancer and Leukemia Group B (CALG-B), the Southwest Oncology Group (SWOG), and the North Central Cancer Treatment Group (NCCTG). In advanced, metastatic NSCLC our investigators have made major contributions to the development of many "standard" chemotherapy regimens including EP, carboplatin (CBDCA) + paclitaxel, cisplatin (CDDP) + CPT-11, and CDDP + gemcitabine (Hainsworth et al., 1989; Jagasia et al., 2001; Johnson et al., 1996; Paul et al., 1994). Some of this work also was conducted within the cooperative group setting, but our investigators were clearly among the driving forces behind these efforts. Some examples of the cooperative group work include the identification of paclitaxel’s activity in NSCLC (Chang et al., 1993) that ultimately led to its testing in a key phase III trial in ECOG that resulted in CDDP + paclitaxel becoming a new standard therapy for advanced NSCLC (Bonomi et al., 2000). In addition, three of the four arms of a pivotal randomized phase III chemotherapy trial (E1594) that helped define “standard” treatment in advanced NSCLC were piloted at Vanderbilt. The results of the latter study were published in The New England Journal of Medicine (NEJM) (Schiller et al., 2002).
VICC investigators also are among the major contributors to the development of new “targeted” approaches in lung cancer. These efforts have included the development of EGFR TKIs and anti-angiogenesis agents such as bevacizumab. We were key contributors to the clinical development of both gefitinib and erlotinib in NSCLC (Arteaga and Johnson, 2001; Giaccone et al., 2004; Herbst et al., 2004; Johnson, 2003a,b; Johnson and Arteaga, 2003; Miller et al., 2003). We also designed and led the pivotal randomized phase II and phase III trials evaluating bevacizumab with chemotherapy in NSCLC (Johnson et al., 2004) (Sandler et al., 2006). The latter trial demonstrated a highly statistically significantly survival advantage in favor of the bevacizumab arm; the results of which were published in the NEJM (Sandler et al., 2006). All of these initiatives involved the collaborative efforts of many individuals from many institutions, but our investigators certainly were in the vanguard of much of this work. Collectively the results of the aforementioned trials have helped set standards for treatment of SCLC and NSCLC throughout the United States and around the world.
To continue these efforts to improve the outlook of lung cancer patients, and to facilitate the translational mission of the VICC, several outstanding recruits have been successfully recruited to the thoracic oncology group in recent years. Among these is Pierre Massion, M.D., recruited to Vanderbilt in 2001. Dr. Massion has been integral to growing the translational research portfolio of the thoracic oncology group. His research focuses on lung tumorigenesis and the use of genomic and proteomic approaches to identify molecular markers of lung neoplasia and to test those in multidisciplinary early detection strategies. He has also become a leader in applying proteomic approaches to study lung cancer. In particular, he is performing tissue and serum-based proteomic analysis to discover new candidate biomarkers of tumor progression and response to therapy in a cohort of high-risk individuals who develop lung cancer. He also is exploring new technological advances to improve our protein discovery and identification efforts. In collaboration with Drs. Caprioli (HT) and Carbone, preinvasive lesions in bronchial biopsy and invasive lung cancer were profiled by MALDI MS (Yanagisawa et al., 2003; Massion et al., 2004; Rahman et al., 2005) and discriminatory proteins between lung cancer and controls were identified of by LC-MSMS proteomics and Phage-display recombinant antibody library (serum, plasma or pleural fluid) (Amann et al., 2006; Taguchi et al., 2007; Yildiz et al., 2007). Building on these studies, Drs. Massion, Carbone, Caprioli (HT) and Liebler (ST) propose to prospectively validate and identify serum proteins from the proteomic profile predictive of response to EGFr TKIs and develop signatures of response to chemotherapy (SPECS trial). Dr. Massion is also part of the Lung Cancer Biomarkers Group (LCBG) consisting of scientists from the Early Detection Research Network (EDRN), Lung Cancer Specialized Programs of Research Excellence (SPOREs), the NCI and others LCBG’s objective is to formulate specimen reference sets to be used for testing biomarkers for early detection or diagnosis of lung cancer. At present four reference sets have been planned using serum and plasma samples.
Another new key recruit to the T/HN program, but involved in collaborative research even prior to his arrival, is William Pao, M.D., Ph.D., who was recently recruited from Memorial Sloan-Kettering Cancer Center, where he had established an international reputation in translational research. He is widely known for his pioneering work in the discovery and characterization of EGFR mutations and acquired secondary resistance mutations (Pao et al., 2004; Balak et al., 2006; Ding et al., 2008). Most exciting is his recent finding that the combination of an irreversible tyrosine kinase inhibitor and cetuximab is highly active in refractory EGFR-mutated NSCLC (Regales et al., 2009). This observation has led to a new investigator-initiated clinical trial employing this combination in patients who previously responded but then progressed on an EGFR TKI. Overall, Dr. Pao’s research focuses on identification of genes involved in the pathogenesis of lung tumors and stratifying tumors into clinically relevant molecular subsets. Using information derived from these experiments, Dr. Pao seeks to improve treatment for patients with NSCLC. His research has yielded important insights to mechanisms of lung tumor sensitivity and resistance to EGFR inhibitors. Dr. Pao is the author of more than 50 publications; is actively involved in numerous professional associations, including the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO); and has served as a journal editor for PLoS Medicine, Cancer Research, and the Journal of Clinical Oncology. He also is leading the VICC Personalized Medicine initiative (described below).
In addition, we successfully recruited three new thoracic surgeons to the T/HN Program, Jon Nesbitt, M.D., Eric Lambright, M.D., and Eric Grogan, M.D., as well as two additional medical oncologists Vicki Keedy, M.D., and Leora Horn, M.D. Each of these clinical investigators has significant interests in the mechanisms of lung cancer tumorigenesis, tissue, clinical and outcomes data collection and data bases, as well as development of clinical trials using preclinical data generated from this program.
A metric of the national and international prominence in translational research achieved by the VICC lung cancer research team is the funding and successful competitive renewal of the Vanderbilt SPORE in Lung Cancer in 2007. Preliminary data generated from the Vanderbilt Lung SPORE in collaboration with five other Lung SPOREs was the basis of a successful “team science” U01 grant application led by Vanderbilt Lung SPORE investigators titled “Strategic Partnering to Evaluate Cancer Signatures” (SPECS). The Vanderbilt Lung SPORE is the cornerstone of the proposed tissue and research resources available to this consortium. This is the only SPECS grant funded in lung cancer. Accrual to this trial is going extremely well, and we are the source of virtually all of the patients accrued to date (>50).
Head and Neck Cancer
Vanderbilt has a long tradition of excellence in Otolaryngology and in the clinical care of patients with head and neck cancer. With four dedicated head and neck oncology surgeons and three dedicated head and neck medical oncologists, VICC is a leader in the clinical management of head and neck cancer and dominate the region in this field. Our head and neck group is responsible for more than 250 new cases per year and numerous patients are referred to our center for assistance with management of difficult or rare problems. In 2003, Dr. Yarbrough was jointly recruited by the Cancer Center (using CCSG Developmental Funds) and the Department of Otolaryngology. The objective was for Dr. Yarbrough was to build head and neck translational research within VICC through collaboration with the extant head and neck clinical research team led by Barbara Murphy, M.D., as well as VICC basic and translational researchers. Shortly after his arrival, Dr. Yarbrough assisted the Cancer Center and the Division of Medical Oncology with recruitment of Christine Chung, M.D., a young investigator who rapidly became a highly productive independent investigator. In 2006, Jill Gilbert, M.D., was recruited to supplement treatment-related clinical trials efforts focused on head and neck tumors and to allow Dr. Murphy to increasingly focus on supportive care initiatives within VICC albeit with an emphasis on H&N cancer. Dr. Gilbert also serves as the Vanderbilt representative to the head and neck cancer clinical practice guidelines committee of the National Comprehensive Cancer Network (NCCN) and on the Head and Neck Cancer Committee, Working Group, and Cancer Core Committee within the Eastern Cooperative Oncology Group (ECOG). The addition of Dr. Gilbert has augmented the number of trials, the number of investigator-initiated trials and accrual to head and neck treatment-related trials. Additionally, she has initiated trials for treatment of papillary, medullary, and anaplastic thyroid cancer. Based on faculty recruitment in this area, the large volume of head and neck tumor patients treated at Vanderbilt, and continued support of the Cancer Center during the past funding cycle, the research activities of the head and neck team have grown substantially.
One example would be the work of Dr. Chung, who was among the first to characterize molecular profiles of tumors from head and neck cancer patients using DNA microarrays and to correlate these findings with the clinical outcomes of this patient population (Chung et al., 2004). The results showed that tumors sharing the same pathological diagnosis of head and neck squamous cell carcinoma (HNSCC) had four distinct molecular gene expression profiles and these molecularly defined groups had distinctly different recurrence and survival outcome. These data provided additional information to current prognostic factors and rationale for individualized patient care. These findings have become the basis of a more widespread use of this technology in the characterization of many cancers but in particular those of the head and neck. Subsequently, she found that one of the four molecularly defined subgroups reflected activation of EGFR pathway (Cancer Cell in 2004; funded by a NIH R21 grant). In a follow-up study, she found that a significant number of these patients had increased EGFR gene copy numbers either by polysomy or gene amplification (Journal of Clinical Oncology, 2006). Recognizing the importance of EGFR signaling and its potential as a therapeutic target in the treatment of head and neck cancer, Dr. Chung continued her EGFR signaling-related research. She identified an EGFR-activation signature and modulation of this signature by EGFR inhibitors such as cetuximab (a monoclonal antibody directed against EGFR) and erlotinib (a small molecule inhibitor of EGFR tyrosine kinase), and further developed this signature as a predictive biomarker of EGFR inhibitor therapy in the treatment of head and neck cancer. This latter work is currently funded through her NIH R01 grant entitled “Molecular signatures of HNSCC in response to targeted therapies.”
Through gene expression analyses, pathways associated with poor survival in HNSCC were identified. This work contributed to initiation of an institutional trial (VICC HN 0501, a phase II weekly bortezomib + docetaxel w/ recurrent and/or metastatic HNSCC; PI: Chung) and a cooperative group study (ECOG 1304: randomized phase II bortezomib with and without irinotecan in Pts Recurrent/Metastatic Head & Neck CA – PI: Gilbert) designed to determine the utility of NF?B inhibition for improvement of response and survival in refractory HNSCC (Chung, 2006).
The VICC head and neck group were also among the leaders in the development of molecular tools to augment detection of metastases within sentinel nodes and for validation of sentinel node technology for use in HNSCC (Shores et al., 2004). The use of sentinel node biopsy instead neck dissection offers many advantages; however, validation of the technique for HNSCC was necessary before widespread adoption. Vanderbilt investigators helped design the cooperative group trial (ACOSOG Z0360) that is now complete, with a manuscript accepted for publication (Civantos et al., J. Clin.Onc., In Press.).
In addition, the head and neck team has been at the forefront of studies that support the importance of taxanes in the treatment of HNSCC. Specifically, Anthony Cmelak, M.D., led a multi-institutional phase II trial employing docetaxel with concomitant radiotherapy in high-risk postoperative patients with HNSCC. This study was the impetus for further definitive trials including a phase III study in which Drs. Cmelak and Murphy were key contributors. The latter study, published in the NEJM, culminated in FDA approval of docetaxel in the management of patients with stages III/IV HNSCC. (Posner et al., 2007). Dr. Gilbert serves as co-PI of the ECOG group trial (E1302) using taxanes ± gefitinib in recurrent or metastatic HNSCC. These studies have helped define the role of taxanes for concomitant chemoradiation and for induction chemotherapy.
Through the CCSG-funded Human Tissue Acquisition and Pathology Shared Resource, the CCSG has assisted Drs. Yarbrough and Murphy in the development and maintenance of a remarkable head and neck clinical database and biospecimen repository that includes more than 1,700 patient specimens. This repository has served as the foundation for much of the translational research within the head and neck group and has been used in many studies, including those published in Cancer Cell and NEJM. Specimens collected include: cancer tissue, normal epithelia adjacent to tumor, normal tissue from non-cancer patients, metastatic nodal deposits, whole blood, lymphocytes, plasma, serum, saliva, and mouth rinse. These resources are available to all researchers whose studies have head-and-neck-cancer relevance, and they have been widely used by investigators within and outside the institution.
In summary, the T/HN program is composed of highly interactive and collaborative investigators, and ongoing interactions are present both within and outside of Vanderbilt. The strong NCI funding base of the investigators enhances the T/HN as a vibrant new research program. The Cancer Center environment promotes interactions of all program members through regular programmatic meetings, application and administration of many multi-investigator studies, career development, and innovative pilot projects. In fact even before the formal merger of these two research groups, interactions were commonplace. One striking example of early cooperation between the organ-site specific investigators within the T/HN Program is the initiation of an InterSPORE Phase 0 dasatinib neoadjuvant trial that enrolls both lung cancer and head and neck cancer patients. This trial investigates a src inhibitor that fits nicely with the targeted therapy research and development strategies at the core of this program as well as with the VICC Personalized Cancer Medicine Initiative overall.
About the Program Leaders
David Carbone, M.D., Ph.D., Program Co-Leader – Dr. Carbone is a Professor in the departments of Medicine, Cancer Biology, and Cell and Developmental Biology and is the Harold L. Moses Chair in Cancer Research. He graduated summa cum laude from Amherst College in 1977 and received an M.D. and a Ph.D. in Molecular Biology and Genetics at Johns Hopkins University in 1985. He then did an internal medicine internship and residency at The Johns Hopkins Hospital through 1988, followed by a medical oncology fellowship at the NCI. In 1991 he was appointed assistant professor at the University of Texas Southwestern Medical Center and was promoted to associate professor with tenure in 1995. He was recruited to Vanderbilt University in 1996, where he was promoted to full professor in 1998. He is also Director and Principal Investigator of the Vanderbilt SPORE in Lung Cancer and the Strategic Partnering to Evaluate Cancer Signatures (SPECS) U01 consortium. His research interests, grant support, and publications have focused on lung cancer, and specifically proteomic and expression array signature development, lung cancer genetics, cancer immunotherapy, tumor-associated immunosuppression mechanisms, and gene therapy. Recent research directions include molecular profiling of lung cancers and preneoplasias, especially the use of mass spectrometry-based proteomics. He has more than 200 peer-reviewed publications and review articles, has served on several NCI grant review panels, including the clinical program project parent committee, and has continuous NCI funding since early in his career. He has served on organizing committees for both ASCO and AACR and is currently chair of the Lung Biology subcommittee for the Eastern Cooperative Oncology Group and serves on the Board of Scientific Counselors for NCI.
Wendell Yarbrough, M.D., Program Co-Leader – Dr. Yarbrough is an Associate Professor with appointments in the departments of Otolaryngology and Cancer Biology, and is an Ingram Professor of Cancer Research at Vanderbilt. Dr. Yarbrough was recruited to Vanderbilt in 2003, just prior to the submission of the previous CCSG renewal application, to initiate the translational research program in head and neck cancer. Dr. Yarbrough has worked to build the infrastructure for the program with activities including recruitment and mentorship. Dr. Yarbrough is a tenured associate professor, Director of the Barry Baker Laboratories for Head and Neck Oncology and previously served as vice chair of the Head and Neck Organ Site Committee of the American College of Surgeons Oncology Group. He also serves on the Editorial Board of Head & Neck. Research in the Yarbrough lab is centered on tumor suppressors and regulation of cell growth and survival with strong interest in molecular distinctions that segregate head and neck squamous cell carcinoma, particularly related to human papilloma virus infection (HPV). Dr. Yarbrough has served as the PI of clinical trials and is the PI at Vanderbilt for the recently initiated Inter-SPORE lung and head and neck trial, “Comparison of Biomarker Modulation by Inhibition of EGFR and/or Src Family Kinases Using Erlotinib and Dasatinib in Head and Neck and Lung Cancers.” Dr. Yarbrough has mentored medical students, served as thesis director for graduate students, and mentored postdoctoral fellows and young faculty, including Dr. Christine Chung, a productive independent investigator in T/HN.
Areas of Research Program Expertise
New Drug Development for Metastatic/Recurrent Disease
VICC has three medical oncologists dedicated to head and neck cancer therapy. Drs. Gilbert, Chung, and Murphy are responsible for the development and implementation of a number of investigator-initiated trials and cooperative group studies evaluating the efficacy, toxicity, and biologic mechanisms for a number of new agents. Investigators have recently reported the results of three consecutive studies evaluating irinotecan in metastatic/recurrent disease. Two of the studies were investigator-initiated trials conducted through the VICC Affiliate Network (VICCAN). The initial manuscript, published in 2007, was the first study to report the efficacy of irinotecan in head and neck cancer. The second manuscript reported the efficacy of irinotecan in combination with cisplatin (Gilbert et al., 2007;2008). The third study, reported at ASCO by Dr. Gilbert, is a Phase II cooperative group trial (ECOG1304) evaluating the combination bortezomib concurrent or followed by irinotecan (Gilbert et al., 2009).
Additional investigator-initiated studies include a Phase II trial of docetaxel and bortezomib that was developed and subsequently reported by Dr. Chung. An important component of this study is the laboratory correlative studies funded by Dr. Chung’s Damon Runyon Clinical Investigator Award. More recently Dr. Gilbert conceived and developed a CTEP-sponsored head and neck cancer study comparing cetuximab plus sorafenib vs. placebo. The trial is open at five academic institutions through the NCI-sponsored Southeastern Phase II Consortium. Dr. Chung is conducting the laboratory correlatives for this trial and Dr. Murphy is conducting the supportive care correlatives.
T/HN investigators also have a long history of participating in ECOG trials to evaluate new treatments for metastatic and locally recurrent HNC. In addition to the studies mentioned above, Dr. Gilbert served as co-PI on ECOG 1302, a phase III randomized trial comparing docetaxel vs. docetaxel + gefitinib in previously treated patients with recurrent or metastatic head and neck cancer. Dr. Chung is a co-Chair for the correlative studies within the head and neck cancer committee. Of note, Dr. Carbone chairs the Lung Cancer Biology subcommittee of the Thoracic Committee for ECOG.
Combined Modality Therapy
Vanderbilt Investigators have been instrumental in the development and conduct of key trials examining the use of taxanes as primary treatment for locally advanced head and neck cancer. For example, Dr. Cmelak served as the study PI and Dr. Murphy served as the quality-of-life PI for E2399, a larynx-perseveration trial based on the results of an investigator-initiated trial conducted by VICCAN (Cmelak, 2007a,b). Importantly, this study (E2399) was the first prospective trial to demonstrate a survival benefit for head and neck cancer patients with HPV-positive disease. Drs. Cmelak, Murphy, Chung, and Gilbert are involved in the development of the follow-up ECOG trial for patients with HPV positive disease. Additionally, Vanderbilt investigators have contributed significantly to the landmark studies describing the survival advantage for post-operative chemoradiation (Cooper et al., 2004) and the survival advantage of docetaxel, cisplatin and 5-FU (TPF) vs. cisplatin and 5-FU (PF) induction therapy; both studies were reported in NEJM (Posner et al., 2007). Based on preclinical studies carried out in this laboratory, Dr. Lu has several radiation therapy-related trials under way, including a study testing the utility of lithium for central nervous system protection, and a trial combining RAD001 an inhibitor of mTOR with radiation for NSCLC brain metastases.
In addition to cooperative group studies, members of the head and neck team have conducted investigator-initiated trials evaluating novel induction and concurrent treatment regimens. Dr. Cmelak reported the results of a pilot trial with single agent docetaxel in high-risk post-operative patients (Cmelak et al., 2007a,b) and Dr. Chung has reported the result of a novel combination of Phase II trial of induction chemotherapy (oxaliplatin and pemetrexed) in patients with locally advanced head and neck cancer (ASCO).
Supportive Care
Dr. Murphy directs the pain and symptom management initiative within VICC’s Cancer Epidemiology, Prevention and Control research program. However, her clinical interest remains focused on therapy of head and neck tumors and she serves as the head and neck team leader. Dr. Murphy has assembled research and clinical teams that focus on several key areas related to thoracic and head and neck cancers: swallowing function, nutrition and metabolism, psychiatric issues, neurocognitive changes, coping, and lymphedema. Underlying themes are the etiological role of inflammation in treatment-related effects, psychosocial effects of disease and therapy, and development of patient-reported tools for measurement of outcomes. Dr. Murphy participated in the validation of the Mucositis Daily Questionnaire – head and neck – one of the most commonly used patient-reported outcomes (PROs) for assessment of mucositis. She has also reported the development of the Vanderbilt Head and Neck Symptom Survey, a tool for screening symptom burden in patients treated with radiation therapy. In addition, she is working with colleagues to validate a separate tool designed to assess the lymphedema in head and neck cancer patients. Dr. Murphy has participated in a number of pharmaceutical trials evaluating supportive care agents for head and neck cancer patients. She is one of the founders of the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN), designed to collect observational data to describe patterns of care for patients with head & neck cancer (Murphy, 2009).
In total, T/HN investigators have participated in 22 investigator-initiated supportive care trials over the past five years. Two of these trials focus on lung and head and neck cancer, four trials are exclusive to head and neck cancer, and one trial is exclusive to lung cancer. The investigator-initiated trials primarily focused on lung and head and neck cancer have enrolled 490 patients.
Thyroid Cancer
Prior to 2008, VICC had a paucity of therapeutic trials directed at thyroid cancers. Dr Gilbert, in cooperation with members of the endocrine faculty members in Surgical Oncology and Medicine, has initiated a clinical and translational research program in thyroid malignancies. Dr. Gilbert is responsible for development of a portfolio of clinical trials for advanced thyroid cancer and serves as the local PI for these investigations. Ongoing studies include a Phase II trial of the MEK inhibitor, AZD6244 (AstraZeneca), in refractory papillary thyroid cancer patients, and a Phase III trial of the multi-kinase inhibitor XL184 (Exelixis) in medullary thyroid cancer.
Airway Epithelial Cancer Biology
Airway epithelial research is at the core of basic and translational research within the T/HN Program. Epithelial research within the Epithelial Biology Center focuses on signaling pathways, tumor suppressors, viral initiators, and molecular characterization of tumors of the lung and head and neck. This center interacts heavily with the other programmatic efforts, particularly personalized cancer medicine.
Another ongoing project with clear translational implications comes from the laboratory of Thao Dang, M.D. Dr. Dang (T/HN) previously identified a chromosome translocation involving the Notch3 locus on chromosome 19p in a young female patient with NSCLC (Dang et al., 2000). This prompted her lab to study the biological relevance of Notch3 in lung cancers. Notch signaling is known to play a fundamental role in normal development and cell-fate determination in a variety of multi-cellular organisms. Notch3 is overexpressed in approximately 40% of lung cancers (Haruki et al., 2005a; Haruki et al., 2005b) although its activation by translocation is rare (Haruki et al., 2005a), implying other mechanisms of upregulation in the majority of cases. Although Notch signaling can be growth-promoting or growth-inhibitory depending on cellular context, in NSCLC, its function seems to be oncogenic. Dr. Dang demonstrated that constitutive Notch3 activation in developing lungs of transgenic mice inhibits terminal differentiation of type I pneumocytes, resulting in a neonatal lethal phenotype, with mice developing the histological appearance of diffuse adenomatous hyperplasia. Even more interestingly, she found that there is a highly statistically significant association between Notch3 expression and EGFR expression. She hypothesized there may be an important interaction between these pathways and later found that inhibition of Notch3 signaling increased sensitivity of tumor cell lines to EGFR TKIs up to two orders of magnitude (Haruki et al., 2005b). Inhibition of the Notch3 pathway in NSCLC cell lines increases sensitivity to EGFR TKIs, by nearly 40-fold. In H460 cells, which are markedly resistant to AG1478 (IC50 = 23.8 µmol/L vs. 8.3 µmol/L), inhibition of Notch3 also increased sensitivity to the inhibitor. Dr. Dang is now working with AstraZeneca and Abgenix to develop Notch3 inhibitory antibodies to be used in combination with EGFR targeting drugs like cetuximab or erlotinib.
Continuing the program’s interest in Notch, it is well known that Notch activation requires proteolytic cleavage of the receptor by a ?-secretase protein complex (Konishi et al., 2007). Because ?-secretase is required for proteolytic cleavage of Notch receptors, Dr. Dang hypothesized that these inhibitors might possess activity against Notch signaling in lung cancer cells. In fact, ?-secretase inhibitors have been shown to reduce angiogenesis and induce apoptosis in other systems, further supporting the hypothesis that these compounds may have utility in the treatment of patients with cancer. Accordingly, Dr. Dang tested the antitumor activity of the ?-secretase inhibitor MRK-003 (obtained from Merck) in both in vitro and in tumorigenicity models. The drug inhibited Notch3 signaling, reduced tumor cell proliferation, inhibited serum independence, and induced apoptosis of lung cancer cell lines in vitro and in vivo using mouse xenograft models (Konishi et al., 2007). In light of these data we have established collaborations with Merck (MK-0752) and Eli Lilly to test the effects of their ?-secretase inhibitors on Notch3 function in NSCLC and pancreatic cancers, and are nearly ready to open a Phase I/II clinical trial based on this work in clinical trial THO-0893 (Ph I/II MK0752 W/EGFR Tyrosine Kinase Inhibitor Erlotinib Previously Treated Metastatic/Recurrent NSCLC). The trial is to be funded in part through an R21 tht is currently under review and written by Dr. Keedy, Dr. Dang’s co-PI on this project.
Dr. Yarbrough has both interest and expertise in HPV and characterization of molecular differences between HPV-associated and non-HPV-associated HNSCC. Recently, his efforts have focused on receptor tyrosine kinases signaling and he has active collaborations with Drs. Jennifer Grandis (University of Pittsburgh) and Gordon Mills (MD Anderson). Through a joint research effort with Drs. Chung and Slebos, the PI3K pathway was identified as differing between HNSCC based on HPV status and is now a research focus (Slebos et al., 2006) (Yarbrough et al., 2007).
Dr. Yarbrough’s lab continues to investigate the role of a putative tumor suppressor, LZAP, whose expression is decreased in up to 30% of HNSCC. His group has shown that LZAP inhibits proliferation, invasion, anchorage-independent growth and in vivo tumor growth and that it regulates ARF, p53 and RelA (Wang et al., 2007; Wang et al., 2006). Knockout of this putative tumor suppressor in a mouse model is under way. Preliminary results suggest that mice with targeted LZAP form lung cancer around one year of age.
Dr. Chung has had interest in characterization of gene expression differences in HNSCC to advance clinical and translational goals. She has identified expression profiles that correlate with HPV expression, NF?B activation, and EGFR activation within HNSCC. She has shown that increased EGFR gene copy number correlates with poor prognosis in HNSCC. Her current studies will correlate EGFR activation profiles with response to EGFR inhibition using models and patient samples (Chung et al., 2006a). Characterization of gene expression profiles that differ in HNSCC based on HPV expression has led to the analyses of the PI3K pathway in Dr. Yarbrough’s lab (see above). Dr. Chung also discovered that NF?B was activated in a subset of HNSCC and that NF?B activation correlated with outcome, leading to an investigator-initiated trial using the proteasome inhibitor bortezimab in recurrent HNSCC (Chung et al., 2006b).
Personalized Cancer Medicine
The T/HN program has development of personalized therapy and molecular targeting as major goals, and is leading the effort in VICC to routinely fingerprint cancers for informing clinical decision-making. This has long been a theme of the Vanderbilt Lung SPORE, and with the recruitment of Dr. Pao and the new findings of the relevance of HPV status and genetic mutational status in both cancer types, the efforts of this program will lead the VICC’s Personalized Cancer Medicine Initiative. This effort represents activities in individual investigators’ laboratories, the Translational Research Laboratory (a VICC shared facility for analyses of tumor specimens and development of preclinical data), and a strong collaboration with the Department of Pathology to establish CLIA-certified “reflex” genetic testing. This will establish routine genetic analysis as part of standard patient care for lung, head and neck, and other cancers at the VICC.
Another example of VICC research attempting to match patients to the most appropriate therapy comes from the laboratory of Dr. Carbone. His group examined the prospect of using matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) of unfractionated, pretreatment sera to identify NSCLC patients with improved survival after treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) gefitinib and erlotinib (Taguchi et al., 2007). VICC investigators were among the first to use MALDI MS imaging for the analysis of peptides or proteins present on tissue surfaces and in serum (Chaurand et al., 1999; Stoeckli et al., 2001). To develop a proteomic signature that might be used for predictive purposes, investigators collected serum specimens from NSCLC patients prior to EGFR TKIs treatment (including subjects enrolled in the ECOG trial E3503). Protein spectra were then independently acquired at Vanderbilt and the University of Colorado; the raw 
spectral data were also analyzed by a third independent site (Biodesix) to ensure reproducibility. Next, a prediction algorithm was developed based on a training cohort of 139 patients and subsequently evaluated in two additional cohorts of NSCLC patients, treated with either gefitinib or erlotinib, and control cohorts not treated with an EGFR TKI. The classification algorithm was based on eight distinct mass-to-charge (m/z) features that identified patients likely to have improved outcome with EGFR TKI therapy (Figure T/HN 2). Predicted outcomes were highly reproducible, with a concordance of 97%. Notably, a significant survival benefit was predicted in two blinded validation patient cohorts, including patients with clinical features not commonly associated with a good outcome following EGFR TKI therapy (e.g., squamous cancers and smokers). The algorithm did not predict improved outcome in patients treated with chemotherapy or surgery alone (i.e., patients not treated with EGFR TKIs), indicating that the protein signature is not simply a prognostic factor. Correlation with updated E3503 survival data confirmed a highly statistically significant correlation with the MALDI protein signature status (P< 0.001), a marginally significant association of EGFR mutation with survival (P=0.05), and no correlation with KRAS mutation status. The protein signature status was independent of both RAS and EGFR mutation status in distinct contrast to colon cancer. This VICC-defined MALDI predictor remains a potent and highly clinically significant predictor of survival after first-line treatment with erlotinib, independent of mutations in KRAS and EGFR. These data suggest that serum protein profiles derived via MALDI MS can be used to select NSCLC patients who have an improved survival after treatment with EGFR TKIs. This biomarker is now being assessed in the intergroup trial N0723 known by the acronym MARVEL, a Phase III biomarker validation study of second-line therapy in patients with advanced NSCLC (NCT00738881). Validation of the protein signature is an important secondary endpoint of this high-priority intergroup study. Dr. Carbone is ECOG PI of the MARVEL study.
Dr. Pao joined the Vanderbilt faculty in March 2009 as the Assistant Director of Personalized Cancer Medicine for VICC and a member of our Thoracic Oncology Group. Dr. Pao was one of the first investigators to identify and characterize the EGFR mutations in lung cancers associated with sensitivity to EGFR TKI (Pao et al., 2004). He was also among the first to identify causes of resistance to the EGFR TKIs including the EGFR T790M mutation and MET amplifications (Bean et al., 2007; Pao et al., 2005). To further study the role of the T790M mutation in lung tumorigenesis, Dr. Pao developed mice with inducible expression in type II pneumocytes of EGFRT790M alone or together with a drug-sensitive L858R mutation. These mice develop lung adenocarcinomas that require the mutant EGFR for tumor maintenance and are resistant to erlotinib (Regales et al., 2007). Most recently, Dr. Pao has used this mouse model to develop strategies to overcome T790M-mediated resistance. When the gene expression patterns of tumors with or without the resistance allele were compared, two of the most overexpressed genes in tumors included epiregulin and amphiregulin, known ligands of EGFR, raising the possibility that an autocrine loop contributes to EGFR mutant lung tumorigenesis. When the irreversible EGFR TKI inhibitor BIBW-2992 was used in combination with cetuximab, 7/8 T790M expressing animals had a complete response after four weeks of treatment. Based upon this work, Dr. Pao has established an agreement with Boehringer-Ingelheim to undertake a pilot study using BIBW-2992 with cetuximab in NSCLC patients with acquired resistance to EGFR TKIs. The results of this work has lead to an investigator initiated study employing cetuximab with erlotinib in patients with known mutation and who progressed after an initial response to erlotinib. This study is being done in collaboration with investigators at Memorial Sloan-Kettering Cancer Center.
The head and neck cancer investigators in the program are also advancing personalized cancer molecular medicine. Although the role of the human papilloma virus (HPV) in the etiology of HNSCC has been gaining acceptance for a decade, its significance for therapy has only recently emerged. In one example, Dr. Cmelak was involved in the most definitive study to date suggesting that HNSCC associated with HPV responds better to therapy and is associated with improved survival relative to HNSCC not associated with HPV (Fakhry et al., 2008). Based on the prognostic significance of HPV in HNSCC, Drs. Chung and Yarbrough have established CLIA certified screening for all patients with oral cavity and oropharynx squamous cell carcinoma who have tissue diagnosis performed at Vanderbilt. It is evident that HPV is important for prognosis and it is becoming clear that HPV should be considered in trial design. An investigator-initiated trial for intensification of therapy in HPV-negative oropharyngeal patients is in the early stages of development by Dr. Chung.
Another striking example of personalizing cancer treatment came from the collaborative efforts of several medical oncologists at VICC and other institutions in a study led by Dr. Chung. The EGFR inhibitor cetuximab is the first targeted agent approved for HNSCC, but its use, particularly in the southern United States, can be limited by a relatively high rate of anaphylactic reactions with the initial infusion. This clinical observation led the head and neck team to initiate a study that identified the portion of the cetuximab molecule (galactose-alpha-1,3-galactose) likely responsible for the anaphylactic reaction. This work was published in the NEJM (Chung et al., 2008). Thus, while the head and neck research group is more recently established compared to the lung group, its members have made significant contributions to understanding of molecular defects in head and neck squamous cell carcinoma and toward advancement of therapy.
Dr. Chung’s research interest is development of biomarkers using genomic and proteomic technology to predict tumor behavior, including response and recurrence. The use of EGFR inhibitors is increasing in HNSCC, and her research also focuses on mechanisms of resistance and applying this information to Phase I/II trials and correlative studies of novel therapeutics for new anti-cancer treatments and improved patient selection. Dr. Chung has also designed and completed a trial using bortezomib and docetaxel for recurrent HNSCC, based on molecular differences identified between high-risk and low-risk HNSCC. Bortezomib was used as an indirect inhibitor of NF?B based on expression data indicating that the NF?B pathway was activated in high-risk tumors and that those patients with high-risk tumors had increased recurrence and decreased disease-free survival.
Modeling/Preclinical Testing
Clinical trials of new and targeted agents in HNSCC are impeded by expense, relatively low numbers of patients eligible for Phase I or II trials, and anticipated low response rates. Eligibility for trials, especially Phase I-II, is often limited to patients with advanced tumors that have failed standard therapy, a fact that may contribute to the low observed response rates. Additionally, response to any single targeted agent may be uncommon because of redundancy in signaling to critical downstream effectors or other genetic defects that promote resistance. The expense and effort of clinical trials to determine efficacy of targeted agents coupled with the low response rates observed for individual agents is a major problem, suggesting that better mechanisms for patient selection and/or prediction of response are needed. However, both clinical trials and current model systems seem inadequate for this task. To assist with patient selection and prediction of response, development of pre-clinical testing and modeling for thoracic and head and neck tumors is a major goal of the program.
Inadequacy of animal models of cancer to mimic the human condition has slowed development of new therapeutic agents and led the Yarbrough lab to focus on creation of a human-in-mouse model of HNSCC that more faithfully represents the diversity human tumor compared to modeling of cell lines. This model has been optimized and currently can successfully model tumors in more than 70% of patients. Before modeling, the tumors are grown short-term in culture and can be genetically manipulated at this time. In order to monitor tumor growth and response to therapy without expensive anatomic imaging or animal sacrifice, we have engineered primary HNSCC tumor cultures to express luciferase before placing the tumor cells into mice. Tractability, low expense, and relatively high success rate suggest that this model is suited for pre-clinical testing of novel and targeted agents in HNSCC.
Expertise of the Yarbrough lab in short-term culture of HNSCC has led to inter-programmatic collaborations within the Cancer Center. Dr. Alissa Weaver’s (HT) lab collaborated with the Yarbrough lab and showed that primary cultures of HNSCC formed invadopodia and degraded extracellular matrix, and that cortactin was localized to areas of invadopodia. This work described a critical role for cortactin for secretion of metalloproteinases (Clark et al., 2007). Dr. Andries Zijlstra (HT) is currently is using primary HNSCC cells to determine the effect of hypoxia on mobility and invasiveness using the chorioallantoic membrane (CAM) model.
Outreach
Outreach is a priority of T/HN. The major risk factor for both non-small cell lung cancer and HNSCC is use of tobacco. Many patients present with advanced stage disease contributing to low cure rates and increased morbidity of therapy. A few examples of our interactions with the community are described below.
To increase community awareness of head and neck cancer, Drs. Yarbrough and Chung have for the pats six years led the Oral and Head and Neck Cancer Awareness Week (OHANCAW) activities at Vanderbilt and the Nashville Veterans Administration (VA) Hospital, respectively. The Cancer Center has been intricately involved in these educational and awareness campaigns, specifically with planning, advertising, and media relations to promote the activities to the greater Nashville community. Yearly, OHANCAW activities include a public awareness campaign within the medical campuses and in the Nashville community with television and radio coverage and public service announcements. Within Vanderbilt, the patient closed-circuit television carries notifications regarding the times and dates and carries messages describing risk factors and signs and symptoms of HNSCC. “Table tents” are placed in the cafeteria containing similar information. Dr. Dana Marshall (Meharry-Vanderbilt Alliance) in the Department of Surgery at Meharry has used the infrastructure and expertise at Vanderbilt to establish a biospecimen repository and to initiate head and neck cancer awareness activities and screenings at Meharry Medical School for the past two years.
In addition to the OHANCAW activities, the head and neck team participates in community education, awareness and screening activities throughout the year. Examples of activities that have been supported by the Cancer Center and the head and neck team include outreach and screenings at: a local church, Meharry dental school, NASCAR truck series racing garage, and the National Bluegrass Music Convention.
International outreach within the head and neck group is led by James Netterville, M.D., who organizes and travels with a full-service surgical center to Nigeria each year. The group packages and carries necessary equipment, supplies, and medicine. Personnel that travel with the team include surgical and clinic nurses, scrub technicians, surgeons, residents, medical students, anesthesiologist and anesthesia staff, and a pathologist. This remarkable effort culminates in two weeks of surgical and non-surgical therapy for the people of Nigeria in a regional medical outpost. During the year, patients who otherwise would have no access to the level of medical care required to treat or diagnose their conditions await arrival of this mission. While mission personnel are in Nigeria, more than 100 patients are typically treated surgically and many more are examined in clinic, diagnosed, and treated non-surgically. Local medical personnel are invaluable in organizing patients to be seen and treated during the mission trip and in providing post-treatment care and follow-up.
Biospecimen Repository
The thoracic and head and neck clinical programs significantly emphasize biorepositories in support of translational research. The thoracic biorepository has been in operation since 2000 and has collected more than 2000 tissue and 10,000 biofluid samples to date, with complete clinical outcome annotation data. It has assembled and maintains 18 lung cancer tissue microarrays for research use, using software from Aperio and Ariol. It is directed by Adriana Gonzalez, M.D. in the Department of Pathology, with the assistance of a manager, two tissue technicians, a research nurse, and two data managers. The VICC has been of substantial assistance in the development of the informatics tools available to this resource, as well as supporting routine pathology services such as immunohistochemistry and cryosectioning. Biospecimen repositories with annotated clinical databases provide a solid foundation for translational research. During the previous funding period of the CCSG, the head and neck biospecimen repository and lung biospecimen repositories were formalized. The lung biorepository has more than 27,000 samples collected to date, including: serum (>12,500), plasma (>7900), frozen tumor resections (>3500), tumor biopsies (>3150) and bronchial brushes (>350). The head and neck repository has accrued more than 1700 patients and 263 non-cancer volunteers who contributed more than 8191 biospecimens including: saliva, mouthrinse, blood, tumor tissue and non-tumor tissue. Additionally, platforms are being established as part of our Personalized Medicine Initiative for the routine mutational analyses of lung adenocarcinoma patients.
Program Members
- Blackwell, Timothy Scott, M.D.
Rudolph H. Kampmeier Professor of Medicine, Cancer Biology, and Cell and Developmental Biology; Director, Division of Allergy, Pulmonary, and Critical Care Medicine and the Center for Lung Research; Pulmonologist - Carbone, David P., M.D., Ph.D.
Harold L. Moses Chair in Cancer Research; Director of Specialized Program of Research Excellence in Lung Cancer; Medical Oncologist - Cmelak, Anthony J., M.D.
Associate Professor; Radiation Oncologist - Dikov, Mikhail, Ph.D.
Assistant Professor; Researcher - Gilbert, Jill, M.D.
Associate Professor of Medicine; Director, Hematology/Oncology Fellowship Program; Section Chief, Solid Tumor Oncology; Medical Oncologist - Gonzalez, Adriana L., M.D.
Assistant Professor of Pathology; Researcher - Grogan, Eric L., M.D., M.P.H.
Assistant Professor of Thoracic Surgery; Thoracic Surgeon - Hande, Kenneth R., M.D.
Professor of Medicine and Pharmacology; Associate Director, Hematology/Oncology Fellowship Program; Medical Oncologist - Horn, Leora, M.D., M.Sc.
Assistant Professor of Medicine; Assistant Director, Educator Development Program; Medical Oncologist - Keedy, Vicki L., M.D.
Assistant Professor of Medicine; Clinical Director, Saroma Program; Assistant Medical Director, Clinical Trials Shared Resource; Medical Oncologist - Lambright, Eric S., M.D.
Assistant Professor, Thoracic Surgery; Surgical Director, Lung Transplant; Chief of Thoracic Surgery, VA Hospital; Thoracic Surgeon - Loyd, James E., M.D.
Rudy W. Jacobson Professor of Medicine; Researcher - Lu, Bo, M.D., Ph.D.
Associate Professor; Radiation Oncologist - Massion, Pierre, M.D.
Associate Professor of Medicine (Allergy, Pulmonary & Critical Care) and Cancer Biology; Pulmonary and Critical Care Medicine Doctor - Murphy, Barbara A., M.D.
Associate Professor of Medicine; Director, Cancer Supportive Care Program; Director, Head and Neck Research Program; Medical Oncologist - Nesbitt, Jonathan C., M.D.
Associate Professor; Thoracic Surgical Oncologist - Netterville, James L., M.D.
Mark C. Smith Professor of Otolaryncology; Director Head & Neck Oncologic Surgery; Associate Director Bill Wilkerson Center for Otolaryngology and Communication Sciences; Head and Neck Surgical Oncologist - Newman, John H., M.D.
Elsa S. Hanigan Professor of Pulmonary Medicine; Professor of Medicine (Allergy, Pulmonary & Critical Care Medicine); Researcher - Pao, William, M.D., Ph.D.
Associate Professor of Medicine; Ingram Associate Professor of Cancer Research; Director, Personalized Cancer Medicine; Medical Oncologist - Pedchenko, Tetyana V., Ph.D.
Research Instructor; Researcher - Putnam, Joe B. (Bill), M.D.
Professor and Chair of Thoracic Surgery; Ingram Professor of Surgery; Professor of Biomedical Informatics; Thoracic Surgeon - Rickman, Otis B., D.O.
Director of Bronchoscopy; Assistant Professor; Interventional Pulmonologist - Roden, Dan M., M.D.
Professor of Medicine and Pharmacology; William Stokes Professor of Experimental Therapeutics; Researcher - Slebos, Robbert, Ph.D. , M.H.S.
Research Assistant Professor of Cancer Biology and Otolaryngology; Researcher - Walker, Ronald C. , M.D.
Professor of Clinical Radiology & Radiological Sciences - Worrell, John A., M.D.
Professor of Radiology and Radiological Sciences; Researcher - Yarbrough, Wendell G. (Dell), MD, FACS
Associate Professor Otolaryngology and Cancer Biology; Director, Barry Baker Laboratory for Head and Neck Oncology; Head and Neck Surgical Oncologist
