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Nearly 65,000 patients are diagnosed with cancer of the head and neck in the United States each year. These cancers could affect the nasal passages, sinuses, mouth, throat, larynx (voice box), swallowing passages, salivary glands and thyroid gland. Skin cancers that develop on the scalp, face or neck also may be considered head and neck cancers.
At Johns Hopkins, our team of physician-scientists are leading the field in new discoveries in the basic sciences, clinical research, and in the training of the next generation of specialists devoted to these diseases.
A grant from the National Cancer Institute's highly competitive SPORE program was awarded to the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in 2002 to speed research on new treatments for head and neck cancers.
SPORE stands for Specialized Program of Research Excellence and the funds are one of the most sought-after by researchers nationwide because they focus on turning research into results – linking basic science discoveries with new tests and therapies that help patients.
As part of the Johns Hopkins Head and Neck Cancer SPORE, investigators are studying the role of HPV (human papilloma virus) in cancer development and how the virus is transmitted to the upper airway. While the cause of most squamous cell head and neck cancers are linked to environmental exposures (primarily tobacco and alcohol use), 15 to 20 percent of these cancers occur in non-smokers and non-drinkers. Scientists at the Johns Hopkins Kimmel Cancer Center were the first to discover that the human papillomavirus (HPV) also is a likely cause of certain cancers of the head and neck and is an indicator of improved survival.
Additional studies are looking at the BRAF gene, which involves a subtle change in a chemical base that makes up the molecular code of DNA. When this coding error occurs, it causes the gene to be stuck in the “on” position making cells continuously grow and divide, ultimately into cancer. Researchers at the Johns Hopkins Kimmel Cancer Center are developing blood tests to find this mutation among patients at risk for cancer as well as therapeutic drugs that act by blocking mutant proteins caused by BRAF mutations.
In this next phase, the Johns Hopkins Head and Neck Cancer SPORE will continue to fund five research projects, three cores, a career development and research developmental program.
The SPORE team’s newly proposed research programs are:
We and others have demonstrated that silencing of tumor suppressor genes associated with promoter hypermethylation is a common feature of many human cancers. We have identified several novel tumor suppressor genes inactivated by promoter hypermethylation, as well as candidate genes for use in detection strategies. We propose continue to identify and characterize hypermethylated genes in squamous cell carcinoma of the head neck (HNSCC) and will identify novel promoter hypermethylated genes by: (1) A candidate gene approach based on testing genes found to be hypermethylated in other tumors or on the functional structure and biologic plausibility of the candidate gene and (2) A functional screen looking for genes that are up-regulated following treatment with demethylating agents (5-Aza-deoxycytidine). Newly identified hypermethylated genes will be characterized for functional significance and biologic activity in tumor progression. We will apply a modified pharmacologic unmasking approach to define promoter hypermethylated genes whose inactivation contributes to drug resistance to conventional chemotherapeutic and pathway (EFGR) directed therapy. Candidate hypermethylated tumor suppressor genes will be validated in drug resistant cell lines by transfection of candidate genes in in vitro and in vivo mouse models. These genes will then be validated in prospective trials and retrospective cohorts treated with conventional chemotherapy and EGFR pathway specific agents. Novel promoter hypermethylated targets will be incorporated into a second SPORE proposal (project #2) for use as markers for the early detection and monitoring of patients with head and neck cancer.
Early detection of cancer of the mouth and throat (head and neck squamous cell carcinoma [HNSCC]) would result in substantial improvement in survival for the 40,000 Americans diagnosed with this disease each year while reducing morbidity associated with treatment. Changes in DNA that underly tumorigenesis are ideal molecular markers for highly sensitive and specific approaches to early detection. We have had promising results in pilot projects for detection of HNSCC in oral rinses (saliva) and serum of affected individuals using hypermethylation markers identified during the first funding period by Project 1. In the proposed new funding period, it is anticipated that the number of promising markers identified in Project 1 will double or triple . In order to produce an accurate, useful and cost-effective detection test, it will be necessary to combine markers that have shown initial promise into detection panels. However, the presence of some markers in saliva and serum of healthy control subjects requires that detection panels be compartment specific.We will assemble and verify candidate markers and panels through the assessment of tumor-specific hypermethylation of promoter regions in tumors, premalignant lesions, exfoliated cells in oral rinse specimens, and serum. Quantitative methylations specific PCR which is amenable to high-throughput application will be employed. The prevelance of alterations in sets of tumors will be assessed, followed by evaluation of the presence of identical markers in clinical specimens (saliva and serum). Simple sensitivity and specificity estimates will be explored in various panel combinations. The proposed panels of markers will then be tested in samples from subjects enrolled in premalignant and post-treatment surveillance studies (aims 2 and 3). Subjects will be recruited at the Johns Hopkins Medical Institutions and the MD Anderson Cancer Center. The utility of marker panels for detection and prediction of recurrence/progression will be explored.
The association between the high-risk type-16 of the human papillomavirus (HPV-16) and a subset of head and neck squamous cell carcinomas (HNSCC) has recently been established. Given the causative role of HPV-16 in a subset of head and neck cancers, both prophylactic and therapeutic vaccines targeted to HPV-16 are accepted as highly relevant for the prevention and treatment of HPV-HNSCC. The HPV viral oncoproteins, E6 and E7, are constitutively expressed in HPV-associated cancers; therefore, they represent ideal target tumor antigens for the development of antigen-specific vaccines. In preclinical studies, we have found that a DNA vaccine comprised of a model tumor antigen (HPV-16 E7) which is physically linked to the immunomodulatory protein calreticulin (CRT), results in potent E7-specific CD8+ T cell immune responses and anti-tumor effects against an E7-expressing tumor model in vaccinated mice. This vaccine has also been proved effective against E7-expressing murine tumors with down-regulated Major Histocompatibility Complex (MHC) class I molecules; an important finding, given a significant proportion of advanced stage HNSCC down-regulate MHC class I molecules as a means of immune evasion. In addition, we found that the combination of CRT/E7 DNA vaccination and a mild chemotherapeutic agent, Epigallocatechin-3-Gallate (EGCG), a compound found in green tea, acted synergistically to enhance tumor-specific T cell immune responses, as well as enhance anti-tumor effects, resulting in a higher cure rate than either DNA vaccination or EGCG alone. These findings have prompted us to investigate whether the combination of intradermal administration of CRT/E7 DNA vaccine via gene gun and oral EGCG administration is safe and able to generate E7-specific CD8+ T cell immune responses in patients with advanced HPV-associated head and neck cancers.
Head and neck squamous cell cancer (HNSCC) remains a significant cause of morbidity worldwide, with approximately 400,000 new cases per year. Ongoing advances in combined modality therapy (CMT) continue to improve locoregional control and thus survival; however, 60-70% of patients still experience recurrence within two years and 20-30% develop distant metastases.
Upregulation of EGF-R expression and aberrant activation of kinase cascades downstream of this receptor occur early in the process of carcinogenesis and play a major role in malignant progression. The level of EGF-R expression correlates with recurrence and poor prognosis in HNSCC. A well tolerated anti-EGF-R monoclonal antibody, cetuximab, has shown remarkable activity against HNSCC, including statistically significant improvement in survival for patients with locally advanced disease treated with radiotherapy, leading to its regulatory approval for this disease. As a downstream component of EGF-R signaling, src is known to mediate resistance to EGF-R blockade. Dysregulated src leads to aberrant signaling of several pathways and events. Activated src can phosphorylate the EGF-R, upregulate VEGF-R and production of VEGF, leading to enhanced tumor survival and angiogenesis. In addition, src lies at the interface between the EGF-R and the STAT3 pathway. STAT3 is a key determinant of sensitivity to EGFR-targeted therapy, and STAT3 activation is dependent on both EGFR and src. Thus, aberrant activation of src may modulate resistance to EGF-R directed therapy and combined inhibition of both targets may be additive or synergistic.
Based on these observations, we propose a prospective, two arm, phase I/II intervention study of the combination of radiation (RT), cisplatin, cetuximab and dasatinib in patients with locally advanced HNSCC of the oral cavity (OC), oropharyx (OP) and hypopharynx (HP). Extensive correlative studies will be carried out in order to explore mechanisms of activity and resistance to these combinations as well as predictors of response, outcome and toxicity. These correlates include: immunohistochemical assessment of EGF-R pathway component phosphorylation in sequential biopsies; establishment of primary tumor heterotransplants; measurement of circulating endothelial cells and determination of tumor blood flow by -O H2O-PET.
This project will take advantage of a unique opportunity to develop targeted therapy for thyroid cancer. We and others have found that the ras/raf/MEK signal transduction pathway is activated by specific genetic events in almost all cases of papillary thyroid cancer, and we have recently shown that thyroid cancer cell lines are remarkably sensitive to MEK inhibition. In addition, MEK inhibition leads to upregulation of a group of thyroid-specific genes necessary for iodine uptake. In this project, we will pursue these findings to develop and translate optimal strategies for use of MEK inhibitors, alone and in combination, for therapy of thyroid cancer.
Sensitivity of thyroid cancer cell lines to AZD6244, a novel MEK inhibitor, will be evaluated both in cell culture and in xenografts, and correlated with BRAF and other mutation status. The potential role of the PI3K pathway as an escape pathway from MEK inhibition will be evaluated. Potential molecular markers for efficacy of the drug will be developed.
To develop combination therapy approaches, signal transduction pathways that are activated in thyroid cancer cells will be evaluated as potential therapeutic targets. Initially, we will concentrate on the PI3K signal transduction pathway, since it has been shown to be activated in most cases of thyroid cancer; additional promising pathways will also be evaluated. A potential mutation, conferring resistance to AZD6244 in a thyroid cancer cell line, will be explored. Such a mutation could indicate inherent resistance to AZD6244, or could be a potential mechanism for development of resistance during AZD6244 treatment.
The ability of MEK inhibition, alone and in combination, to induce biologically relevant reactivation of iodine uptake will be assessed in cell culture and in xenograft models. These studies should provide important molecular information on the effects of this novel MEK inhibitor on differentiation in thyroid tumor cells, and will form the basis for future clinical trials of these drugs on thyroid cancer patients.
Relevance: There are approximately 26,000 new cases of thyroid cancer per year in the United States, a 3-fold increase in the past three decades. In approximately 10% of these cases there is recurrent disease that is refractory to radioiodine and other therapy, with substantial mortality. Our studies to develop targeted therapy for thyroid cancer, will address this unmet medical need.
The Cores support the research programs (Core #1 - Pathology/Tissue Core, Core #2 - Administrative/CLinical Core, Core #3 - Biostatistics and Bioinformatics Core.
This Core resource will provide comprehensive biostatistics and bioinformatics consultation and collaboration to all projects in the proposed Johns Hopkins Head and Neck SPORE. In addition, it will provide support for data storage, informatics, and computing, and assist with the identification and solution of complex data tasks arising in the course of project activities. Core members will work with project investigators across a wide spectrum of activities, encompassing data acquisition (including study design, feasibility of objectives, availability of public-access genomic information, and data storage), statistical quality control (including artifact detection and preprocessing of data from genomic technologies), data analysis (including visualization, biostatistical modeling, and assistance with manuscript writing), and development of innovative customized biostatistics and bioinformatics methodologies and tools if required by specific projects. The proposed Head an d Neck SPORE Biostatistics Core will be housed in the Division of Clinical Trials and Biometry of the Department of Oncology, an active and committed group of biostatistics and bioinformatics faculty members, with access to state-of-the art equipment and a broad range of expertise. This Core resource is the continuation of an existing resource within the original and current Head and Neck SPORE program at Johns Hopkins. Core members have a strong commitment to this SPORE, stemming from: a) a history of collaboration with the investigators of this as well as other SPORE projects, b) an active and independently funded agenda of synergistic projects, and c) a demonstrated interest and understanding of both the biological and analytical questions and challenges. All proposed projects are anticipated to make use of this resource.
Over the past decade, knowledge about the pathogenesis of human tumors has been attributed to and limited by the availability of well-characterized human tissues and fluids. With this in mind, tissue/biologic fluid facilities have emerged as a means of overseeing specimen collection, storage, processing and distribution for investigative studies. The purpose of the Specimen Resource is to provide human tissues, biologic fluids and expert pathologic interpretation to SPORE investigators; and to maintain a large and diverse specimen bank for future studies.
The Specimen Resource will collect tissues/biologic fluids in a manner that meets the needs of the individual investigators without compromising clinical patient care; store these samples in such a way as to ensure long-term security and easy accessibility; process samples so that they are suitable for further analysis; and distribute samples to investigators in a timely fashion.
To maximize translational impact of the projects, specimens are collected and processed under the supervision of pathologists in close collaboration with a multidisciplinary team of clinical specialists and basic research investigators with a common expertise in neoplasia of the upper respiratory tract. A concerted effort to collect and bank tissue specimens and biologic fluids from the upper respiratory tract has been an ongoing effort since 1990.
These materials have been collected with appropriate IRB approval and patient consent. The specimens are primarily obtained from patients with head and neck squamous cell carcinoma or from patients at risk of developing this tumor. The fresh frozen specimen bank currently houses 26,092 specimens from 5,147 patients including 3,381 carcinomas, 4,838 phenotypically normal tissues including mucosa taken from the surgical margins of cancer resections, 4,691 oral rinses/swabs, 3,831 plasma samples, 5,352 serum samples, and 166 fine needle aspirates. These samples are cataloged in a state of the art database (i.e. HAND database) and efficiently stored for efficient retrieval. In many cases, the samples have already been processed (e.g. microdissected for enrichment of tumor DNA) and are available in the form of extracted DNA, RNA and/or protein. The Specimen Resource is staffed by pathologists with expertise in neoplasia of the upper respiratory tract, and has ready access to a laser capture microdissection facility, a tissue array facility, an immunohistochemistry facility, and an in-situ hybridization facility.
The Career Development Program (Arlene Forastiere) aids the emergence of new investigators and the Research Developmental Program (David Sidransky) provides rapid funding of innovative directions.
The Johns Hopkins Kimmel Cancer Center also has received SPORE funding for six other cancers: breast, cervical, gastrointestinal, lung, lymphoma, and prostate.