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Keystone Home » The Keystone Program in Head and Neck Cancer

The Keystone Program in Head and Neck Cancer

The Team

Depending on stage of diagnosis and location of tumor, head and neck cancers are treated surgically, or by a combination of radiation and chemotherapy. Surgery is highly successful at curing the majority of early stage tumors. For later stage tumors, that have invaded into surrounding tissues or metastasize to lymph nodes or more distant sites, radiation coupled with drugs and other systemically acting agents are the only treatment options. Although the last two decades have seen significant progress in controlling or curing advanced disease, there is a long way to go.

The research efforts of the members of the Head and Neck Cancer Keystone seek to maximize synergy in understanding and seeking to override the sources of resistance to therapy. Many of the physicians and scientists in this program work on specific proteins identified as highly relevant to head and neck cancer. Epidermal growth factor receptor (EGFR) is both an oncogenic “driver” of head and neck tumor malignancy, and an important target of many therapeutic agents used for clinical management of this disease. P53 is a tumor suppressor inactivated or lost in many head and neck tumors: studies of this protein offer insight into the likely prognosis and best treatment choices for individual patients. Through studies of these and complementary projects, this Keystone seeks to make significant advances in management of head and neck cancer.

Co-Leaders:   Research Focus:
 

Drew Ridge, MD, PhD

Dr. Ridge directs clinical research on head and neck cancer and has a strong role in translational research. His clinical practice focuses on head and neck and endocrine tumors, including nonsurgical management, organ preservation, new surgical techniques and early and advanced thyroid tumors.

Ridge is recognized nationally and internationally for his expertise in treating patients with head and neck cancer. In 2006, a grateful patient honored him by establishing and endowing the John A. Ridge Surgical Oncology Fellowship, which provides for the two-year training of a physician in the field of surgical oncology.

Ridge co-chairs the Previously Untreated Locally Advanced Head and Neck Cancer Task Force for the National Cancer Institute (NCI). He has been a member of numerous federal advisory groups, including NCI grant review panels, panels for the National Institute of Dental and Craniofacial Research (NIDCR), the National Institutes of Health/NCI review group for Specialized Program of Research Excellence (SPORE) grants and think tanks on head and neck cancer for NCI and NIDCR. Read More »

Surgical oncologist and clinical investigator: combined modality therapy, organ preservation, risk-based management
 

Erica Golemis, PhD

The Golemis group seeks to define the changes in cell signaling that occur as tumors spread by metastasis and develop resistance to drugs, with the ultimate goal of inhibiting these processes. Research in the laboratory has two major themes. One set of research projects focuses on study of the Cas protein family, a group of proteins that provides a hub assembly groups of signaling proteins essential to cancer progression. Complementary projects, performed in collaboration with Fox Chase Cancer Center physician-scientists (Drs. Igor Astsaturov and Joshua Silverman) use computer-based bioinformatic approaches and mid-throughput screening to identify genes that sensitize cells to targeted and classic cancer therapies. Read More »

Signaling networks controlling cancer development and drug response
     
Members:   Research Focus:
 

Gregory Adams, PhD

“Monoclonal antibodies” are pure, defined preparations of antibodies that can be used to block the action of individual proteins associated with cancer. Monoclonal antibodies that bind EGFR (such as Erbitux) are valuable tools in non-surgical treatment of head and neck cancers. The Adams lab is focused on understanding the role of the strength of antibody binding to EGFR on tumor targeting and therapeutic efficacy. High levels of EGFR are correlated with a poor prognosis and resistance to therapy in squamous cell carcinoma of the head and neck (SCCHN). Research from this group addresses the idea that optimizing the binding strength (“affinity” of anti-EGFR antibodies for their target protein could enhance their efficacy in the treatment of SCCHN and other cancers. Read More »

Engineering therapeutic antibodies
 

Igor Astsaturov, MD

Epidermal growth factor receptor (EGFR) plays the central role in growth and metastatic behavior of head and neck squamous cell carcinoma (HNSCC), which is a major tobacco- and alcohol-related malignancy in the US, rivaled only by lung cancer. Using therapeutic agents that target EGFR in HNSCC improves the survival and cure rates for some patients. Unfortunately, a significant number of patients have tumors with frontline (pre-treatment) or acquired (post-treatment) resistance that limits the clinical efficacy of anti-EGFR therapy. The Astsaturov’s lab interests are focused on development of new treatment strategies utilizing systematic screening approach to find new signaling proteins that can be blocked simultaneously with EGFR, thuus resulting in much potency of EGFR-targeted and other therapies. One set of projects investigates the role of DUSP (dual specificity phosphatase) proteins in increasing tumor killing induced by EGFR-targeting therapeutics. A second research effort investigates a set of proteins that act together to modify fats to produce cholesterol, which Dr. Astsaturov has established influence the susceptibility of head and neck cancer cells to drugs that target EGFR. Read More »

Enhancing EGFR-targeting drugs
 

Hossein Borghaei, DO

Monoclonal antibodies (pure, defined preparations of antibodies that can be used to block the action of individual proteins) play a major role in the treatment of patients with various malignancies, including cancers of the lung, head and neck. The exact mechanisms of action of these agents remain largely unknown. Although reducing pro-cancerous tumor signaling is thought to be the primary mechanism of action of the EGFR-targeting monoclonal antibody cetuximab (Erbitux), antibody-dependent cellular cytotoxicity (ADCC), in which the antibody encourages the immune system to attack the tumor, also plays a role. The Borghaei group explores immunological responses arising as a result of cetuximab therapy-associated ADCC, with the goal of augmenting these responses to achieve longer lasting effect of therapy. We are also interested in the interaction of various signaling pathways and potential role of inhibiting multiple growth and proliferation pathways in lung cancer cell lines with the intention of developing rational clinical trials with multiple molecularly targeted agents. Read More »

Clinical trial design; immune system interactions with drugs
 

Margie Clapper, PhD

Hormones such as estrogen can have powerful effects on the development and aggressiveness of tumors. As part of the Head and Neck Keystone, Dr. Clapper's lab is examining the contribution of hormones to head and neck cancer. Areas of specific laboratory interest include the characterization of genes that regulate the metabolism of estrogens in the human tongue during early tumor development, and the effect of polymorphisms (naturally occurring genetic variants) in these genes on an individual’s overall risk for head and neck cancer. The laboratory is also examining the potential impact of hormonal replacement therapies on the growth of head and neck tumors, in experiments using human tongue carcinoma cells grown to produce tumors (“xenografts”) in mice. Read More »

Hormonal effects on tumor growth
 

Roland Dunbrack, PhD

Protein-targeted agents such as the EGFR-binding antibody Erbitux are valuable therapeutic tools in head and neck cancer, and other cancers. Development of next-generation agents with still greater efficacy involves detailed understanding of the molecular basis by which these agents bind and inactivate their targets in tumors. The Dunbrack group concentrates on research in computational structural biology, including homology modeling, fold recognition, molecular dynamics simulations, and bioinformatics. In developing these methods, the group uses methods from various areas of mathematics and computer science, including Bayesian statistics and computational geometry. In collaboration with other Keystone scientists (Robinson, Adams, Astsaturov, Golemis), the Dunbrack group makes models of cancer-relevant protein targets, enabling basic research and therapeutic development. Read More »

Modeling protein structure to design next-generation therapeutics
 

Brian Egleston, PhD

Well-run clinical studies are the foundation of improvements in cancer treatment. Often, it is difficult to separate the effects of a promising new therapeutic agent from confounding factors influencing the overall health of a patient. Dr. Egleston has developed novel statistical methodologies that account for missing data and potential confounders in the assessment of treatment effects. He is also skilled in state of the art approaches including hierarchical Bayesian, propensity score, competing risk, cost effectiveness, and latent variable methods. Dr. Egleston has collaborated with many of his colleagues in the Head and Neck Keystone (Burtness, Golemis, Clapper, Borghaei, Fang, Godwin) to maximize the potential of their basic and clinical research.

Biostatistical approaches to optimize treatment effectiveness
 

Carolyn Fang, PhD

Over the past decade, it has become clear that psychosocial, behavioral, and biological factors can interact to influence cancer incidence and outcomes. For head and neck cancers, risk factors include smoking, drinking, and sexually transmitted viruses such as human papillomavirus (HPV). The Fang group has been investigating the interrelations among HPV status, cell-mediated immunity to HPV, and psychosocial and behavioral correlates of immune response to HPV in patients with head and neck cancers. These studies are complementary to those performed in the Murphy group, which address individual variance in the HPV target protein and key tumor suppressor, p53. In other work, the Fang group is developing a web-based multimedia intervention program for head and neck patients who have recently completed treatment. The goal of this work is to develop an easy-to-access, web-based program that can facilitate adaptation to cancer and enhance quality of life among cancer survivors. Read More »

Viral influences on cancer: enhancing quality of life among cancer survivors
 

Elizabeth Hopper-Borge, PhD

A major problem in cancer therapy is resistance to chemotherapeutic agents. The Multidrug Resistance Proteins (MRPs) are a family of proteins that pump toxic chemicals out of cells. Although MRP proteins provide a useful defense mechanism against environmental toxins, abnormally increased activity of some of these proteins in cancer causes problems for effective management of tumors. The Hopper-Borge group studies one of the more recently discovered MRP subfamily members, MRP7, which is abundant in head and neck cancer cells, and confers resistance to various drugs including the taxanes (paclitaxel and docetaxel) and other drugs that are used in the treatment of head and neck cancers. Read More »

Factors leading to multiple drug resistance in cancer
 

Eileen Jaffe, PhD

Targeted cancer therapies use small molecules (drugs) and antibodies to block the function of proteins that induce cancer. EGFR is an important therapeutic target in head and neck cancers. Rather than existing as an isolated single protein with a constant shape, an EGFR protein molecule undergoes dynamic interactions with additional copies of EGFR, and interacts with additional neighbors: these larger complexes of EGFR molecules are known as "quaternary structure assemblies". EGFR exists as a equilibrium of quaternary structure assemblies; research in the Jaffe laboratory addresses the idea that it may be possible to manipulate this equilbrium for therapeutic advantage, for example by developing drugs that bind selectively to cancer-associated EGFR structures and limit their action. Read More »

EGFR structure and complex interactions
 

Andres Klein-Szanto, MD

Tumors that have invaded through surrounding tissues and metastasized to distant sites are more difficult to treat than tumors that remain confined to their initial point of origin. The Klein-Szanto group studies the proteins PACE - 4 and furin during the early and late stages of tumor progression because these enzymes activate cancer related biomolecules. Abnormally high levels of these enzymes correlates with aggressive tumor fe atures both in mouse models and in human tumors, including malignant oral tumors . Small molecule inhibitors of these proteins, such as chloro - methyl - ketone (CMK) , decreases and even abolishes the invasive/maligna nt phenotype of tumor cells in experimental models. Through studies of these and other metastasis-associated proteins, such as Vsnl-1, the Klein-Szanto group seeks to find novel means to control tumor progression. Read More »

Factors governing tumor metastasis
 

Miriam Lango, MD

Dr. Lango is a head and neck surgeon as well as an ear, nose and throat specialist. She has a special interest in tumors located in the upper aerodigestive tract, thyroid, skull base and sinonasal tract. She also specializes in swalling-related functional outcomes. Her area of treatment expertise is minimally-invasive surgery. Read More »

Head & neck surgeon, Laryngologist
 

Ranee Mehra, MD

Dr. Mehra is a medical oncologist with expertise in the treatment of head and neck cancer, lung cancer and thyroid cancer. She is a member of the Eastern Cooperative Oncology Group head and neck core committee. She is interested in developing new therapeutic regimens for cancer care, and conducts clinical trials with newer agents to treat head and neck and thoracic malignancies. Her research also focuses on studying pharmacogenomic biomarkers that can predict for resistance to therapy in head and neck cancer. Read More »

Medical oncology clinical investigator: Pharmacogenomics and predictive biomarkers
 

Jeffrey Peterson, PhD

The Peterson laboratory has extensive expertise in the development of protein-targeted small molecule inhibitors ("chemical biology"). This research team studies molecular signaling pathways whose dysregulation contributes to cancers of the head and neck. “Kinases” are proteins that modify other proteins by adding phosphate groups to specific amino acids on their surface: such modifications can completely alter that activity of the modified protein, impacting cell growth. This group is elucidating the biology of a poorly understood kinase called Activated Cdc42-associated kinase (Ack) that binds directly to EGFR, an important player in the development of head and neck cancers. The goal of the Peterson group is to validate Ack as a novel therapeutic target, and develop inhibitors of Ack that enhance the clinical management of head and neck cancer. Read More »

Genes influencing response to EGFR-targeted therapies
 

Matthew Robinson, PhD

The Robinson lab is focused on developing antibody-based therapeutics designed to exploit the abnormal cellular signaling networks that drive cancer formation and progression. Overexpression of the EGFR receptor in head and neck squamous cell carcinoma (HNSCC) is correlated with aggressive disease and poor patient outcome. Despite this correlation, therapies that target and block EGFR (e.g., the antibody cetuximab (Erbitux) and drugs such as erlotinib (Tarceva) and gefitinib (Iressa)) have modest clinical efficacy in many patients. One reason for this modest efficacy may be that EGFR is one of a small “family” of proteins which have similar tumor-promoting activities: in some treatment-resistant tumors with blocked EGFR, its relative ErbB3 may be compensating for its functions. Recent work from a number of laboratories has suggested that ErbB3 is becoming increasingly recognized as playing a role in the development of resistance to erlotinib and gefitinib in a number of cancers. The Robinson laboratory has developed a set of therapeutic antibodies that simultaneously block EGFR and ErbB3. They are testing the idea that these antibodies will be efficacious in the setting of HNSCC, and could potentially reverse acquired resistance to EGFR-targeting drugs. They are also working collaboratively with the Dunbrack and Roder groups to design further enhanced antibodies targeting the EGFR protein family. Read More »

Next-generation therapeutic antibodies
 

Heinrich Roder, PhD

Cancer is caused by changes that affect specific proteins. Many valuable targeted therapies use small molecules (drugs) and antibodies to block the activity of cancer-associated proteins. In order to understand the fundamental mechanisms by which cancer-associated mutations act, and to better design new targeted therapies, it is critical to be able to study protein folding and structure at a very high level of resolution. Research in the Roder group is aimed at understanding the principles that govern the folding of globular proteins. The group explores the early stages of protein folding by coupling advanced rapid mixing methods with structurally informative conformational probes, such as intrinsic and extrinsic fluorescence probes, and protection of individual amide hydrogens from solvent exchange monitored by NMR. The group also participates in collaborative studies involving NMR and other spectroscopic methods aimed at elucidating the structure, dynamics and macromolecular interactions of proteins of intense biomedical interest, working with the Robinson, Dunbrack, and Murphy groups to address problems relevant to cancer of the head and neck. Read More »

Protein folding
 

Ilya Serebriiskii, PhD

Dr. Serebriiskii is an expert in bioinformatics (the use of computer modeling to understand biologically and medically relevant cellular processes). Working collaboratively with Dr. Golemis, Dr. Serebriiskii has developed extensive resources to analyze the signaling of EGFR and other proteins commonly involved in head and neck cancers. Together with Dr. Astsaturov, he has spear-headed efforts to search through this “network” of cancer proteins to identify which specifically influence the response of tumors to both targeted and chemotherapy. His ultimate goal is to exploit these basic research findings to nominate more effective, “next generation” combination therapies to cure advanced head and neck cancer.

Bioinformatic analysis of oncogene networks
 

Aruna Turaka, MD

Dr. Turaka is a radiation oncologist with expertise in the treatment of lung cancer, lymphoma, and head & neck malignancies. She is a member of the "Lung Clinical Trials working group" (LCT-WG) at the division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI). During fellowship training at Fox Chase Cancer Center, she developed the database for head and neck cancer patients treated with IMRT. The results were presented at different national meetings including AHNS, AAPM, ASTRO and the Multidisciplinary Head and Neck cancer symposium. Her research interests include developing clinical trials with the collaboration of the medical, thoracic oncology teams for lung cancer, Merkel cell carcinoma and lymphoma at FCCC. Her area of expertise also includes stereotactic ablative radiation therapy for the primary and metastatic lung carcinoma, use of image fusion technologies like integrating PET/CT and MRI for treatment planning purposes while designing the radiation treatments for various pulmonary neoplasms and challenging lymphoma cases. She is also involved in various co-operative group trials including Radiation Therapy Oncology Group (RTOG), American College of Surgeons Oncology Group (ACOSOG) and American College of Radiology Imaging Network (ACRIN).

Bioinformatic analysis of oncogene networks
 

Dong-Hua Yang, MD, PhD

Dr. Yang's research includes: 1) Application of Immunohistochemistry (IHC) for both basic and clinical research, and 2) Gene regulation on embryogenesis, organogenesis, tumorigenesis and multi-drug resistance. The main focus is on the application of immunohistochemistry (IHC) and automatic quantitative analysis (AQUA) on both basic and clinical research, particularly in biomarker characterization and discovery. Specifically, including: 1) Develop IHC assay for new biomarkers 2) Automated Quantitative Analysis (AQUA) assay development and validation 3) Ovarian cancer biology and multi-drug resistance

Application of immunohistochemistry (IHC) and automatic quantitative analysis (AQUA) on both basic and clinical research
 

Jian Qin (Michael) Yu, MD, FRCPC

Yu – Dr. Yu's research interests involve PET and targeted therapy in oncology. He is involved in several imaging trials with cooperative groups, such as the Radiation Therapy Oncology Group (RTOG), Gynecologic Oncology Group (GOG) and American College of Radiology Imaging Network (ACRIN). Dr. Yu also participates in several industry-sponsored national and international studies for drug development and evaluation.

PET and targeted therapy in oncology