ISSUE
               
Research in Focus
Dr. Brian Schmidt Outlines His Vision for the Bluestone Center for Clinical Research


From left: Dr. Yi Ye, Postdoctoral Research Fellow; Dr. Jenny Zhang, Research Associate; Dr. John Dolan; and Dr. Brian Schmidt. (Photos by Jon Roemer)




Molecular research portion of Dr. Schmidt's lab.




Dr. Ye and Dr. Schmidt in the electrophysiology lab.




The "think tank".




Another view of the molecular lab.




Computer stastions for data analysis.




Dr. Brian L. Schmidt, an oral and maxillofacial surgeon specializing in oral cancer, genomics, and pain, has joined NYUCD as Director of the Bluestone Center for Clinical Research and Professor of Oral & Maxillofacial Surgery.

Dr. Schmidt, DDS, MD, PhD, brings a medical emphasis to the Bluestone Center-a facility located in the NYU College of Dentistry that is dedicated to the development, implementation, and analysis of clinical research. He is the recipient of over $7 million in federal, industry, and private foundation funding to date, including a gift of $3.5 million from an anonymous donor to advance his research at NYUCD.

Dr. Schmidt comes to NYUCD from the University of California, San Francisco (UCSF), where he treated thousands of patients suffering with diseases of the head and neck. Dr. Schmidt's training in surgical oncology was put to use daily with surgical management of oral cancer patients in Northern California. At UCSF he directed the Oral and Maxillofacial Oncology Fellowship and the Oral and Maxillofacial Surgery Residency Training Program. He was also the Vice Chair of the Department of Oral and Maxillofacial Surgery.

Recently, Global Health Nexus spoke to Dr. Schmidt about his vision for the Bluestone Center.

Global Health Nexus (GHN): What attracted you to NYUCD?

Dr. Schmidt: At UCSF, my central focus involved diagnosis and treatment of head and neck cancer. I was also intimately involved with the education of students and with my own basic science laboratory. Although my basic science research offered some intriguing insights into cancer progression and the mechanisms of cancer pain, clinical testing facilities and staff were in short supply. Accordingly, I was not able to parlay our basic science findings into better treatment or better palliative care for my patients. This was a frustrating situation because so many of my patients were suffering from excruciating pain from cancer or secondary to painful and debilitating cancer treatments.

Prior to visiting NYUCD, I focused on two separate streams of effort. On the one hand, I ran a clinical practice and on the other, I ran a basic science laboratory. In the laboratory I studied those aspects of cancer that most affected the quality of life of my patients, but I was resigned to the fact that the two streams of effort remained perpetually divided since I was unable to conduct the clinical trials necessary to bring our findings to the patients who needed them. Trials in patients undertaken for evaluating our laboratory findings would occur only if others saw merit in our work and chose to take our findings to patients in a setting that allowed for the scientific scrutiny of a clinical trial. On my first visit to the Bluestone Center, the largest center of its kind in any dental school in the world, it was immediately evident to me that I could conduct substantive clinical research with knowledge gleaned from my laboratory experiences. The promise of this facility, above all else, inspired me and inspires many of my colleagues who seek solutions to the morass of difficult clinical problems experienced by patients.

After several interviews, I recognized that there were other investigators at NYU who had research interests similar to mine. These researchers often use our clinical failures and inadequacies to form and refine the focus of their inquiry as basic scientists. For example, I observed investigators within the NYU Cancer Institute, the NYU College of Nursing, and NYUCD who were genuinely interested in studying and treating the symptoms that cancer patients face throughout progression and treatment of their disease. I could sense that NYUCD has achieved a good deal of momentum in this respect and I wanted to be a part of that.

GHN: What are your goals as Director of the Bluestone Center?

Dr. Schmidt: I would like the Bluestone Center to increase activity in the area of cancer research. Of course, the Bluestone's location in the dental school provides an ideal venue for investigating oral cancer and oral symptoms related to treating all types of cancer. Cancer treatment and the way we study cancer is changing. Due to the confluence of several unique features of oral cancer, this disease can be employed as a productive model for the study of other cancers and the pain they produce. Oral cancer, unlike most other cancers, occurs in a readily accessible area of the body. Accessibility is particularly important for my investigations of cancer pain. Oral cancer, then, is a logical place to start when seeking clues about the development of cancer pain as well as studies elucidating more general aspects of cancer progression. Skin cancer is rarely painful at the primary site. For this reason, skin cancer is rarely used in pain studies.

Let me explain. When scientists want to characterize or quantify molecules associated with lung, breast, prostate, and other major cancers, they must cut out the cancer and analyze it in a laboratory. These approaches are limited because once the cancer has been excised, the blood flow to the tumor is terminated. When this occurs, the cancer no longer produces or induces the same mediators that it does while in the body. The oral cavity, by contrast, is very accessible, making it the only site in the body, other than the skin, where a molecular study of cancer and cancer pain mechanisms can be conducted while the cancer remains in-situ. Since pain is the most common symptom associated with oral cancer, this disease can be exploited as a model in the study of cancer pain.

GHN: The NIH recently awarded a joint $1.25 million grant for a cancer pain study that you are leading in collaboration with the Boston Biomedical Research Institute (see related story on p. 86). In conversations regarding that grant, you mentioned that cancer pain research is more important now than ever before. Why is that?

Dr. Schmidt: Thanks to advances with earlier cancer diagnosis and improved cancer treatment, cancer patients are living longer today. While living longer, many patients are not cured. The cancer is controlled but still present and often slowly progressing. For too many people, living with cancer then results in years of chronic pain and limited function. Many of these individuals cannot work or even get out of bed.

Outside of survival, the cancer patient's most common primary concern is pain. Studies have shown that the number one fear for cancer patients is the likelihood of a painful death. Despite this, little emphasis and few research dollars have been directed at cancer pain. Cancer pain management has not kept up with advances in cancer treatment. For oral cancer patients, approximately 50 percent will die from the cancer. Almost all of those who die of the cancer will experience debilitating pain during the process. Physicians and nurses still rely on high doses of narcotics and non-steroidal anti-inflammatory drugs. These analgesics yield limited relief and have significant side effects that degrade quality of life for those suffering from this disease. The extraordinary difficulties associated with pain management in my patients are, ironically, exacerbated by longer survival times, since many of these survivors develop a tolerance to the narcotics. Ever larger opiate doses are then required for those we are not able to cure. That's why it's more important than ever before to investigate therapies for managing cancer pain.

GHN: How does your research relate to translational work that can be applied directly to patients?

Dr. Schmidt: I have just begun a new collaboration with the Boston Biomedical Research Institute to investigate the molecular mechanisms of oral cancer pain. The findings from this study will ultimately provide a better understanding of the causes of both oral cancer pain and pain associated with other forms of cancer. This work will spur the development of more sophisticated analgesics that are capable of blocking the physiological mechanisms specific to cancer pain.

A second area of basic science research that we hope will lead to clinical trials is our work identifying the role of the protease-activated receptor 2, or "PAR2," in cancer pain. PAR2 is a G protein-coupled receptor that is involved with neurogenic inflammation. A postdoctoral fellow in my lab, Dr. David Lam, and I completed a pilot study funded by the NIH/NIDCR to demonstrate that PAR2 is involved in head and neck cancer pain. Targeting PAR2 in the cancer microenvironment may be a promising new approach to treat or even prevent chronic cancer pain. We hope to test a drug designed to block PAR2 in cancer patients at the Bluestone Center.

We are also planning two additional clinical trials, to be conducted in the Bluestone Center, using novel treatment approaches for cancer pain. We anticipate that at least one of these studies will begin next year.

GHN: What is the role of genomic markers in your study of oral cancer progression?

Dr. Schmidt: The progression of oral cancer is unpredictable. Some patients respond well to surgery while others develop recurrences and metastases that are often lethal. We still can't reliably predict the course of oral cancer. To address this deficiency, a collaborator of mine, Dr. Donna Albertson, and I are planning to conduct a clinical trial using early chromosomal changes in oral cancer patients to predict outcome. If trends in my initial findings, which were supported by a grant from the NIH/NCI, are borne out, oral cancer treatment in the future could be tailored to the individual. If genetic markers were to suggest a poor prognosis, clinicians could design an aggressive treatment plan or even an attenuated treatment plan if treatment was shown to lack efficacy in this group. Alternatively, if the prognosis were good, the treatment strategy might follow a more conservative path. We are seeking funding to take this study into human clinical trials at the Bluestone Center.

GHN: Please discuss your other areas of interest relating to quality of life for cancer patients.

Dr. Schmidt: As cancer patients live longer and receive additional drugs to keep them alive, they will experience complications related to treatment that we did not expect. We are already seeing this with certain drugs such as bisphosphonates and osteonecrosis of the jaw. I predict that in the near future, many types of cancer will become similar to HIV/AIDS; we are not able to cure the disease but we can control it with some degree of predictability. Unfortunately, the drugs used to control cancer have significant short- and long-term side effects. Understanding and minimizing side effects of treatment medications will be a critical component of maintaining a high quality of life for these patients.

Oral complications secondary to the radiation or chemotherapy used to treat many different forms of cancer are notorious for interrupting optimal treatment regimens and greatly diminishing quality of life in patients. For many reasons, research to improve this area of medicine has been neglected. I would like to foster more research on the oral complications of cancer and cancer treatment at the Bluestone Center. Mucositis, oral pain, and xerostomia are very common during and after chemotherapy. Acute, severe pain from chemotherapy-induced oral mucositis is a clinically and economically significant public health problem. Oral mucositis is commonly observed during chemotherapy for all types of cancer and bone marrow transplants. These oral complications are not rare. For patients who undergo hematopoietic stem cell transplantation, the incidence approaches 50 percent. In head and neck cancer patients receiving combined chemotherapy and radiation therapy, the incidence approaches 100 percent. Aside from causing severe suffering, mucositis often causes early termination or lengthened treatment time to allow the ulcers to heal. For patients with solid tumors who receive myelosuppressive chemotherapy, the oncologist must reduce the dose and hospitalize the patient twice as often in individuals who develop mucositis relative to those patients who do not develop mucositis. Dose alteration or discontinuing chemotherapy can also impact cure rate. When patients are taken off chemotherapy, the cancer can progress and become resistant. We have a very poor understanding of the cause of mucositis, mucositis pain, and xerostomia. Most importantly, we have no treatment.

We have a tremendous wealth of expertise at NYUCD in a wide range of oral diseases. I hope to establish the prevention and treatment of oral complications from chemotherapy, such as mucositis, as a priority. Dr. William Carroll, Director of the NYU Cancer Institute, has a genuine interest in supporting the study and management of symptoms related to cancer and has played a central role in drawing investigators together.

I plan to build on and facilitate successful research and clinical initiatives from numerous faculty researchers, including Drs. Pat Corby, David Hirsch, Ross Kerr, Dan Malamud, Joan Phelan, Andrew Spielman, Mark Wolff, Victoria Raveis, Hillary Broder, David Sirois, Robert Glickman, Ken Fleisher, Joseph Guttenplan, Peter Sacks, Marcela Romero Reyes, Miriam Robbins, Deepak Saxena, Donna Shelley, Karen Raphael, Michael Turner, Seiichi Yamano, and others.

There are also investigators at NYU studying cancer complications that arise outside the oral cavity. For example, Dr. Marilyn Hammer, an Assistant Professor at the NYU College of Nursing, and an expert in oncology nursing, has published a large study showing that hematopoietic cell transplant recipients have difficulty controlling their blood glucose and that glucose levels affect mortality. She and I are collaborating on a project in which we hypothesize that specific cytokines contribute to poor glucose control in cancer patients and that these same cytokines are also responsible for producing pain. Dr. Hammer has recently been awarded an NIH grant to examine strategies for controlling glucose levels in cancer patients.

GHN: What are your plans to train future clinical researchers?

Dr. Schmidt: In my view, the biggest gap in biomedical research is the lack of continuity between basic science and translational science. When I attend large scientific meetings, I see how far ahead the basic science is compared to the clinical research. Most basic scientists are not clinicians so only a few of these scientists are fully aware of the problems that patients face during the progression of disease and during treatment with toxic therapies. As a result, it is difficult to develop a sense of urgency when we look to science for solutions to the problems that we see in the clinic. This disconnect is the reason I took the job at the Bluestone Center. I wanted the opportunity to apply the findings we were making in the laboratory to patients in clinical trials. I also wanted to focus my basic science efforts on those problems that affect patients and on those clinical problems that receive little attention in most laboratories.

In the past, much emphasis and funding had been directed toward supporting integrated training programs, for example, the MD/PhD and DDS/PhD programs. These programs have not been as successful in creating career clinician scientists as many had hoped. I wish to tackle this problem from a different angle by informing young basic scientists about problems that we see in the clinic. In this way I hope that they will become interested in clinical studies early in their career. I don't think that this is just wishful thinking because ever since I started recruiting postdoctoral scholars to my laboratory, I have observed basic scientists developing a strong interest in clinically relevant research. Redirecting the focus of just a small percentage of the basic scientists to clinically oriented hypotheses could have a significant effect on clinical care in our lifetime. Moreover, attracting a small group of scientists to a problem will quite often draw in the minds and creativity of many more scientists as other interesting problems arise from the cascade of efforts that develops at a nidus of interest. The productivity of an individual's entire career may be entirely refocused as a result of early exposure and redirection toward clinically relevant investigation.

As an example, I currently have a postdoctoral researcher in my laboratory, Dr. Yi Ye, who wishes to complete the master's in Clinical Research program at NYUCD. She has a PhD in neuroscience and she is currently studying basic mechanisms of cancer pain in my laboratory. She has identified a mediator that is responsible for cancer pain in our preclinical model. She and I are currently working to develop a clinical trial to test an antagonist to the mediator that she has identified. When she completes the master's in Clinical Research program, I hope she will maintain involvement in the clinical trials that will test her discovery. Yi is a wonderful example of how we might go about recruiting, training, and mentoring researchers to address the formidable challenges that we now blindly approach in the clinic. We currently work in the absence of a scientifically supported fund of knowledge for many aspects of managing the symptoms of these dreaded diseases and the side effects of the medications used to treat them.

GHN: Looking ahead five years, where do you hope or anticipate that the Bluestone Center will be in terms of its research profile and influence?

Dr. Schmidt: To begin, Vice Dean Lou Terracio (who served as the Interim Director of the Bluestone Center), Dr. Corby (Associate Director), and all of the Bluestone staff have done an outstanding job running the center for the years prior to my arrival after the tragic loss of Jonathan Ship. As a result of their labor and diligence, the Bluestone Center boasts a reputation for integrity and efficiency in conducting clinical trials and generating reliable clinical data. That will always remain our priority.

In five years, I expect to see clinical trials with investigators from other colleges and schools within NYU. Additionally, I envision that a critical mass of investigators will use the Bluestone facilities to conduct cutting-edge dental research as well as pioneering research on symptoms, especially oral symptoms that afflict patients with cancer and other diseases.

I also hope that within that time period some of the investigators and students who have learned how to conduct clinical trials while in the Bluestone Center will have started their own research initiatives and will be directing clinical trials at other institutions.

In my own work, I want to be testing a minimum of one new drug each year for the alleviation of symptoms related to cancer. It is almost too much to hope that one of those drugs might make it all of the way to the marketplace but that is most assuredly one of the milestones that I hope to reach in my career.