2001 Researchers at Work:Hopkins Announces its First CRF Grant Awards
For as long as state-by-state statistics on the number of cancer cases have been compiled, Maryland has ranked high on the list, even climbing to number one in the nation in 1990. Baltimore City has an even worse record. The city leads the state and nation in deaths due to cancer-related air pollutants and prostate cancer. But, the news is not all bad.
Researchers throughout the state have uncovered novel ways to combat the disease. New genetic causes of cancer, promising anti-cancer drugs and vaccines, and biological screening targets may allow cancers to be prevented or detected in very early, curable stages. The first research grants under the CRF, $100,000, one-year projects, were funded in July. They provide a unique opportunity to expand upon prior discoveries with innovative approaches that can be used to address the specific needs of our own Baltimore City neighborhoods ravaged by high cancer rates.
CRF Research Grant Summaries:
Cervical Cancer
Cornelia L. Trimble, M.D.
A System Using Dimers to Identify HPV16 E7-Specific T cell Response to Improve Understanding of Cancer Risk Factors Cervical cancer has long been linked to the sexually transmitted human papillomavirus (HPV). HPV-associated cervical disease is three times the national average within Baltimore City’s minority communities. A newly established Cervical Diseases Center at Johns Hopkins and within these communities begins clinical studies of HPV-targeted interventions to stimulate immunity to HPV antigens and prevent the initiation of cervical cancer.
Lung Cancer
Anthony Alberg, Ph.D.
Estimation of the Joint Influence of Active and Passive Smoking on Cancer Incidence Using the unique Johns Hopkins resource, the 30-year-old Washington County cohort study, investigators will estimate the effects of active and passive smoking on all cancer sites. Calculation of site-specific cancer incidence will be done. The contributions of all sources of tobacco smoke will be estimated and reported.
Lung Cancer Prevention
Julie Brahmer, M.D.
Researchers are studying DNA obtained from lung sputum samples to identify tumor suppressor genes silenced by a genetic alteration known as hypermethylation. Researchers believe this alteration can be reversed with certain drugs reactivating the genes and their roles of suppressing tumor growth. Among the drugs being studied for their ability to “demethylate” suppressor genes are two natural products.
Shyam Biswal, Ph.D.
Chemoprevention and Biomarker Discovery for Cigarette Smoke-induced Lung Cancer
Construction of a cigarette smoke exposure facility for small animal exposure and validation of a mouse model for cigarette smoke-induced lung cancer by Hopkins investigators is opening new avenues for lung cancer biomarker discovery and the preclinical trials of chemopreventive agents. Proteomics, which studies the expression, function, and interactions of proteins expressed by genes, is a new tool for discovery in cancer research. Hopkins investigators are now leading the first attempt to use proteomics in this mouse model to identify protein biomarkers associated with the onset of lung cancer after exposure to cigarette smoke. The scientists are seeking to identify proteins that will help in diagnostics, intervention, and risk assessment of cigarette smoke-associated lung cancer. Several chemopreventive agents will be evaluated.
Breast Cancer
Yin Yao, M.D., Ph.D.
BRCA2 Mutations: Relating Genetic and Epidemiological Studies of Common Cancers
While the BRCA1 and BRCA2 mutations provided key insights into the molecular genetic causes of breast cancer, they may be just one piece in a much larger puzzle. In epidemiological studies, 67 percent of families with four or five cases of early onset breast cancer could not be linked to these genes. Hopkins scientists believe other genes work with BRCA2 to increase breast cancer risk and to control the age of onset and are studying the BRCA2 pathway to identify other genetic culprits in breast cancer.
Kathy Helzlsouer, M.D., M.H.S.
Ductal Lavage as an Adjunct to Mammography
The ability of mammography to detect early breast cancer is reduced in younger women and women with dense breast tissue. Ductal lavage is a technique used to flush cells from the lining of breast cancer ducts, where breast cancer begins. The cells can then be examined to determine if cancerous cells are present, similar to a pap test for cervical cancer. It is not known yet how well this technique can pick up early cancers and if it is better than existing screening methods. It could be a powerful addition to available screening techniques, to improve early breast cancer detection rates, particularly among women at high risk for developing breast cancer. This study will take the first steps to determine the sensitivity and specificity of ductal lavage.
Oral Cancer
Joseph Califano, M.D.
Molecular Screening in a Population at Risk of Head and Neck Cancer
Hopkins scientists are analyzing DNA of cells obtained from oral rinses and blood from 900 participants, including Caucasian, African American and Latino volunteers at high risk for head and neck cancer, to look for early genetic events in the development of squamous cell cancers of the head and neck. The participants also receive a free head and neck examination to screen for cancer. This disease can best be treated when caught in an early stage, but some of these cancers (those that occur at the base of the tongue, in the tonsils and larynx) are often difficult to detect through conventional methods. Molecular analysis, to look for subtle genetic changes in cells shed in saliva and blood, could lead to new prevention, diagnostic and treatment methods.
Maura Gillison, M.D., Ph.D.
Human Papillomavirus and Risk of Oropharyngeal Cancer:
A Case Control Study
Tobacco and alcohol use are known to contribute to the development of oral cancers. Hopkins scientists hypothesize that the sexually transmitted human papillomavirus may augment these risks. Prior studies suggest that HPV-positive head and neck cancers may comprise a distinct molecular, clinical, and pathologic disease very different from other types of the disease. They are further exploring the role of HPV in the initiation of certain oral cancers in the presence of the more traditional risk factors.
Colon Cancer
Victor E. Velculescu, M.D., Ph.D.
Mutational Analysis of Colorectal Cancer Genome
Though scientists have revealed cancer as a genetic disease caused by alterations in specific genes, many of these genes have yet to be identified. This is particularly true of colon cancer, where Hopkins researchers were among the first to identify a series of genetic mutations associated with this disease. They continue this work with a genomewide analysis of colon and rectal cancer to identify the compendium of genetic changes in colon cancer, including those that may be prevalent among certain minority groups, revealing novel approaches to screening and diagnosis.
Maria Cruz-Correa, M.D.
Epidemiology of Loss of Imprinting in Colorectal Cancer in Maryland
The loss of imprinting of the IGF2 gene may be a genetic alteration common to colon cancer that could serve as a potential biomarker for the disease. In a unique combined cancer genetics and epidemiological approach, researchers are using tissue obtained in screening colonoscopies to characterize the role of loss of imprinting of the IGF2 gene in colorectal cancer in Marylanders.
Prostate Cancer
Bruce J. Trock, Ph.D.
Impact of Environmental Cadmium Exposure on Prostate Cancer Risk in the Baltimore Metro Area
Cadmium is one of the few environmental exposures linked to prostate cancer. Hopkins scientists believe that this metal may generate damaging free radicals and displace beneficial zinc in prostate cells, potentially contributing to the development of cancer. They are testing this hypothesis in studies of cadmium, zinc, and selenium levels in prostate tissue samples from men known to work or reside in high cadmium exposure areas.
Multiple Cancers
Elizabeth Platz, Ph.D.
Jim Zabora, Sc.D.
Kathleen M. Conlan, M.S.
The Laborers International Union of North American (LIUNA) Prospective Cohort Study on Cancer
While the causes of many cancers remain unclear, there are certain behaviors, including cigarette smoking, certain diets, environmental exposures, and alcohol use, that are known to increase cancer risk. Hopkins investigators are working with a 800,000-member, racially diverse and economically modest labor union to identify modifiable behaviors and environmental factors linked to breast, lung, prostate, and colon cancers. The first step in assembling the cohort is to identify a method of data collection that will yield the greatest and most reliable responses from the union members in Maryland. The racial diversity of the group in the Maryland locals may help uncover racial variations in cancer rates and lead to new interventions that could reduce statewide cancer risk.
Saeed R. Khan, Ph.D.
Novel Drug Development for Solid Tumors
Hopkins scientists are working in the laboratory to synthesize bioactive molecules and create new anti-cancer drugs to treat prostate, breast and colon cancers. These new compounds are being designed to be selectively toxic to cancer cells, particularly at metastatic sites now resistant to standard therapies, while sparing normal cells from damage. The project will provide critical capacity for small molecule drug development at our institution.
Hee-Soon Juon, Ph.D.
Cancer Educational Program for Korean American Women: Pilot Study.
Cancer is a leading cause of death among Korean women age 24 to 64. Breast and cervical cancers are among the most commonly diagnosed cancers in Korean American women. These women have low usage of mammography and pap tests because they lack knowledge of screening and have limited access to these cancer-screening methods. Hopkins clinician-scientists are working with local Korean churches to develop culturally sensitive materials to educate women and enroll them in screening programs in an effort to impact cancer death rates.
2002 Researchers at Work
Promise:
Breast Cancer
Kala Visvanathan, M.H.S., M.D.
Association Between Growth Factor Levels, Ornithine Decarboxylase Expression and the Risk of Proliferative and Noninvasive Breast Disease
Women with proliferative benign breast disease have an increased risk of breast cancer. In order to implement effective preventive strategies, it is necessary to identify which women will go on to develop breast cancer and to distinguish between those cancers that will be non-invasive and manageable and those that will become invasive and difficult to treat. The goal of this study is to find biomarkers that would make it possible to select out women with proliferative or non- invasive cancer who are at risk of developing invasive breast cancer. These markers would be used in the clinic as targets for chemopreventive agents.
Leisha A. Emens, M.D., Ph.D.
Timed Sequential Therapy with Cyclophosphamide, Doxorubicin, and a Breast Cancer Vaccine
This investigation focuses on an immune-system boosting vaccine used in combination with timed sequential doses of chemotherapy. Advanced breast cancer is often attributed to the failure of post-surgical therapies to destroy all remaining cancer cells. These resistant cells ultimately result in metastatic disease with very poor cure rates. Activating the immune system with anti- tumor vaccines represents a promising approach to overcoming drug resistance and driving the immune system to eradicate resistant tumor cells. The researchers believe integrating the vaccine approach with traditional chemotherapy and/or radiation therapy can work in synergy to destroy tumor cells.
Cancer Detection and Prevention
Ingo Ruczinski, M.D., Ph.D.
Analysis of SNP Microarray Data Using Logic Regression
Investigating the relationship between subtle DNA changes, known as polymorphisms, and cancer could help identify new biomarkers for early detection as well as potential targets for drug therapy. The investigators have developed a sophisticated computerized technology for analyzing data to uncover such relationships and, in addition, reveal genetic cancer-related differences that may exist between races, helping to uncover the cause of high cancer rates among certain minority groups.
Head and Neck Cancer
Maura Gillison, M.D., Ph.D.
Head and Neck Cancer Resource: A Joint Resource for Head and Neck Cancer Research at the University of Maryland and Johns Hopkins Medical Institutions
Head and neck cancers, and particularly oral cancers, are among the most devastating cancers affecting Marylanders. Significant basic and clinical research has been conducted independently at Johns Hopkins and the University of Maryland and could be accelerated with joint research endeavors. Collaborations already under way include studies of molecular genetic detection of head and neck cancer in saliva and tissue, the association between the human papilloma virus (HPV) and head and neck cancer and genetic culprits in oral cancers. Additional proposed projects include studies in rarer populations affected by head and neck cancers, such as non-smokers and non-drinkers, that would essentially be impossible to complete without collaboration between institutions. The ability to double the number of patients studied and share resources, such as tissue samples, data, and biostatistical information, is expected to lead to more rapid discoveries and advances in the treatment of head and neck cancers.
Prostate Cancer
Michael A. Carducci, M.D.
Drug Development Strategies for Solid Tumor Malignancies
Cellular biology advances have revealed an expanding number of genetic abnormalities unique to cancer cells and believed to be involved in the development, growth, and spread of tumors. Researchers are now studying several drugs, known as target compounds, that specifically home in on these abnormalities, and rather than destroy tumors, appear to halt their growth and prevent them from spreading and invading healthy tissue and organs. Investigators will begin studies of these targeted compounds in animal and tumor models using sophisticated imaging technology to monitor drug delivery to tumors and changes in tumor size. Clinical trials for prostate cancer are proposed in collaboration with Howard University and the community centers participating in the CRF Baltimore City Cancer Plan.
Charles G. Drake, M.D., Ph.D.
Immunological Intervention for Prostate Cancer
African American men who develop prostate cancer are generally younger than their white counterparts, have more extensive disease, and a higher incidence of related bone pain. In addition, mortality rates among African Americans are three times greater than those of white men. These observations, coupled with the incurable nature of the disease, underscore the need for novel therapies to reduce the incidence and death rates from prostate cancer, particularly among African American men. This study uses new therapies that manipulate the immune system to generate a response against evolving prostate tumors as well as a combined vaccine/chemotherapy approach in hopes of identifying new, curable therapies for an often unresponsive tumor.
Smoking Cessation
Miyong T. Kim, R.N., Ph.D.
Developing and Testing a Multilevel Community-Based Smoking Cessation Intervention Program for Korean American Community in Maryland
While much progress has been made among Americans overall in smoking cessation, Korean Americans, particularly men, continue to have high rates of smoking and smoking-related diseases, including lung cancer. Language and cultural barriers often impede the usefulness of established anti-smoking programs among this group. Working with the Korean Resource Center, the study team will utilize Korean health care providers, churches, social clubs, and news media to develop and implement a culturally sensitive smoking cessation program to decrease smoking rates and smoking-related cancer occurrence and death in this population.
Solid Tumors
Saeed R. Khan, Ph.D.
Novel Drug Development for Solid Tumors
This research involves the development of new agents to target metastatic prostate, colon, and breast cancers. Among those already in development is a prostate specific antigen (PSA)-based pro-drug therapy that involves the administration of inactive drugs that become turned on and activated against cells with increased PSA activity. Similar agents also are in development for colon and breast cancers.
Progress:
Lung Cancer
Shyam Biswal, Ph.D.
Chemoprevention and Biomarker Discovery for Cigarette Smoke-induced Lung Cancer
Construction of a cigarette smoke exposure facility was funded under a previous CRF grant and is now being used in animal trials to measure cancer-causing particles, including carbon dioxide, nicotine, and acrolein. These animal models are revealing new information about smoking-related carcinogens and the cellular changes that ultimately result in lung cancer. This work has been published in two scientific journals and was reported at the Society of Toxicology annual meeting in March 2002. The investigators are now expanding their research to identify and test chemopreventive agents that could block the negative impact of cigarette smoke on cells, or specific cellular changes that could serve as biomarkers for the early detection of lung cancer.
2003 Researchers at Work
The tobacco Master Settlement Agreement, and resulting Cigarette Restitution Fund (CRF), have not been without controversy. Cigarette Manufacturers are crying “foul” and threatening to withhold payments. More and more states are caving to economic pressures and using tobacco settlement funds to fill shortfalls in their budgets rather than tackle the health effects of cigarettes on which the law suit was won.
While this tug-of-war continues to make headlines, Maryland is set apart; serving as a national model for its dedication of restitution funds to impact cancer rates in the State. The one-time, $53 billion awarded to states may seem like a lot of money, but in comparison, cancer costs the nation an estimated $107 billion annually and brings a single manufacturer revenues of over $8.5 billion* a year. Investing in cancer discovery today will result in much greater savings to our State in the long run by reducing our cancer incidence and death rates that rank among the highest in the nation.
Through collaborative projects and community partnerships, Johns Hopkins scientists and clinicians have used CRF grants effectively and efficiently, enabling them to better identify carcinogens in the Maryland environment, understand why certain Maryland communities suffer disproportionately high cancer rates, solve some of the remaining mysteries about how cancer cells originate, grow and spread, access and advance key technologies in cancer discovery, develop new methods of screening and detection, and introduce new therapies. Following are the most recent advances made by CRF recipients at Johns Hopkins:
Marc Ostermeier, Ph.D.
Creation of Cancer Therapeutics and Diagnostics by Combinatorial Domain Insertions
This novel approach combines laboratory and clinical science to seek general methods for developing molecular switches with potential to control the delivery of drugs and cellular function. This includes turning genes “on” or “off” in order to prevent the development, or change the course of cancer. In addition, molecular switches, when designed as molecular sensors, can be used as diagnostics in the detection and diagnosis of cancer. Using a pioneering biomedical engineering method called domain insertion to create a large library of hybrid genes, investigators will develop the methodology for engineering molecular switches that have applications in drug transport, control of gene expression, and molecular sensors. The strategy can be applied to a variety of tumors, including lung, breast, colon, and prostate cancers.
Kristen H. Kjerulff, Ph.D.
Racial Disparities Among Cervical Cancer Patients
Dr. Kjerulff has directed a series of landmark studies on women’s gynecological health. In this study, she is investigating the reasons for the disproportionately high rates of advanced cervical cancer incidence and mortality among African American women in Maryland. She will follow African American and Caucasian women under active treatment for cervical cancer to identify factors, such as obesity, exercise habits, life stresses, access to care as well as differences in health perceptions and other attitudinal factors that could be associated with the progression of cervical cancer. The results of her study are expected to lead to interventional programs that address racial, ethnic, and socioeconomic disparities that may contribute to differences in stage of diagnosis, progression of disease, and death rates.
Dina L. G. Borzekowski, Ed.D.
Smoking Cessation for Youth: A Comparison of Internet-Based and School-Based Interventions
Epidemiological research shows a clear link between smoking cigarettes and cancers of the lung, mouth, pharynx, esophagus, pancreas, uterus, cervix, kidney, and bladder. While these diseases occur in adulthood, they are often the result of behaviors initiated in adolescence. More than half of Maryland 12th graders say they have experimented with cigarette smoking, while one quarter smoke regularly, approximately a half pack per day. After this experimentation and use of cigarettes, many teens (approximately 56 percent) attempt unsuccessfully to quit. Eight years later, 70 percent are still smoking. While a variety of smoking cessation programs exist, few are designed or accessible to adolescents. This project will study the benefits of three smoking cessation interventions for adolescents—one delivered through an internet web site, another through in-person school based counseling groups, and a third that combines both approaches. The investigators believe the internet, which is easily accessed and enjoyed by adolescents of all backgrounds, income levels, and geographic regions, will provide a non-threatening, confidential medium for teens and improve the success of smoking cessation among this group.
Jean Ford, M.D.
Lung Cancer Disparities Among African American Men
Lung cancer is the leading cause of cancer death in the U.S., and African American men have a higher incidence rate when compared to Caucasians. This disparity is due principally to a high incidence of lung cancer among African American men. While specific genetic alterations have been linked to the initiation and progression of lung cancer, these genetic findings have not been replicated in African American population. In addition, gene mutations, which may occur only in individuals of African descent, have not been studied. Investigators will work with African American volunteers to identify specific biomarkers indicative of lung cancer susceptibility and further study known genetic pathways that modulate and repair DNA damage caused by carcinogen exposure among this population.
Racial/Ethnic Variation in Steroid Hormone Concentration Across Age in U.S. Men
William G. Nelson, M.D., Ph.D.
Elizabeth A. Platz, Sc.D., M.P.H.
Sabine Rohrmas, Ph.D., M.P.H.
Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among U.S. males. Incidence rates in Maryland are the second highest in the U.S. with death rates above the national average. As prostate cancer is more common among African American men than Caucasian men, the investigators are working to understand the reasons for the disparity in an effort to alter the course of the disease. The researchers will be studying levels of sex hormones, including androgens and estrogen. These hormones are necessary for normal development and function of the prostate and may influence prostate cancer development. Higher levels of these hormones have been reported in young African American men aged 18-22 and 31- 35, than Caucasian men the same age, but less difference between the races at age 40-50. The investigators plan to measure hormone concentrations in African American, Caucasian and Mexican American men aged 4 to over 90 to help explain and develop interventions for age-related racial disparities in prostate cancer rates.
Racial Disparities in Patterns of Care for Breast Cancer
Genevieve M. Matanoski, M.D., DrPh, CTR
This research focuses on unique cultural factors related to delays in treatment and lack of access to care in underserved urban and rural communities. Investigators will study differences in patterns of care, the influence of other health conditions, socioeconomic status, health insurance, distance to treatment clinic, and tumor characteristics to determine if they explain racial differences in death rates.
Pilot Study: Sidney Kimmel Comprehensive Cancer Center Cancer Prevention and Control Population Resource
Elizabeth Platz, Sc.D., MPH
Aravinda Chakravarti, Ph.D.
Cancer rates in Maryland are 11 and 6 percent higher than the U.S. average for Maryland men and women respectively. Moreover, explanations for the State’s unique cancer statistics remain largely unknown. These and other SKCCC investigators will develop a Cancer Prevention and Control Population Resource by collecting information on demographics, exposures, and family history of cancer as well as obtain blood samples from SKCCC outpatients and their relatives and friends. The investigators will use this resource to identify genetic and other biomarkers of cancer and early detection and apply these findings to clinical interventions that should help reduce the excess cancer risk in Maryland. | 
