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Conquest - 2004 Research Awards

Making the Connection 2001-2008

2004 Research Awards

Date: April 20, 2010

MARYLAND QUICKLY stood out as a national model when it was among
the first states to put its tobacco money into the Cigarette Restitution Fund,
directly targeting cancer problems specific to Maryland, including high rates of
smoking-related cancers, providing cancer education, screening, and treatment
to the state’s uninsured, taking on Baltimore’s high rate of prostate cancer—the
highest in the nation, and Maryland’s excess cancer risk and deaths due to air

The main goal of the Multidisciplinary Translational Program for the Development
of Treatment Strategies for Lung Cancer is to build stronger connections between laboratory and patient-based research, according to program director CHARLES RUDIN, M.D. , P H . D. Working collaboratively with researchers and clinicians throughout the institution involved in lung cancer work, his team applied basic science knowledge about the genetic and cellular steps that lead to the initiation and progression of lung cancer to improve early detection and risk assessment.

Clinical trials already planned include a study of the drugs Bexarotene and Celecoxib
for their ability to interfere with cellular changes linked to lung cancer and a study of
the drug Eriotinib in patients with advanced non small cell lung cancer (NSCLC). ?

The cancer burden is particularly problematic for the African-American population, as
African-American men are 50 percent more likely to develop lung cancer than white
men. In addition, African Americans have higher death rates from lung and bronchial
cancers when compared to white Americans. Both cancers are smoking related. Investigators led by FRANCIS STILLMAN, E.D. D. , used community-based participatory research methods to better understand the complex factors that influence tobacco use among 18- to 24-year-old blue-collar African Americans. The study data was used to develop appropriate and culturally relevant intervention strategies for this group. This research also received CRF funding in 2007. ?

Research directed by KATHY HELZLSOUER, M.D. , M . H . S . , applied an evidence-based approach, incorporating cost-effectiveness measures, to develop a
priority list of cancer control interventions and strategies for public dissemination. The
evidence-based rankings were compared with rankings of the committees contributing to
the Maryland Cancer Control Plan. Two priority rankings were developed, one for
interventions where evidence of effectiveness already exists and another for areas where research is needed. Priorities will be ranked by levels of evidence as well as public health
impact and should aid in the translation of research to community interventions. ?

Research by ANN C. KLASSEN, PH.D. , was aimed at improving patterns of cancerrelated outcomes among the State’s disadvantaged populations, including African
Americans, elderly, new immigrant groups, and residents of low-resource communities.
This work contributed to theory and methods for social sciences and cancer control
and answered specific questions of regional and community significance, such as the
assessment of local cancer control needs and the evaluation of local service programs.

ELLEN K. SILBERGELD, PH.D. tested the hypothesis that environmental arsenic
exposures from poultry production contributes to the increased rates of smokingrelated
and other cancers among people living on the Eastern and Western Shores of Maryland. Arsenic is a known human carcinogen, and increased risks of skin, bladder
and lung cancers have been associated with contaminated drinking water exposure. Low
levels of arsenic exposure increase the carcinogenic effects of UV rays and chemicals in
cigarette smoke by inhibiting DNA repair. Silbergeld and team defined and mapped
environmental sources of arsenic exposure, examined pathways of exposure—particularly
contamination of drinking water—and studied the use of biomarkers to evaluate arsenic exposure and susceptibility.

Proteomics is the newest frontier in cancer research, delving deeper into the genetic
alterations associated with cancer to understand the signaling proteins expressed by
these genes and how they can be exploited to improve prevention and treatment. Recent
data established an association between inflammation and the progression of cancer.
Several clinical trials are now under way to explore whether decreasing inflammation can
suppress the advancement of several types of cancers. One particular protein, Nrf2, was
found in mice models to reduce inflammation of the lungs in response to cigarette smoke,
allergens, and other inflammatory agents. Using proteomics, researchers led by SHYAM
BISWAL, PH.D. , worked to identify target proteins of the Nrf2 gene to use as potential
biomarkers in cancer prevention drug trials.

Exposure to drinking water carcinogens and organic contaminants, such as agricultural
pesticides and synthetic endocrine disruptors, remain an important unsolved public health
problem in Maryland. In research directed by ROLF U. HALDEN, PH.D. , P. E . , investigators looked at the potential of drinking water as a source of exposure to carcinogens and, as a result, high rates of cancer incidence and death in our region. The project sorted out the types and concentrations of cancer-causing agents in chlorinated drinking water supplied by public works as well as local residential drinking water wells. It has been well established that some by-products of chlorination are carcinogenic, and sampling from these two sources of drinking water allowed isolated studies of the effect of
chlorination as well as the identification of other carcinogens. The study used cuttingedge
microarray technology to uncover changes in gene expression patterns in newborns
due to water contamination.

VICTOR VELCULESCU, M.D., PH.D. , and team took a closer look at chromosomes 8 and 15. Loss of chromosome 8p is considered particularly important in colon cancer, as it appears to be a marker of invasive disease and poor prognosis. Chromosome 15q is thought to harbor a tumor suppressor gene that is inac-tivated in colon cancer and may be a factor in both hereditary forms and the early stage of sporadic cases of colon cancer.

Investigators performed the first comprehensive study of somatic mitochondrial mutations in a series of gastrointestinal tract cancers—esophageal, pancreatic and colon cancers—related to tobacco exposure. ANIRBAN MAITRA, M.B.B. S . , and team will use this assay as a tool for early detection of smoking-related colon cancers. The research will help pinpoint the most frequently occurring mutations for each tumor type and correlate mutations to ethnicity in order to identify biomarkers for early detection among the
general population and minority groups.

The repair of double strand breaks in DNA is central to maintaining the integrity of genes. This repair mechanism may be affected by a biochemical process known as Non-Homologous End-Joining (NHEJ). Research by LES HANAKAHI, PH.D. , revealed a
new understanding of NHEJ at the molecular level. Deciphering how it works, and
more importantly, how it sometimes fails, may provide new clues about the development
of tumors. Investigators hope to identify drugs that decrease NHEJ efficiency and affect gene integrity in cancer cells. The use of these drugs could increase the effectiveness of radiation therapy by making cancer cells unable to repair damage after treatment.

The identification of a familial pancreatic cancer gene would be a major advance in understanding pancreatic cancer. A novel approach called GINI (gene identification
through nonsense-mediated decay inhibition) was used to identify gene abnormalities
linked to prostate cancer and JIM ESHLEMAN, M.D. , P H . D. , and team believe it also could help identify genes whose altered expression patterns are potential culprits in pancreatic cancer.

This study brought investigators from a wide range of disciplines together to conduct
research on hormones related to prostate cancer. The project, led by ELIZABETH PLATZ, SC.D. , M . P. H . , provided needed information on the role of sex steroid hormones in the origination of prostate cancer and other important diseases of aging men. Hormonal differences, at different ages, are suspected to account for race and ethnic differences in the occurrence of prostate cancer.

STEVEN PIANTADOSI, PH.D. , and team focused on cultural and other factors that may cause treatment delays or block access to care. A collaborative study that used various data sources provided a detailed view of the Kimmel Cancer Center patient population and revealed why and how patients make choices about where they go for cancer care.

To address environmental health issues, more and more investigators are turning to molecular technologies. SHYAM BISWAL’s DNA microarray core facility allows investigators to uncover the function of genes and their interaction in genetic pathways, among other analyses. The new facility has already been useful in helping uncover novel targets for drug interventions, including Nrf2, which has had a major impact on stress pathways research in cancer. These technologies also have been used to explore gene expression alterations resulting from human fetal exposure to drinking-water carcinogens.
Biswal has used core technology to pinpoint genetic susceptibility factors for chronic obstructive pulmonary disease, a risk factor for lung cancer.

ELLEN SILBERGELD, PH.D. brought attention to urban fishing, an underrecognized
environmental risk. Urban waterways are often jeopardized by sewer overflows, garbage dumping, domestic animal waste, storm water runoff, lawn chemicals, disposition of air pollutants, and leaks from an aging sanitary infrastructure. Silbergeld finds that the contamination goes beyond chemical to microbiological and that consumption of fish from these waterways is not the only risk. Normal hand-to-mouth activities in fishing, such as eating, smoking, baiting hooks and taking fish off of hooks, transfer pathogens, including viruses, microparasites and pathogenic bacteria as well.

The scientific foundation of cancer prevention is continually being shaped by new technologies. Among these new technologies is the study of cancer-related proteins found in human plasma, and a new plasma proteomics core facility was constructed to provide a powerful way to explore the influence of environmental agents on the human body. The facility has electropheresis, scanning, and analysis equipment interfacing with existing technologies and imaging for protein discovery and understanding. The result, say researchers JOHN GROOPMAN, PH.D. , and JAMES D. YAGER, PH.D. , will
be new insights into the contribution of environmental chemicals—particles, metals and dietary carcinogens—to the formation of cancer so that we can develop more rational approaches in prevention.

Epidemiological evidence suggests that fruits and vegetables reduce the risk of getting cancer and other chronic diseases. Unfortunately, current data also show that only about 39 percent of Americans think they should eat at least five servings daily, and the numbers are even lower among African-Americans and low-income populations. CRF investigator ANN KLASSEN, PH.D. , has begun an educational program to encourage better eating
habits among African-American women living in public housing in urban areas.

While more than 80 percent of chronic obstructive pulmonary disease (COPD) and lung cancer patients are smokers, only 15-20 percent of smokers get COPD and only 10-15 percent of smokers get lung cancer. SHYAM BISWAL, PH.D. , sought to find out why to uncover the body’s own defense mechanisms against environmental triggers and identify those genetically predisposed to smoking- related diseases, such as lung cancer.
Because the genetic factors that contribute to susceptibility are largely unknown, he continues to sift through candidate genes. His breakthrough study in 2002 showed that activation of a master gene, Nrf2, can turn on antioxidant genes. Using this paradigm for investigating cigarette smoke effects on lungs and genes, Biswal’s research focused on
enumerating the genes controlled by Nrf2 and their role in causing disease.

Next, he conducted a whole-genome assessment for multigenetic influences of Nrf2, in search of ways to fight drug resistance and oxidative cell damage, and to mitigate damage caused by cigarette smoke and other environmental factors.
With limited funding, it is critical to spend wisely, choosing prevention and detection strategies shown to be effective and supporting research for those strategies with promise. To help inform decision- makers, a team of investigators led by KATHY HELZLSOUER, M.D. , documented an evidence-based approach to evaluate the data supporting the recommended strategies outlined in the Maryland Cancer Control Plan. The project consisted of engaging technical experts, performing a comprehensive literature
search, reviewing the content and quality of the literature, synthesizing the evidence, and organizing strategies into categories. Her study revealed there are strategies with good evidence of effectiveness, such as breast feeding to reduce breast cancer mortality. Implementation of these strategies should reduce the cancer burden in Maryland.

Hormonal therapy has been quite effective in treating women with hormone-responsive breast cancers. The drug tamoxifen, the standard choice for hormonal therapy, has helped decrease recurrence rates and the spread of breast cancers. Unfortunately, in many women, after a period of time, cancer cells become resistant to the drug, and it no
longer works. With combined funding from the CRF, Avon Foundation, and Flight Attendant Medical Research Institute, breast cancer researcher BEN PARK, M.D. , is purchasing chemical drug libraries to screen for compounds that specifically kill or inhibit the growth of tamoxifen-resistant cancer cell lines without interfering with cells responsive to tamoxifen. Adding such a drug to therapy could potentially be a major breakthrough in treating hormonally-resistant breast cancers.

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