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Conquest - 2006 Research Awards

Making the Connection 2001-2008

2006 Research Awards

Date: April 20, 2010

Despite our great progress and a significant decline in cancer incidence and deaths in
Maryland, cancer rates remain above the U.S. average. The cause of Maryland’s higher
rates are largely unknown, so the identification of genetic and other biomarkers of risk
is believed essential to developing clinical interventions for the prevention and early
detection of cancer. The Cancer Prevention and Control Population Resource Core, opened in 2004 and directed by ELIZABETH PLATZ, SC.D. , M.P. H . , and AVARINDA CHAKRAVARTI, PH.D. , offers Johns Hopkins cancer researchers a centralized bank of blood samples and self-reported exposure data to quickly and efficiently identify biological markers of cancer risk and initiation. With continued CRF support, Core investigators and staff are now working to collect samples and information from 1,000 adults each year. Core samples are racially diverse, coming from Caucasians, African Americans, and Hispanics, and because the majority of participants are Marylanders, results of biomarker studies will directly apply to and benefit Maryland citizens. This research also received CRF funding in 2003, 2005, and 2007.

No cancer illustrates the need for early detection better than pancreatic cancer. Because it is almost always fatal, diagnosing the cancer early is essentially the only hope for cure. Smoking and family history are urrently the only known risk factors for the disease, but ALISON P. KLEIN, M.D. , director of the National Familial Pancreas Tumor Registry at Johns Hopkins, the world’s largest database on familial pancreatic cancer, is working to gain is working to gain an even better understanding of what causes this lethal form of cancer. Her three-year plan is focused on identifying the key gene alterations and environmental factors that start pancreatic cancer. Klein and colleagues could then develop prevention-based screening methods for those at high risk. This research
also received CRF funding in 2005.

We now know that cancer is a genetic disease and are beginning to understand the specific changes that occur in cell checkpoints that cause cell signaling to run amok and lead to the unchecked cell growth that is the hallmark of cancer. Identifying the errors in these cell signaling pathways opens the door to correcting them with drugs that block errant signaling. Recent data indicates that over-expression of a gene known as EGFR results in a poorer outcome for patients with esophageal cancer. MICHAEL GIBSON, M.D. , is conducting clinical trials combining the drugs gefitnib and cetuximab with chemotherapy and radiation therapy are underway to see if adding these drugs, which block EGFR expression, improve outcomes for patients with esophageal cancer that has begun to spread.

All cancers are not the same. Classification of cancers is important for correct diagnosis
and treatment. Currently, the best-defined models of cancer classification are in the
leukemias and lymphomas in which discrete genetic changes have led to more specific
diagnoses and successful therapies. SARAH J. WHEELAN, M.D. , PH.D. and team are
applying the same methodology to breast cancer by searching for additional molecular
genetic markers to aid in diagnosis and treatment. They are particularly interested in an aggressive and treatment-resistant subtype of breast cancer known as basal-like cancer. The work has allowed them to refine the characteristics of this breast cancer, and they are hopeful it will lead to a new cancer marker to improve early detection and treatment outcomes.

A 2002 study of 500,000 adults found an 8 percent increase in lung cancer risk due
to increased levels of ambient fine particulate matter. Ambient particulate matter is a
general term used to describe a mixture of solid particles and liquid droplets in the air.
It includes everything from smoke and fumes to dust and pollen. Fine particulate
matter is formed from chemical reactions of particles in the air and is small enough to more significantly penetrate and cause harm to the respiratory system when it’s breathed in, potentially contributing to diseases such as lung cancer. The Bloomberg School of Public
Health was awarded a Science to Achieve Results grant (STAR) from the Environmental
Protection Agency to form the Johns Hopkins Particulate Matter Research Group and study the health risks of particulate matter air pollution. Additional funding from the CRF has given investigators, led by ALLISON GEYH, PH.D. , a unique opportunity to
explore the causes of these health effects. Center investigators will combine detailed
monitoring and particulate matter samples collected nationwide with analysis of
national databases on air pollution, mortality,and hospitalization to determine the impact of exposure on pulmonary and cardiovascular diseases. The team is particularly interested in identifying elemental metals and metal-containing compounds in the air. It is known from occupational studies that some metal-containing compounds are toxic and associated with the development of cancer. Identifying such compounds in ambient particulate matter
could, for the first time, provide a possible explanation for the linkage between ambient
particulate matter and risk of lung cancer mortality.

Smoking is the single most preventable cause for death and disease in the United
States. It increases the risk for lung and other cancers as well as cardiovascular and respiratory diseases. A nurse-run program directed by ROBIN P. NEWHOUSE, PH.D. , R . N . , is aiming to reduce lung cancer incidence and death rates in Maryland by improving the success of smoking cessation efforts for smokers discharged from acute-care hospitals. An inpatient nurse-delivered smoking cessation program will be tested with 150 patients. The study will compare standard education (written information, surveys, and a film on smoking cessation) with more intensive and individualized intervention, including a personal in-hospital smoking cessation counseling session by nurses. If the nursedirected intervention is more successful at helping patients to quit smoking, support
for a standardized program will be initiated in the state’s acute-care hospitals.

Cancer is a disease of aging, with the majority of cases occurring in people 65 and older. Clinical cancer research is not adequately representing cancer’s most common victims, say experts. Patients with cancer are living longer and experiencing better quality of life as a result of advances in cancer care, but they say, this growing number of elderly cancer patients has been underrepresented in cancer clinical trials. A newly established Geriatric Oncology Program at Bayview Medical Center, directed by GARY R. SHAPIRO, M.D. , seeks to address this issue by initiating elder-specific clinical trials, promoting older cancer patients’ participation in clinical trials, understanding and overcoming barriers to their participation in clinical trials, and improving risk assessment for older patients to maximize treatment effectiveness without compromising quality of life.

Genetic aberrations that render cells incapable of executing cell death not only promote cancer, but also contribute to the resistance of cancers to anticancer agents. Unraveling mechanisms to unleash the cell death program in tumors that harbor such genetic changes could lead to effective therapeutic interventions against cancer. The research of ATUL
BEDI, M.D. , has provided fundamental  insights into the molecular mechanismsthat underlie the dynamic balance between death signals and key determinants of tumor-cell survival. Based on these insights, he is developing and testing therapeutic strategies that are designed to activate death receptor signaling in conjunction with a blockade of key molecular determinants of tumor-cell survival. These studies provide a foundation for
collaborative translational projects aimed against a broad range of cancers.

Translational studies represent the bridge between the laboratory and patient care. It
is of particular interest now because of the many emerging therapies generated by new
basic science research of cancer. Despite the push to get new therapeutic ideas out of
the laboratory and to the patient, experts say very little has been written in the scientific
literature about translational clinical trial methodology. Even programs like the NCI SPORE (specialized programs of research excellence), put in place more than 10 years ago to speed translational research, have not led to the formulation of translational
clinical trial methods. STEVEN PIANTADOSI, M.D. , PH.D. , and team will design the first formal statistical translational clinical trial methodology and create software that makes this complex mathematical package widely available to clinical trial statisticians at cancer centers throughout the country.

Gene discovery has made a major impact on cancer research and treatment. However,
the amount of collected data is expanding more rapidly than our ability to sort it out.
Statistically analyzing tumor suppressor genes and oncogenes linked to cancer may
reveal key information about the biological causes driving poor cancer prognosis. The
investigators, led by JEANNE KOWALSKI, PH.D. , are beginning with a leukemia
model. Having identified a relationship between a deletion in chromosome 7 and a
more lethal form of acute myeloid leukemia, the research team has developed a computerized, statistical method to better understand this deletion and mathematically
decipher its significance and connection to specific tumor suppressor genes. The model
can also be used to quantify epigenetic factors (modifications to the DNA that occur
without mutating genes) and to compare commonalities in genetic alterations among
different types of cancer.

The goal of drug therapy for cancer is to be as toxic as possible to the cancer cell while minimizing the toxicity to the normal cell. In recent years, investigators have found that combining drugs not only targets varied aspects of cancer cell behavior but also improves the independent action of each drug and the overall success of treatment. Yet this approach also complicates dosing calculations, requiring measurements of the toxicity and effectiveness of not one drug, but of several, while at the same time, determining how interactions between drugs impact on these measurements. Now, to identify and
quantify drug synergies, a research team directed by ELIZABETH SUGAR, PH.D. , is developing a model to calculate the highest tolerable dose and also identify equally effective doses that may have lower toxic effects to normal cells.

Deciphering the complex process of cell signaling in cancer origination and progression
is the focus of MICHAEL OCHS, PH.D. As more is understood about the proteins involved in transforming normal cells into cancer cells, clinicians and investigators have been able to pinpoint key signaling activity that could be targeted with cancer therapies.They will create a bioinformatics model of cell signaling networks to increase understanding of cancer and the signaling malfunctions that help it grow and spread, its
response to treatment, and how it recovers from attacks by anticancer drugs. This
model will, for the first time, allow investigators to simultaneously measure the
activation state of multiple signaling proteins and the cell behavior correlated to
this activity. This model will also help verify that new biologically-targeted drugs are actually hitting their targets.

Cancer has been identified as a genetic disease. Still, understanding why environmental
exposures cause genetic changes that make certain people susceptible to developing cancer while leaving others unscathed, has been a bit of a mystery. In lung cancer, cigarette smoke is a clear environmental factor, but why smoking leads to genetic changes that cause lung cancer in just 10 to 20 percent of smokers is largely unknown. Now, using
advancing knowledge of the human genome and DNA samples from smokers in the Baltimore metro area, SHYAM BISWAL, PH.D. , and PAUL STRICKLAND,
PH.D. , will perform wholegenome association studies using a newly developed technology called SNP (pronounced snip). SNP allows investigators to rapidly pinpoint differences in nucleotides (the cellular alphabet of ATCG that makes up the coding sequences of genes) among individuals and populations and help uncover novel genes and regions of susceptibility for cancer. Investigators will study smokers who have developed lung cancer and those who have not. Of specific interest will be African Americans, who
have higher lung cancer death rates.

Metastasis is the leading cause of cancer death, and pancreas cancer ranks high on
the list of lethal cancers. One major reason for this, say researchers, is that at the time
of diagnosis, about 80 percent of patients have cancers that have already spread or
begun to spread. Existing drug therapies have been of little benefit to these patients
with few surviving beyond one year. WELLS MESSERSMITH, M.D. , and team believe change may lie in a genecalled SRC, a member of the tyrosine kinase family of genes. These genes are thought to be good therapeutic targets for managing cancer because the proteins they encode play key roles in controlling cell growth, differentiation, and nearby tissue invasion. They suspect it is one of the mechanisms driving pancreas cancer and
are testing a drug, called AZD0530, for its ability to inhibit SRC and extend survival.
Their findings are of particular significance in Maryland, which has had one of nation’s
highest rates of pancreas cancer.

Science Watch, a newsletter published by Thomson Scientific names CRF investigators
STEPHEN BAYLIN, M.D., JAMES HERMAN, M.D., and DAVID SIDRANSKY, M.D. as best in their field, calling the Kimmel Cancer Center a cancer research powerhouse. With more than 90,000 references between them, the three, along with Kimmel Cancer Center researchers Bert Vogelstein, M.D., and Kenneth Kinzler, Ph.D., were named as the most frequently cited in cancer research from 1995-2005. Calling them, “doctors of the decade,” Science Watch editor Christopher King said, “The impressive number of citations these exceptional researchers have received is evidence of their profound influence on modern scientific thought.”

ANIRBAN MAITRA, M.B. B. S . , has been awarded the Maryland Science Center’s 2006 Outstanding Young Scientist Award. Sponsored by the Maryland Academy of Sciences, the award includes the Allan C. Davis Medal and a cash award. Maitra’s laboratory is exploring the development of novel therapies for treating pancreatic cancer by identifying the genetic pathways causing the disease. The Maryland Outstanding Young Scientist award program was established in 1959 to recognize the extraordinary contributions of young scientists in the state of Maryland. Many former recipients have gone on to distinguished careers in science.

CHARLES M. RUDIN, M.D. , P H . D. , associate professor of oncology, received a
Burroughs Wellcome Fund Clinical Scientist Award in Translational Research for his work on novel therapeutic strategies for smallcell lung cancer. The award supports the career development of U.S. and Canadian physician-scientists whose work bridges the gap between basic research and patient care.  

“In the history of medicine, the greatest progress has been made in the application of biology to the behavior of humans through public health initiatives. Based on the biology of cancer, there is great potential to prevent the disease through lifestyle and medical interventions. The success of cancer research relies on a continuum, and prevention and control must be a part of it. Cancer research is not an either-or proposition. It is all interconnected.”


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