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Conquest - 2008 Research Awards

Making the Connection 2001-2008

2008 Research Awards

Date: April 20, 2010

LUIS DIAZ, M.D. , received a diversity grant to support his studies of the bacterialytic
cancer therapy Clostridium novyi- NT. The genetically modified bacteria destroys cancer cells in the oxygen-starved core of tumors but shows no interest in tissues not harboring cancers. A single intravenous injection of the bacteria spores was successful in animal models, destroying tumors up to 30 percent of the time. Clinical trials in patients with metastatic colon cancer have since begun. ?

Earlier studies have suggested there may be a common genetic predisposition to all smoking-related cancers. In this new study, researchers TERRY BEATY, PH.D. ,
ALISON KLEIN, PH.D. , and LI WANG, PH.D. , will use data collected from the National Familial Pancreas Tumor Registry at Johns Hopkins to determine if cancers other than pancreatic cancer occur at a greater rate than expected among these families and to look for clusters of smoking-related cancers. ?

Epigenetics is a powerful clinical tool to improve the diagnosis, prognosis, and treatment of cancer patients and is moving ever closer to clinical reality. Recent technical advances like MSP (methylation specific polymerase chain reaction) can now be used to determine if genes are hypermethylated, the hallmark of epigenetic alterations that can lead to the silencing of key tumor suppressor genes. An Epigenetics Core Laboratory, directed by MALCOLM BROCK, M.D., would make state-of-the-art DNA methylation analysis
available to CRF investigators, and eventually to investigators throughout Johns Hopkins, ensuring accurate and reliable DNA methylation laboratory results. ?

Esophageal and lung cancers develop through progressive molecular events that include epigenetic alterations, or alterations to genes that occur without actually mutating the DNA. These epigenetic alterations may result from environmental exposures as well as inflammation, and epigenetic expert JAMES HERMAN, M.D. , believes they are among the first events in the development of these cancers. Herman will use animal models to
determine if environmental exposures produce a chronic state of inflammation,
leading to epigenetic alterations that ultimately result in cancer. ?

The NRF2 gene has been linked to treatment resistance, but its mechanisms are not yet fully understood. Leading NRF2 expert SHYAM BISWAL, PH.D. , will perform a systematic metabolic profile of lung cancer cells with a deregulated NRF2 gene and
pathway to help gain an understanding of how it causes lung cancer cells to become
resistant to therapy. Biswal, working with GEOFFREY GUMIN from University of
Maryland, began screening 1280 compounds that can knock down NRF2 in patients. The best candidate will be used in lung cancer patients to block resistance to chemotherapy. ?

Providing the highest quality care leading to the best patient outcomes depends on welldefined and available indicators, knowledge of institutional performance, and analysis
that sheds light on the quality improvement process. This project, led by NORMA
KANAREK, PH.D. , incorporates a collaboration of clinicians treating the most prevalent
cancers—prostate, breast, colorectal, and lung cancers—and an epidemiologist to prioritize indicators from the Johns Hopkins Hospital Cancer Registry and assemble
a multi-year database of Johns Hopkins Kimmel Cancer Center patient demographics and care patterns. Lessons learned from these common cancers also will be applied o less common cancers. This method will help highlight quality care, enhance clinical trial access, and identify the key factors in achieving the best cancer outcomes. ?

CRF investigators ELIZABETH PLATZ, M.P. H . , S C . D., SRINIVASAN YEGNASUBRAMANIAN, M.D. , PH.D., ANGELO, DEMARZO, M.D. , PH.D., WILLIAM NELSON, M.D. , PH.D. , and CHARLES DRAKE, M.D. , PH.D. , believe that hypermethylation (increased methylation to genes that can  ultimately silence key tumor suppressorgenes) and inflammation caused by environmental insults conspire to influence the early stages of prostate cancer. The investigators will use a multi-faceted approach to determine whether environmental exposures influence hypermethylation, leading to chronic inflammation inside the prostate gland and if, jointly, they increase
the risk of prostate cancer. ?

ACI female rats develop mammary cancers within 12-14 weeks following treatment
with estradiol, an estrogen. This animal model is receiving increasing attention as a
way to determine the mechanisms of human breast cancer development associated
with persistent and elevated estrogen exposure. Investigator JAMES YAGER, PH.D., will study the roles of estrogen metabolism and altered gene expression and DNA methylation driving breast cancer development induced by estradiol. ?

NILOFER AZAD, M.D. , is a clinicianscientist specializing in colorectal and other GI cancers. She recently completed a four-year fellowship in medical oncology at the National Cancer Institute (NCI). At the NCI, Azad worked with the leader of the Phase I Drug Development Group, giving her the skills to develop her own phase I/II drug development program in GI oncology. ?

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., plans to find out why and use it to help 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 is now focused on enumerating the genes controlled by Nrf2 and their role in causing disease. Next he will conduct a wholegenome 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.

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