Ann R. Kennedy

faculty photo
Richard Chamberlain Professor of Research Oncology
Member, University of Pennsylvania Cancer Center
Professor of Radiation Biology, Department of Radiation Oncology, University of Pennsylvania School of Medicine
Department: Radiation Oncology

Contact information
195 John Morgan Building
3620 Hamilton Walk
Philadelphia, PA 19104-6072
Office: 215 898-0079
Fax: 215 898-0090
Graduate Group Affiliations
Education:
A.B. (Biology)
Vassar College , 1969.
M.S. (Radiation Biology)
Harvard University , 1971.
D.Sc. (Radiation Biology)
Harvard University, 1973.
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Description of Research Expertise

KEY WORDS:
Cancer, proteases, protease inhibitors, cancer prevention, oncogenes, gene expression, radiation acute effects, space radiation.

RESEARCH INTERESTS:
Biological effects of radiation, with emphasis on carcinogenesis, cancer prevention and acute radiation effects.


CONTRIBUTIONS TO SCIENCE:
1. I have made extensive contributions to the field of cancer research, with particular focus on radiation carcinogenesis. My studies were the first to show that agents could modify radiation induced transformation in vitro, with publications in 1978 showing that treatment with some agents could result in more malignantly transformed cells and other agents could reduce the number of transformed cells arising from irradiated cell populations. My studies in this area of research introduced the novel concept that radiation carcinogenesis is not an inevitable progression and it can be prevented.

2. We were the first lab to identify protease inhibitors, such as the Bowman-Birk inhibitor (BBI) from soybeans, to be very effective as mitigating agents for radiation induced transformation in vitro. We showed that these agents could prevent radiation and chemically induced carcinogenesis in both in vivo and in vitro systems without toxic effects. I led the efforts for BBI to achieve Investigational New Drug (IND) Status with the FDA, and IND status for BBI was granted in 1992. In the time since, I have held the INDs from the FDA for six different areas of clinical trial research that utilize BBI as a preventative and/or therapeutic agent. These included trials in patients with oral leukoplakia (a pre-malignant condition), benign prostatic hyperplasia, prostate cancer, esophagitis (in patients with lung cancer), gingivitis and ulcerative colitis. It is expected that trials of BBI in patients with muscular dystrophy and multiple sclerosis will begin at some point in the future.

3. Most recently, my lab has focused on the study of space radiation and identification of countermeasures for its effects. Our work in this area was funded through the National Aeronautics and Space Administration (NASA) and the National Space Biomedical Research Institute (NSBRI); and it has led to the important discovery that relatively low doses of space radiations (such as protons), as well as gamma or X-rays, produced disseminated intravascular coagulation in experimental animals. These results importantly contribute to our understanding of acute radiation syndrome in humans, and may lead to changes in the manner in which the biologic effects of radiation exposure are diagnosed, treated and prevented in people exposed to radiation through occupational accidents, radiation terrorism or other catastrophic events.

DESCRIPTION OF RESEARCH:
Research in the Kennedy laboratory has primarily involved studies on the mechanism(s) involved in radiation induced malignant transformation and its modification by various chemical agents in both in vitro and in vivo experimental systems. Cancer prevention continues to be a major focus of research, with the primary cancer chemopreventive agents evaluated being protease inhibitors as well as other classes of agents known to modify free radical reactions. The studies on free radical modifying agents focused on the ability of agents to affect radiation induced oxidative stress, and the ability of protease inhibitors to act as cancer preventive agents focused on the ability of dietary protease inhibitors to inhibit the activity of a protease known as chymotrypsin. Early studies identified the soybean-derived protease inhibitor known as the Bowman-Birk inhibitor (BBI) to be a particularly effective cancer preventive agent. Studies on the mechanism of action of the protease inhibitor suppression of carcinogenesis have focused on the effects of these agents on the expression of specific oncogenes and proteases thought to be involved in the conversion of a cell to the malignant state. Human trials utilizing BBI as a cancer chemopreventive agent started in 1992 and some have been completed recently. Some of the current laboratory work involves studies on the effects of BBI on surrogate endpoint biomarkers (SEBs) of carcinogenesis in tissues of experimental animals treated with BBI.

Much of the most recent work of the Kennedy laboratory has been focused on studies related to the acute radiation risks for astronauts exposed to solar particle event (SPE) radiation. SPEs can involve relatively high doses of radiation that can cause symptoms of the acute radiation syndrome (ARS). The aims of these studies are to determine whether there are adverse acute biological effects like those of the ARS, which are likely to occur in astronauts exposed to the types of radiation, at the appropriate energies, doses and dose-rates, present during an SPE. Kennedy lab. members have performed mechanistic studies on SPE radiation induced adverse effects and their mitigation or prevention by potential countermeasures, with emphasis on hematologic and immune system alterations (with many experiments performed both with and without simulated hypogravity conditions). Some specific examples include SPE radiation effects on: 1) lymphocyte and neutrophil activation and function, and 2) blood coagulation parameters. Among the most notable findings in this area of research is that both space radiations, as well as gamma or x-rays, produce disseminated intravascular coagulation (DIC) in experimental animals at relatively low doses of radiation. Our results indicate that radiation activates the coagulation cascade, which results in radiation induced coagulopathy (RIC), with bleeding/hemorrhage/microvascular thrombosis and organ damage, and the ultimate development of DIC, at relatively low-moderate doses of radiation. Current experiments are aimed at the development of novel agents that may prevent or mitigate the development and/or progression of RIC/DIC in experimental systems.

Description of Itmat Expertise

Radiation induced adverse health effects, including acute effects, carcinogenesis, heart disease, disseminated intravascular coagulation and other diseases/conditions.

Selected Publications

Sanzari JK, Diffenderfer ES, Hagan S, Billings PC, Gridley DS, Seykora JT, Kennedy AR, Cengel KA: Dermatopathology effects of simulated solar particle event radiation exposure in the porcine model. Life Sci Space Res. 6(21-8), Jul 2015.

Sanzari JK, Krigsfeld GS, Shuman AL, Diener AK, Lin L, Mai W, Kennedy AR : Effects of granulocyte colony stimulating factor, Neulasta, in minipigs exposed to total body proton irradiation. Life Sci Space Res. 5: 13-20, Apr 1 2015.

Li M, Holmes V, Ni H, Sanzari JK, Romero-Weaver AL, Lin L, Carabe-Fernandez A, Diffenderfer ES, Kennedy AR, Weissman D : Broad-spectrum antibiotic or G-CSF as potential countermeasures for impaired control of bacterial infection associated with an SPE exposure during spaceflight. PLoS One. 10(3): e0120126, Mar 20 2015.

Billings PC, Sanzari JK, Kennedy AR, Cengel KA, Seykora JT: Comparative analysis of colorimetric staining in skin using open-source software. Exp Dermatol 24(2): 157-9, Feb 2015.

Sanzari JK, Wan XS, Muehlmatt A, Lin L, Kennedy AR : Comparison of changes over time in leukocyte counts in Yucatan minipigs irradiated with simulated solar particle event-like radiation. Life Sci Space Res. 4: 11-16, Jan 1 2015.

Sanzari JK, Billings PC, Wilson JM, Diffenderfer ES, Arce-Esquivel AA, Thorne PK, Laughlin MH, Kennedy AR.: Effect of electron radiation on vasomotor function of the left anterior descending coronary arter. Life Sci Space Res. 4: 6-10, Jan 2015.

Krigsfeld GS, Shah JB, Sanzari JK, Lin L, Kennedy AR: Evidence of disseminated intravascular coagulation in a porcine model following radiation exposure. Life Sci Space Res. 3: 1-9, Oct 1 2014.

Ni J, Romero-Weaver AL, Kennedy AR: Potential beneficial effects of Si-Wu-Tang on white blood cell numbers and the gastrointestinal tract of gamma-ray irradiated mice. Int J Biomed Sci. 10(3): 182-90, Sep 2014.

Billings PC, Romero-Weaver A, Kennedy AR: Effect of gender on the radiation sensitivity of murine blood cells. Gravit Space Res. 2(1): 25-31, Aug 1 2014.

Romero-Weaver AL, Lin L, Carabe-Fernandez A, Kennedy AR: Effects of Solar Particle Event-Like Proton Radiation and/or Simulated Microgravity on Circulating Mouse Blood Cells. Gravit Space Res. 2(1): 42-53, Aug 2014.

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Last updated: 08/26/2015
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