Girja Shukla, Ph.D.

Research Associate Professor of Surgery

Research Program: Clinical Research
VCC Membership Level: Full Member

Contact Information

E303A Given Building
University of Vermont
Burlington, VT 05405

ph: (802) 656-9488
f: (802) 656-5833
Girja.Shukla@uvm.edu

Biography

Dr. Shukla received his Ph.D. in 1981 from Lucknow University in India, followed by a post-doctoral fellowship at the University of Tennessee, Memphis. He held the positions of Scientist A, Scientist B, Senior Scientist C, Project Leader Scientist E-I, and Principal Scientist E-II at the Industrial Toxicology Research Center in Lucknow, India. Dr. Shukla also held Visiting Scientist position at Ottawa University in Canada, University of Michigan, Ann Arbor and here at UVM. In 2001, Dr. Shukla joined the faculty of the Department of Surgery at UVM.

Research

Dr. Shukla's early studies were focused on understanding the possible role of polyamines in the mechanism resistance using squamous cell carcinoma of prostate implanted in intact as well as in castrated male rats subjected to various hormonal treatments. He also studied mechanism of hormonal regulation of cell proliferation and tumor growth in later years, which resulted in understanding the important role of certain lipid molecules (glucosylceramide, ceramide, sphingosine and gangliosides) in hormone-chemotherapy of testosterone-controlled organs. In order to develop an effective anti-cancer drug of this class, Dr. Shukla screened several small molecules and their analogues for their modulatory effects on the glycolipids synthesis and levels in various organs. His studies produced strong evidence for the first time that the treatment with gangliosides can reduce the size of certain testosterone-controlled organs, which later formed the basis of successful treatment of certain tumors in experimental animals by other workers.

Dr. Shukla has also been involved in research projects on the mechanism of action of cadmium, a human lung carcinogen. He identified the possible sequence of biochemical events in the lung carcinogenesis following cadmium inhalation. His studies showed the involvement of oxidative stress-mediated chain of events leading to abnormal gene expression profile, metabolic alterations and cancer development. For the last few years, Dr. Shukla has been engaged in developing targeted cancer therapies. Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules involved in carcinogenesis and tumor growth. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies are believed to be "magic bullets" that specifically kill cancerous cells without harming to normal cells. Dr. Shukla's current efforts focus on identifying molecules that can bind selectively to cancer cells. These molecules are being screened for their effects on cell proliferation, apoptosis, invasion and migration, etc. In combination with toxic chemicals, immunotherapeutic modulators or imaging agents, these molecules can also be used for a selective delivery of required chemicals to cancer cells for a successful killing or diagnostic imaging of tumors. He is using phage displayed libraries as a source of ligand repertoires for identifying molecules that binds selectively to tumor cells. These include uniquely designed beta-lactamase loop libraries as well as a more conventional peptide and single-chain antibody libraries. Beta-lactamase library was constructed in a manner to generate >10^8 diverse sequences into targeting sites engineered into exposed loops of enzyme molecules. Selected tumor-specific ligands from beta-lactamase loop libraries have potential for their use as tumor-targeting agents in prodrug therapy, when used in combination with beta-lactum prodrugs of potent cytotoxic agents. The very first challenge Dr. Shukla had to deal with was to develop methods that are suitable and sensitive enough to work with a limited amount of human tumor samples. He has developed methods that are highly sensitive and require very small amount of tumor cells that can be obtained through minimally invasive methods like fine needle aspiration or core needle biopsies. He has also successfully identified several tumor-selective molecules (peptides) by screening the tumors of breast cancer patients. The laboratory procedures developed in these projects are currently being used in active innovative, Phase 1, clinical studies to identify customized cancer-binding chemotherapeutic agents.

Recent Publications

Pero S, Shukla G, Cookson M, Flemer Jr. S, Krag D. Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells. British Journal of Cancer 2007 96: 1520-1525.

Shukla G, Krag D. Selective delivery of therapeutic agents in diagnosis and treatment of cancer. Expert Opinion in Biological Therapy 2006 6 (1): 39-54.

Shukla G, Krag D. A sensitive and rapid chemiluminescence ELISA for filamentous bacteriophages. Journal of Immunoassay & Immunochemistry 2005 26: 89-95.

Shukla G, Krag D. Phage display selection for cell-specific ligands: development of screening procedure suitable for small tumor specimen. Journal of Drug Targeting 2005 13 (1): 7-18.

Shukla G, Krag D. Selection of tumor-targeting agents on freshly excised human breast tumors using a phage display library. Oncology Reports 2005 13 (4): 757-764.

Pero S, Shukla G, Armstrong A, Peterson D, Fuller S, Godin K, Kingsley S, Weaver D, Bond J, Krag D. Identification of a small peptide that inhibits the phosphorylation of ErbB2 and proliferation of ErbB2 overexpressing breast cancer cells. International Journal of Cancer 2004 111(6): 951-60.

Other Key Publications

Gupta A, Nigam D, Gupta A, Agarwal AK, Shukla G. Effect of quinalphos and cypermethrin exposure on developing blood-brain barrier: Possible role of nitric oxide. Environmental Toxicology & Pharmacology 2000 8: 73-78.

Agarwal R, Gupta A, Datta M, Shukla G. Cerebral antioxidant status and free radical generation following glutathione depletion and subsequent recovery. Molecular & Cellular Biochemistry 2000 209: 55-61.

Shukla G, Shukla A, Potts RJ, Ozier M, Hart BA, Chiu J-F. Cadmium-mediated oxidative stress in alveolar epithelial cells induces the expression of gamma-glutamylcysteine synthetase catalytic subunit and glutathione S-transferase alpha and pi isoforms: Potential role of activator Protein-1. Cell Biology & Toxicology 2000 16: 347-362.

Shukla G, Chiu J-F, Hart BA. Cadmium-induced elevations in the gene expression of the regulatory subunit of gamma-glutamylcysteine synthetase in rat lung and alveolar epithelial cells. Toxicology 2000 151: 45-54.

Eneman JD, Potts RJ, Osier M, Shukla G, Chiu JF, Hart BA. Suppressed oxidant induced apoptosis in cadmium adapted alveolar epithelial cells and its potential involvement in cadmium carcinogenesis. Toxicology 2000 147: 215-228.

Shukla G, Chiu J-F, Hart BA. Enhanced expression of pulmonary gamma-glutamylcysteine synthetase heavy subunit in rats exposed to cadmium aerosols. Toxicology & Applied Pharmacology 2000 163: 249-259.