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Research in the Chandra lab is directed towards understanding the oxidative environment of cancer cells and then using this knowledge to develop therapeutic strategies that will eliminate cancer cells. 

One feature common to numerous cancer cell types is alterations in the intracellular oxidative environment.  The oxidative environment is constantly negotiated and represents a balance between the level of ROS (reactive oxygen species) and the antioxidant systems that disarm or inactivate ROS.  Since ROS are generated as a result of cellular respiration or other normal metabolic processes, intricate networks of antioxidant enzymes are in place and are carefully regulated. 

ROS are versatile in influencing cell outcome. While high doses of ROS cause cell death, low to intermediate levels can urge cells to grow.  Our lab is exploring both of these endpoints.  Model systems studied in the lab include leukemias (the most common pediatric cancer) and brain tumors (the deadliest pediatric malignancy).  One of the leukemia model systems we study are Philadelphia chromosome positive leukemias.  The Philadelphia chromosome is another name for the translocation that yields a fusion gene called BCR/ABL.  The protein product of BCR/ABL is a kinase and in the past decade giant strides in improving patient outcome for Philadelphia positive leukemia patients have been made by better understanding and molecularly targeting the BCR/ABL kinase.  Our lab is specifically interested in BCR/ABL’s ability to alter the oxidative environment of cells.  We are working to understand how that happens and the consequences of this alteration, particularly in terms of cell signaling.

Recent years have seen the development of a body of clinically relevant biologically targeted agents including proteasome inhibitors, histone deacetylase inhibitors, and various kinase inhibitors. Many of these drugs are currently being tested in the clinic or are being used in patients with hematological malignancies. The mechanism of action of some of these drugs is attributable in part to raising ROS levels in the cell.  Examples are adaphostin (a kinase inhibitor), NPI-0052 (a proteasome inhibitor), SNDX-275 and PCI-24781 (HDAC inhibitors). We are studying the source and consequences of ROS generation by these agents and will use these compounds as tools with which to better understand the biology of pediatric leukemias.  We are also addressing the preclinical efficacy of these agents in leukemia model systems using primary specimens from patients and animal models.

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Last updated: 2/4/2013