RETRACTED ABSTRACT: Study of proteomic and BBB permeability changes in brain tumor

4353 RETRACTION NOTICE: The Office of Research Integrity (ORI) of the U.S. Department of Health and Human Services found that Nagendra S. Ningaraj, PhD, had engaged in scientific misconduct by falsifying images presented at the American Association of Cancer Research annual meeting held April 16-20, 2005 [74 Fed. Reg. 48747 (2009); http://ori.hhs.gov/misconduct/cases/Ningaraj_Nagendra.shtml]. Dr. Ningaraj neither admits nor denies any of the allegations in the settlement agreement with ORI, and this agreement should not be construed as an admission of liability. Gliomas account for the majority of malignant brain tumor morbidities in humans, and are usually associated with over-expression of receptor tyrosine kinases (RTKs). As broad spectrum and specific RTK inhibitors (RTKIs) are developed to treat human cancers, a method to quantify RTKIs, and predict patients’ therapeutic response to RTKIs is critical. The evaluation of tumor response to RTKIs and changes in protein patterns in a human brain tumor xenograft before and after treatment with RTKIs can serve as a predictor of therapeutic response. While control of systemic cancers is achieved using RTKIs, control of brain cancers is still an unachieved goal because these RTKIs do not cross the intact blood-brain barrier (BBB). Since human brain tumor capillaries and tumor cells over-express calcium-activated (K Ca ) and ATP-sensitive potassium (K ATP ) channels and regulate BBB/BTB permeability, we employed potassium channel agonists to enhance anti-cancer drug delivery to brain tumors. We correlated clinically relevant dynamic contrast-enhanced (DCE)-MRI method with standard but invasive quantitative autoradiography (QAR) technique in order to measure BBB permeability changes. Using MALDI-MS, we measured RTKI levels and determined the protein expression profiles of human brain tumor xenografts in mice before and after targeted RTKI therapies. Furthermore, we assessed protein changes in brain tumors that may predict therapeutic response to such treatments. K Ca channel agonist, NS-1619 significantly increased MRI contrast-enhancing agent (Magnevist) delivery to brain tumors. We found a very low relative intensity of RTKIs, such as Gleevec and SU11248 in brain tumor xenografts when Gleevec and SU11248 alone was administered. But when these drugs were administered with potassium channel agonists, we observed a significantly enhanced intensity of these drugs in brain tumor tissue. Furthermore, Gleevec and SU11248-induced proteomic changes in brain tumors, which was clearly distinct from untreated brain tumor proteomic profile. We developed a method to rapidly assess a brain tumor’s response to an anti-cancer drug treatment. We developed brain tumor imaging and profiling tools to effectively predict which protein changes occur following RTKI therapy so that patients who are likely to benefit from such therapies can be identified by their unique protein profiles. Furthermore, we tested K Ca and K ATP channels as potential targets for improving anti-cancer drug delivery across the BTB selectively to brain tumors in patients, which may significantly improve control of brain tumors.