Research in the Krishnan Laboratory is focused on the investigation of strategies to improve the efficacy of and minimize the toxicity from radiation therapy. These endeavors fall under two broad themes – one with a nanotechnology focus and the other with a classical radiobiology focus.
Nanotechnology and Radiation Oncology
On the nanotechnology front, the laboratory has pioneered a variety of applications of gold nanoparticles for imaging and image-guided therapies. Our focus is on tiny (~20-nm) nanoparticles for imaging and larger (~150-nm) nanoparticles for therapy of cancer. In the imaging arena, we have fabricated bioconjugated quantum dot nanoparticles for noninvasive real-time quantitative and repetitive molecular imaging of cancers for the expression and activity of cell-surface receptors. To our knowledge, this was the first pharmacokinetic analysis of nanoparticles in vivo (see NCI Nanotech News citation under News from the Lab). We have since developed a novel method to improve signal-to-noise of tumor-specific imaging by reducing non-specific liver uptake of nanoparticles. Along similar lines, the laboratory has utilized bioconjugated gold nanoshells to address the clinical challenge of close or positive retroperitoneal margins following pancreatic cancer resections. These bioconjugated gold nanoshells effectively target pancreatic cancers for intraoperative sensing, imaging and photothermally ablating pancreatic cancer resection margins. Since these nanoshells are activated by light, their clinical utility is limited to tumors that are superficial (intraoperative tumor bed or skin). Therefore, we have worked with Dr. Naomi Halas at Rice and Dr. Amit Joshi at Baylor to develop, characterize, bioconjugate and deploy hybrid nanoshells (with gold and iron oxide functionalities) that can be imaged by magnetic resonance and fluorescence as well as activated by light and alternating magnetic fields that penetrate deeper into tumor. In the realm of cancer therapy, the laboratory has characterized a novel mechanism of sensitizing tumors to radiation therapy by using gold nanoshell–mediated hyperthermia. These experiments outlined an early increase in vascular perfusion after nanoshell-mediated hyperthermia that sensitizes tumors to radiation therapy by overcoming hypoxia and a subsequent unique localized vascular disruption that creates large areas of necrosis and accentuates the radiosensitization observed (see NCI Nanotech News citation under News from the Lab). More recently, the laboratory, in collaboration with Dr. Jeffrey Rosen at Baylor, demonstrated that nanoparticle-mediated hyperthermia preferentially sensitizes cancer stem cells to radiation. In anticipation of eventual clinical translation of such paradigms, the laboratory has actively collaborated with Dr. James Tunnell at UT Austin to non-invasively quantify the concentration of gold nanoshells within tumors using diffuse optical spectroscopy, to non-invasively image (macroscopically) the spatial distribution of gold nanoshells within these tumors using narrowband near infrared imaging, and to characterize (microscopically) the geographic distribution of gold nanoshells and nanorods within tumors using two photon luminescence imaging. The laboratory has also collaborated actively with Dr. Sang Cho at GeorgiaTech to model the radiation dose enhancement achieved by loading tumors with gold nanoparticles and irradiating them with photoelectric range kilovolt x-rays and to model heat generation from optically activated gold nanoshells dispersed within tumors. Building on the converging evidence that targeted accumulation of gold nanoparticles in tumors may improve the visualization of tumors and advance image-guided interventions, the laboratory has served as a center-wide focal point for those interested in investigating the biologic and physical mechanisms of nanoparticle-radiation interaction at a meso-/nano-scale.
On the classical radiobiology front, the laboratory has advanced preclinical concepts and findings to the clinic on a few occasions. This began with the early experience with using small-molecule tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR) as radiation sensitizers in gliomas which led to an NCI-sponsored clinical trial. Unfortunately, despite widespread EGFR overexpression by gliomas, targeting this constitutively active pathway with a highly specific inhibitor failed to improve radiation therapy outcomes for patients. All the same, this experience served as a springboard for future translational endeavors in the laboratory. The laboratory has adopted a strategy of subjecting tumors to a sublethal clinical dose of radiation and then evaluating the surviving cells for specific inducible (as opposed to constitutive) pro-survival pathways that help them overcome the genotoxic insult posed by radiation. The laboratory has an interest in blockade of this inducible radioresistance via inhibitors that have a broad spectrum of activity and work further downstream along the signaling pathway in the hope that they would be less prone to circumvention via redundant signaling pathways. One such pathway identified in colorectal cancers, the NF-κB pathway, can be effectively targeted by curcumin, the active ingredient in dietary turmeric – the consequent radiosensitization of rectal cancers was the focus of a recently completed clinical-translational trial. Along similar lines, the laboratory has characterized the mechanism of synergy between a histone deacetylase inhibitor (vorinostat) and radiation in pancreatic cancer via inhibition of multiple inducible pro-survival pathways. A recently completed phase 1 clinical trial investigating this combination in pancreatic cancer noted significant overlapping toxicity of the combination. Similar radiosensitization strategies are being evaluated in colorectal and pancreatic cancer using agents acquired from industry and Cancer Therapy Evaluation Program (CTEP) at NCI.