Sunil Krishnan, M.B.B.S., M.D., specializes in the radiotherapy treatment of gastrointestinal cancers. Research in Dr. Krishnan's Nanotechnology and Radiation Biology Laboratory includes strategies to sensitize tumors to radiation therapy using nanoparticles, chemotherapy, botanicals, immunotherapy and novel radiation techniques including particle therapy, minibeams and boron neutron capture therapy. He evaluates approaches to protect normal tissues from radiation injury using novel agents.
Dr. Krishnan also studies patterns of gene expression and imaging characteristics in human tumors that predict response to radiotherapy and chemotherapy. His research has been funded by the National Institutes of Health for over a decade.
- Nanotechnology. Dr. Krishnan's laboratory has broad interests and expertise in using metal nanoparticles for sensitizing cancers to radiotherapy. This includes radiation dose enhancement via increased secondary electron showers emanating from irradiated nanoparticles and hyperthermia via optical activation of gold nanoparticles or alternating magnetic field activation of iron oxide nanoparticles. A variety of nanoconstructs have been designed by the laboratory including spheres, rods, triangles, and shells with surface decoration with peptides and antibodies. A major focus of the laboratory is to improve transport and delivery of nanoparticles to enhance tumor uptake. This is accomplished via rational design of novel nanoparticles including stimuli-responsive (pH, tumor microenvironment, etc.) particles, Trojan horse particles, on-demand extrinsically triggered release designs and self-disintegrating clusters; or suppression of reticuloendothelial uptake and clearance via cloaking approaches on nanoparticles or inhibition of macrophage activity.
- Drug-radiation interactions. The Nanotechnology and Radiation Biology Laboratory is one of five national reference laboratories for testing drugs as radiation sensitizers. The focus has been on FDA-approved drugs in the Cancer Therapy Evaluation Program's portfolio of cancer therapeutics, repurposed drugs FDA-approved for other indications, and botanicals.
- High-linear energy transfer (LET) treatments. Dr. Krishnan's laboratory studies the immune effects of high-LET therapy and the potential for coupling this therapy with immunotherapy. Initial investigations focused on proton beam therapy, but with the plans for installation of a carbon ion center at MCF, these studies will be extended to heavier ion species. The team also designs boronated compounds for boron neutron capture therapy, another form of high-LET therapy.
- Novel therapeutic modalities. Work in Dr. Krishnan's Nanotechnology and Radiation Biology Laboratory pioneered proton and orthovoltage minibeam therapy as a means of protecting normal tissues along a radiation beam path and is actively investigating mechanisms of radiation protection. The team explored the use of ultra-high dose rate radiation therapy to protect normal tissues as well and is still interested in finding mechanisms of reported normal tissue sparing when this approach is employed.
- Predictors of radiotherapy outcome. Dr. Krishnan and colleagues in his laboratory described the role of unintentional splenic radiation on causing lymphopenia in pancreatic cancer and the detrimental effect this has on overall treatment outcome. The laboratory has now replicated these findings in animal models and is actively exploring ways to reverse the deleterious effects of lymphopenia. Similarly, the team is actively exploring imaging, genomic, microbiome and other biomarkers of response to treatment, constantly adopting a bedside-to-bench and back tactic.
The laboratory advances many of these multidisciplinary paradigms using an eclectic mix of chemists, biologists, engineers and clinicians working in close harmony. The team also collaborates extensively with other laboratories, not only at Mayo Clinic sites but also at other universities within the U.S. and internationally.
Significance to patient care
Nanoparticles research is early in preclinical development but, when discovery matures, could lead to new treatment approaches for patients currently receiving radiation therapy for cancer. The drug-radiation platform seeks to advance novel therapeutic options for patients receiving radiation therapy currently; a few approaches have already been translated to the clinic and others are in the pipeline.
The high-LET platform is also keen on clinical translation of LET-optimized treatment plans, initially as proof-of-concept studies but subsequently as a new treatment strategy, especially when carbon ion therapy is available at Mayo. Once imaging and genomic biomarkers are defined, they will be validated in prospective studies where poor responders could receive adaptive modifications of treatment to improve outcomes or good responders could receive less intensive treatments including organ-preserving options.
- Chair, Scientific Program and Education Committees, ASTRO Academy, 2019
- Co-Leader, Gastrointestinal Cancer Program, Mayo Clinic Cancer Center, 2019
- Endowed Chair, Florida Department of Health, Radiation Oncology, Mayo Clinic, 2019
- Fellow, ASTRO Academy, 2019
- Editor, Cancer Nanotechnology, 2018