Of the many successful programs within the RRP grant and contract portfolio, several scientific advances are presented below, representing significant advances in treatment development, molecular radiation therapy, quality assurance for high-technology radiation therapy, and international networking.
McEllin B, Camacho CV, Mukherjee B, Hahm B, Tomimatsu N, Bachoo RM, Burma S. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase (PARP) inhibitors. Cancer Res 2010:70;5457-64. Epub 2010:Jun 8.
Dr. Sandeep Burma’s group, Department of Radiation Oncology, University of Texas Southwestern Medical Center, has shown that loss of PTEN in glioblastomas reduces their ability to carry out homologous recombination repair and increases their sensitivity to alkylating agents. In addition, loss of PTEN renders these cells sensitive to PARP inhibition. Dr Burma’s studies of glioblastoma radiosensitivity are funded by R01 CA149461.
Wong C, Stylianopoulos T, Cui J, Martin J, Chauhan VP, Jiang W, Popovic Z, Jain RK, Bawendi MG, Fukumura D. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc Natl Acad Sci 2011:108;2426-31. Epub 2011:Jan 18.
Dr. Dai Fukumura, Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, has been involved in the development of multistage nanoparticles for enhanced tumor penetration. These particles undergo a protease triggered 10-fold size reduction thereby enhancing intratumoral diffusion. Such “shrinking” nanoparticles could potentially serve as efficient carriers of therapeutic agents. Dr. Fukumura’s studies are supported by grant number R01 CA096915.
Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell'antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, Kimmelman AC. Pancreatic cancers require autophagy for tumor growth. Genes Dev 2011:25;717-29. Epub 2011:Mar 15.
Dr. Alec Kimmelman, Department of Radiation Oncology, Dana Farber Cancer Institute, has been studying the importance of autophagy to pancreatic cancer cell growth and radiosensitivity. He and his colleagues have shown that a majority of pancreatic tumors are dependent upon autophagy for survival, thus indicating new potential targets in the autophagy pathway for this tumor type. His studies on autophagy and radiosensitivity will continue to be funded by grant number R01 CA157490.
Li F, Huang Q, Chen J, Peng Y, Roop DR, Bedford JS, Li CY. Apoptotic cells activate the "phoenix rising" pathway to promote wound healing and tissue regeneration. Sci Signal 2010:3;ra13.
Huang Q, Li F, Liu X, Li W, Shi W, Liu FF, O'Sullivan B, He Z, Peng Y, Tan AC, Zhou L, Shen J, Han G, Wang XJ, Thorburn J, Thorburn A, Jimeno A, Raben D, Bedford JS, Li CY. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med 2011:17;860-6.
Dr. Chuan-Yuan Li and his colleagues in the Department of Radiation Oncology, University of Colorado School of Medicine, have developed evidence for a novel mechanism of accelerated tumor repopulation after cytotoxic therapy. His “Phoenix Rising” pathway proposes that caspase activity released from dying cells activates proliferative signals in surviving cancer stem cells. Dr. Li’s work is supported by grant R01CA136748.
Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S, Hayes McDonald W, Olivier AK, Spitz DR, Gius D. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 2010:40;893-904.
Dr. David Gius and colleagues have uncovered a tumor suppressor role for a member of the sirtuin family of proteins that are thought to be involved in regulation of ageing. The Sirt 3 protein has been shown to regulate oxygen radical damage through its effects on superoxide dismutase activity.
In 1995, Dr. C. Yu created a new method of radiotherapy treatments now categorized as intensity-modulated arc therapy (IMAT). Under NCI grant CA 117997, much progress has been made. The advantages and limitations of the IMAT technique have also been better understood. In recent years, single-arc forms of IMAT have emerged and become commercially adopted. The leading clinical example is the volumetric-modulated arc therapy (VMAT).
Dr. Karl D Wittrup's group at Massachusetts Institute of Technology recently characterized DOTA-based (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid) small molecules to be used as ligands specific for tumor-associated surface receptors for cancer diagnosis and therapy. Based on their results demonstrating differential localization of these DOTA-based small molecules serving as proxy receptors on tumor surface, the work is being transferred to develop a pretargeted radioimmunotherapy (PRIT) approach for synthesizing anti-tumor antibodies for clinical development. This work is supported by grant RO1CA101830-07.