Peter A. Crooks, PhD,3 and Ronald H. Shapiro, MD1; 1Indiana University. School of Medicine, 2South Dakota School of Mines and Technology,. 3University of ...
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Posters (P001) DMAPT Inhibits NF-KAPPA B Activity and Increases Sensitivity of Prostate Cancer Cells to X-Rays In Vitro and in Tumor Xenografts In Vivo Marc S. Mendonca, PhD,1 William T. Turchan, BS,1 Melanie E. Day, BS,1 Christopher N. Watson, MD,1 Neil C. Estabrook, MD,1 Helen Chin-Sinex, BS,1 Jeremy B. Shapiro, BS,1 Imade Imasuen, BA,1 Gabriel Rangel, BS,1 David P. Gilley, PhD,2 Nazmul Huda, PhD,1 Peter A. Crooks, PhD,3 and Ronald H. Shapiro, MD1; 1Indiana University School of Medicine, 2South Dakota School of Mines and Technology, 3 University of Arkansas for Medical Sciences Constitutive activation of the pro-survival transcription factor NF-kB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natural product parthenolide is able to inhibit NF-kB activity and sensitize PC-3 prostate cancers cells to X-rays in vitro; however, parthenolide has poor bioavailability in vivo and therefore has little clinical utility in this regard. We show here that treatment of PC-3 and DU145 human prostate cancer cells with Dimethyl-amino-parthenolide (DMAPT), a parthenolide derivative with increased bioavailability, inhibits constitutive and radiation-induced NF-kB binding activity and slows prostate cancer cell growth. We also show DMAPT increases single and fractionated X-ray-induced killing of prostate cancer cells through inhibition of DNA double strand break repair. Finally, we demonstrate that the treatment of PC-3 prostate tumor xenografts with oral DMAPT in addition to radiation therapy significantly decreases tumor growth and results in significantly smaller tumor volumes compared to xenografts treated with either DMAPT or radiation therapy alone, suggesting that DMAPT might have a potential clinical role as a radiosensitizing agent in the treatment of prostate cancer. (P002) Differential Expression of Microrna Between Standard Conventional Dose Versus Ablative Dose Radiation in Colorectal Cancer Shushan Rana, MD, Cristina Espinosa, PhD, Charles Thomas, MD, and Sudarshan Anand, PhD; Oregon Health & Science University Background: The biologic heterogeneity of cancer confers a spectrum of radiation responsiveness warranting radiation dose escalation for certain cancers. However, clinicopathologic propensity for extensive microscopic spread negate strategies to reduce treatment volumes thus inhibiting safe dose escalation. A major regulator of the ionizing radiation (IR) response is microRNA (miR) with a critical function in cancer biology through their ability to regulate hundreds of genes in a gene network through differential sequence complementarity. In this context, we hypothesized the influence of radiation dose escalation on IR-mediated damage will be detectable through differential IR-induced miRNA expression patterns. Methods: We utilized a murine implantation model of CT26 colorectal adenocarcinoma subcutaneous flank xenografts in syngeneic BALB/c mice. Mice received either no irradiation, 2 Gy, 5 Gy, or 10 Gy single dose Cs-137 flank irradiation assisted through lead shielding. At 4 hour post-IR, blood was collected and centrifuged to isolate plasma, and tumors were harvested. We used the Nanostring miR profiling platform and obtained absolute counts for 600 mouse miRs. Nanostring nSolver v3.0 software was used for data normalization and analysis. PCR was performed on candidate miRs to detect their presence in plasma.
Results: We identified four distinct groups of miR expression patterns in tumor bearing mice in response to radiation. The miRs in each group are identified as: 1) increasing linearly with dose 2) increased at 5 Gy threshold and beyond 3) increased at 10 Gy threshold, and 4) decreased at all dose levels. qRT-PCR validation confirms candidate miRs in groups 1, 2, and 3 are expressed in plasma similar to their tissue expression patterns. Conclusion: miRs exhibit differential expression patterns in response to radiation dose escalation in colorectal cancer. (P003) Delivery of Ultra-Rapid Flash Radiation Therapy and Demonstration of Normal Tissue Sparing After Abdominal Irradiation of Mice Billy W. Loo, MD, PhD, Emil Schuler, PhD, Frederick M. Lartey, PhD, Marjan Rafat, PhD, Gregory J. King, PhD, Stefania Trovati, PhD, Albert C. Koong, MD, PhD, and Peter G. Maxim, PhD; Stanford University Introduction: Normal tissue toxicity is the primary constraint on administering curative radiation doses for cancer. A number of groups have recently shown that ultra-fast FLASH radiation delivery spares normal tissues and increases the therapeutic index over conventional radiation delivery. Methods: We developed a preclinical FLASH irradiation system for mice using a clinical linear accelerator. To produce extremely high dose rates over the field of interest, we (1) designed a mouse stereotactic body frame and anatomy-specific lead shields to fit within the head of the linac for a very short source to sample distance; and (2) tuned the output of the 20 MeV electron beam to emulate the current of photon beam mode but without the bremsstrahlung target. We characterized the field flatness, depth dose, and dose rates using Gafchromic EBT2 film in a water equivalent phantom. We then performed total abdomen irradiation on male C57BL/6 mice with doses between 10 and 22 Gy, comparing dose rates of 0.05 Gy/s (conventional), and 70 and 210 Gy/s (FLASH). Individual mouse doses were measured by film dosimetry, and mice were followed for survival. Results: Dose rates reached 210 Gy/s in our system. Field flatness was within 5% over the 2 cm abdomen field. Percentage depth dose was within 10% over 2 cm depth. Of 101 mice receiving 13-19Gy, 29% survived 20 days after conventional (NZ49) vs. 90% after FLASH (NZ59). Logistic regression dose-response for all 178 mice revealed a LD50 of 14.7 Gy for conventional and 17.5 Gy for FLASH (16.6Gy and 18.3Gy for the 70 and 210Gy/s cohorts, respectively), P
