Abstract 1776: Focused ultrasound can act as a chemosensitizer by modulating unfolded protein response with activation of apoptotic pathway

Unfolded protein response (UPR) is a stress response induced in tumor cells because of higher rate of protein synthesis and subsequent misfolding of newly synthesized proteins in the endoplasmic reticulum (ER). To restore normal function of the cell, ER induces the expression of molecular chaperones, such as heat-shock proteins (Hsps) that try to correct protein misfolding. If the correction machinery fails, programmed cell death (apoptosis) could be induced in these cells. Therapeutic focused ultrasound is a promising non-invasive approach to ablate solid tumors. We have demonstrated previously that low intensity focused ultrasound (LOFU) induces mechanical stress in tumor cells and induce UPR. We hypothesized that induction of unfolded/misfolded protein burden in ER by LOFU could sensitize the tumor tissue for chemotherapeutic agents, such as, 17AAG, a HSP90 inhibitor by increasing the ER stress and switching on the apoptotic pathway. We explored whether concomitant application of 17AAG along with LOFU could increase the therapeutic ratio in murine prostate cancer model. RM-1 (murine prostate cancer cells) tumors were subjected to intratumor injection of 17AAG (10mg/kg of body weight, 2/week) and then treated with LOFU (3W at a frequency of 1Mhz, 100% duty cycle) (1/week) for three weeks. Tumor growth was measured twice a week. Three weeks after initiation of LOFU-17AAG treatment cycle, animals were sacrificed and histopathological analysis (HE 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1776. doi:10.1158/1538-7445.AM2011-1776