Abstract 1161: Dimethylaminoparthenolide (DMAPT), an oral nuclear factor kappa B inhibitor (NFκB), enhances radiation therapy and enhances epidermal growth factor tyrosine kinase inhibitor (EGFR TKI) activity
Authors: Morel Katherine L. , Sykes Pamela J. , Gokhale Prafulla C. , Lee Gwo-Shu Mary , Tiv Hong , Sweeney Christopher J. 
Published: July 2017

Abstract
Introduction: NFκB can promote cancer and resistance to therapy as well as mediate tissue injury in response to radiation (XRT). We assessed DMAPT efficacy alone and in combination with XRT, and also with an EGFR TKI, and assessed whether it can mitigate XRT side effects.
Methods: Six-week old male TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) mice received DMAPT (100 mg/kg) orally or vehicle control 3x/week until palpable tumors formed and lung metastases were analyzed histologically. In separate studies, 16 week old TRAMP mice were treated with 100 mg/kg DMAPT 3x over 1 week before 6 Gy whole-body XRT. Cancer and normal tissues were analyzed for apoptosis for up to 72 hours post-XRT. NCr nude mice were inoculated with H1975 (T790M mutation non small cell lung cancer, NSCLC) subcutaneously. When tumors reached 200 mm3, treatment (Rx) commenced: vehicle, DMAPT 100mg/kg/day, EGF TKI-AZD9291 25mg/kg/day, combination.
Results: Long-term Rx with DMAPT extended the median time to palpable prostate tumor by 41.3 (p = 0.0013) days. Chronic DMAPT Rx reduced the number of metastatic lesions/mm2 in TRAMP lungs 20-fold (0.077 ± 0.12 SD) compared to a vehicle control (1.47 ± 1.28 SD) (p = 0.0004). XRT-induced apoptosis doubled in TRAMP prostates (with moderate to high grade PIN lesions) treated with DMAPT prior to 6 Gy XRT (101.3 % increase, p = 0.039). DMAPT induced the greatest radiosensitivity in TRAMP prostates with higher grade PIN (R2 = 0.79, p = 0.0001), while apoptosis frequency in tissues with lower grades of PIN was the same as vehicle control TRAMP mice (R2 = 0.024, p = 0.3). DMAPT also reduced XRT-induced apoptosis in healthy TRAMP spleen (32.9 % reduction, p = 0.003) and rectum (28.7 % reduction, p = 0.0001). In the H1975 experiment, DMAPT monotherapy did not differ from the vehicle controls. In the single agent AZD9291 group, 2 of the 8 mice had resistance emerge during Rx and adding DMAPT to AZD9291 reversed resistance in one of these. Rx was held at Day 220 in 3 remaining AZD9291 treated mice with no evidence of tumor and only 1 mouse was alive with no tumor at day 260. For mice receiving Rx with AZD9291 and DMAPT from D1, resistance emerged in 1 mouse, and at D140 all remaining mice with no evidence of tumor had Rx stopped, and 3 mice were still tumor free at D260. Two mice had regrowth, were retreated, and at D200 without evidence of tumors had Rx held, and one had no tumor at D260 at the end of the experiment. In total, 4 of 8 mice in the AZD9291 and DMAPT had no tumor off therapy at D260.
Conclusion: Radiation and EGFR TKI resistance has been linked to NFκB activation. DMAPT slows down cancer progression and decreases metastatic lesions in a prostate cancer mouse model, protects normal tissue from radiation induced apoptosis, augments radiation induced apoptosis in prostate cancer and augments EGFR TKI efficacy in T790M mutant NSCLC.
Citation Format: Katherine L. Morel, Pamela J. Sykes, Prafulla C. Gokhale, Gwo-Shu Mary Lee, Hong Tiv, Christopher J. Sweeney. Dimethylaminoparthenolide (DMAPT), an oral nuclear factor kappa B inhibitor (NFκB), enhances radiation therapy and enhances epidermal growth factor tyrosine kinase inhibitor (EGFR TKI) activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1161. doi:10.1158/1538-7445.AM2017-1161