Abstract A105: Minnelide, a potent chemotherapeutic agent, causes pancreatic tumor regression.

Background: Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States, with a median survival of less than six months. Our group has previously shown that triptolide, a diterpenoid, and its water soluble variant, Minnelide, inhibits HSP70 expression leading to cell death in pancreatic cancer cells. Aim: To evaluate the potential of Minnelide to increase survival and cause pancreatic tumor regression in vivo. Methods: In order to assess the ability of Minnelide to increase survival and to cause tumor regression, we utilized the following pancreatic tumor models: 1) Pancreatic cancer cells derived from ascites (AsPC1) were orthotopically implanted into the tail of the pancreas of nude mice, and, 2) tumors from human patients were implanted subcutaneously into SCID mice. Both models were treated with either vehicle or Minnelide (0.21 or 0.42 mg/kg QD) at different stages of tumor formation. Animal survival and tumor weight/volume were used as measures of disease progression. HSP70 expression was measured in tumors from Minnelide or saline-treated mice by real time PCR, and immunohistochemistry. Results: In the ascites- derived cell line (AsPC-1) model, Minnelide dramatically extended median survival from 36 days in the saline group to more than one year (experiment terminated on Day 384) in the Minnelide group. The average tumor volume in the saline group was significantly greater (1181 ± 135.91 mm3) than tumors from animals in the Minnelide group (100 ± 6.0 mm3). In the human xenograft subcutaneous model, to study tumor progression, Minnelide treatment was started when tumor volume was 334.996 ± 52.84 mm3. Forty days posttreatment, tumor size in the saline group reached nearly 1000 mm3 at which point animals were sacrificed. At the same time point, tumor size decreased to nearly zero in the Minnelide treated group. In support of these data, average tumor weight decreased from 1160 ± 265.0 mg in the control group to 90 ± 78 mg in the treatment group. To evaluate the ability of Minnelide to cause tumor regression, Minnelide (0.42 or 0.21 mg/ kg QD) treatment was started when tumor volume was 1051.659 ± 141.47 mm3. In both Minnelide groups (0.42 or 0.21 mg/kg), forty days post-treatment, tumor volume decreased from 1051.659 ± 141.47 mm3 to nearly zero. Histological assessment of tumors from these animals showed ablation of pancreatic dysplasia, accompanied by a decrease in HSP70 levels. Conclusion: Using both an orthotopic pancreatic cancer cell line-derived model and human xenograft transplants, we have demonstrated that Minnelide is able to dramatically increase survival and cause tumor regression. We are currently in the process of initiating Phase I clinical trials for this drug. Citation Format: Veena Sangwan, Rohit Chugh, Satish P. Patil, Gunda I. Georg, Selwyn M. Vickers, Ashok K. Saluja. Minnelide, a potent chemotherapeutic agent, causes pancreatic tumor regression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A105.