Pancreatic cancer is one of the most lethal cancers with a five-year survival of <5%. Surgery, which offers the only realistic hope, has a limited role with only about 10% of patients undergoing resection of any variety. Current chemotherapy or radiation therapy regimens offer minimal or no help. Thus, there is a dire need for new agents against pancreatic cancer. Recently, we have studied phospho-valproic acid (P-V), a small molecule that inhibits pancreatic xenografts growth by 96% compared to control, by inhibiting primarily mitochondrial STAT3. Moreover, we have demonstrated successful inhibition of pancreatic cancer growth using phospho-farnesylthiosalicylic acid (P-F), a novel farnesylthiosalicylic acid derivative that strongly inhibits Ras activation. Given that activating kras mutations and aberrant STAT3 expression are important mediators of pancreatic cancer initiation and development, these signaling pathways are attractive targets for chemotherapeutic development. Objective/Hypothesis: We propose to study the two promising drugs P-V and P-F as a novel drug combination for pancreatic cancer treatment. Our hypothesis is that P-V/P-F is an effective drug combination against PC, acting synergistically mainly through their effect on mitochondrial STAT3 and Ras pathways, two signaling pathways critical for pancreatic cancer growth.
Specific Aims : We will pursue the following aims: (1): To determine the efficacy of the P-V/P-F drug combination in preclinical models of pancreatic cancer; (2): To determine the mechanism of action of the P-V/P-F combination in vitro and in vivo; and (3): To evaluate the metabolism and PK/PD of the P-V/P-F combination in cultured PC cells and animals. Study design: Our studies will involve the novel evaluation of the efficacy, metabolism and PK/PD parameters of this novel drug combination in animal models of pancreatic cancer and the assessment of its mechanism of action in vitro and in vivo. Cancer relevance: At the completion of these studies, we expect to have determined key pharmacological parameters of a promising novel drug combination against pancreatic cancer. Given the lack of effective agents against pancreatic cancer, we believe that the proposed work holds the promise of a significant advance in this area.
Given pancreatic cancer's dismal prognosis and the lack of effective agents against it, any progress towards controlling this lethal disease serves public health well. The proposed work is designed to make a contribution towards the development of a novel drug combination for pancreatic cancer treatment. We believe that the proposed work holds the promise of a significant advance in this area and will set the stage for its further evaluation.
| Mallangada, Naveen A; Vargas, Joselin M; Thomas, Swaroopa et al. (2018) A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras. Mol Carcinog 57:1130-1143 |
| Mattheolabakis, George; Wang, Ruixue; Rigas, Basil et al. (2017) Phospho-valproic acid inhibits pancreatic cancer growth in mice: enhanced efficacy by its formulation in poly-(L)-lactic acid-poly(ethylene glycol) nanoparticles. Int J Oncol 51:1035-1044 |
