Pancreatic cancer is the fourth leading cause of cancer death in the United States with a grim 5-year survival rate of less than 5%. Pancreatic cancers are resistant to cytotoxic therapies, and their profound immunosuppressive nature renders patients unresponsive to immunologic therapies. These barriers highlight the urgent need for new therapeutic strategies for this disease. One principal mediator in pancreatic cancer is the Signal-Transducer and Activator of Transcription-3 (STAT3) protein. STAT3 is activated (phosphorylated to pSTAT3) in most human pancreatic cancer specimens and cooperates with activated K-Ras and Pdx to drive initiation and progression of pancreatic ductal adenocarcinoma, as has been demonstrated in mouse models.6 STAT3 signaling is therefore an attractive target due to its role in regulating cell proliferation, apoptosis, invasion, angiogeness and immune suppression. STAT3 inhibition is known to promote apoptosis of human pancreatic cancer cell lines in vitro and in mouse tumor models, and it serves as a convergence point for multiple upstream tyrosine kinases relevant to cell survival. STAT3 targeting may therefore be superior to other approaches for overcoming therapy resistance that is observed in most patients. Finally, STAT3 is inactive in normal pancreas or other differentiated tissues and is not required for pancreatic development or homeostasis as shown by conditional knockout mice. Based on this evidence, STAT3 is an important and clinically relevant target for pancreatic cancer. However, development of inhibitors to directly and specifically inhibit STAT3 protein has been challenging. This is due to the hydrophobic nature of the phospho-Tyr705 site within the STAT3 Src homology 2 domain required for STAT3-STAT3 homodimerization and its downstream effects. Our group previously described a novel lead compound, FLLL32, that directly interacts with the STAT3 SH2 domain, inhibits phosphorylation and DNA binding, and induces caspase-dependent apoptosis of pancreatic and other tumor cell lines. Although FLLL32 was potent and STAT3 specific, its hydrophobic nature was a detriment to bioavailability. We subsequently developed a second generation phosphate pro-drug, FLLL100P. Pharmacokinetic (PK) studies revealed FLLL100P has superior solubility, rapid de-phosphorylation to active FLLL100, and 10-fold higher systemic exposure compared to FLLL32. Importantly, the active FLLL100 metabolite retains STAT3 specificity and similar potency to FLLL32. In this proposal, we will systematically define the in vivo relationship between FLLL100P PK and modulation of STAT3 signaling (PD) in pancreatic tumors. These studies will enable development of dose regimens to achieve FLLL100P concentrations and durations of exposure within pancreatic tumors in vivo for optimal suppression of STAT3 signaling. This has not been accomplished previously, and is therefore essential for movement of these agents further in development. Resulting data will be valuable for guiding further structural or formulation modifications to further enhance their activities and ultimately move them into clinical evaluation in patients with pancreatic cancer.
The Signal Transducers and Activators of Transcription 3 (STAT3) signaling pathway has been identified as a contributor to pancreatic cancer growth and proliferation. This pathway therefore represents a potential therapeutic target for treatment of this disease. This proposal aims to develop therapeutic regimens of novel, selective STAT3 inhibitor compounds to achieve optimal inhibition of STAT3 signaling in mouse pancreatic cancer models. This will be achieved by thorough characterization of the pharmacokinetic-pharmacodynamic relationship of these new agents and application of this information in dose optimization and anti-tumor efficacy studies. Results from this project have the potential to significantly improve the development of STAT3 targeted drug development strategies.
|Zhao, Chengguang; Li, Huameng; Lin, Huey-Jen et al. (2016) Feedback Activation of STAT3 as a Cancer Drug-Resistance Mechanism. Trends Pharmacol Sci 37:47-61|
|Zhao, Chengguang; Xiao, Hui; Wu, Xiaojuan et al. (2015) Rational combination of MEK inhibitor and the STAT3 pathway modulator for the therapy in K-Ras mutated pancreatic and colon cancer cells. Oncotarget 6:14472-87|
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|Lesinski, Gregory B (2013) The potential for targeting the STAT3 pathway as a novel therapy for melanoma. Future Oncol 9:925-7|