Pancreatic cancer (PC) remains one of the least treatable cancers, with high metastatic propensity, poor response to existing therapies and short survivals that have not improved substantially over several decades. Most PC patients will die within the first year after diagnosis and <6% will survive five years. Currently over 40,000 new PC cases and 17,000 deaths a year are reported in the U.S. and it is expected that within a few years PC will become the third leading cause of cancer deaths. Surgical removal of the tumor is possible in less than 20% of PC patients and chemotherapy typically offers only several months of extended survival. It is widely recognized that activating mutations of the KRAS gene are key drivers of pancreatic cancer, yet the KRAS protein has proved refractory to drugging by small-molecule approaches, despite decades of effort. Two investigators on this application, Drs. Gunderson and Goraczniak, invented a new gene silencing technology called U1 Adaptors. In a large proof-of-concept study, U1 Adaptors targeting the BCL2 oncogene were recently shown to effectively suppress growth of human melanoma xenograft tumors in mice, without observable toxicity, when administered twice weekly at low dose (0.034 mg/kg). In comparison to previous generations of gene silencing oligonucleotides, U1 Adaptors are highly stable in vivo and easy to deliver selectively into diseased cells, consistent with their novel mechanism of action. We have teamed with additional investigators who bring expertise in pancreatic cancer (Dr. Carpizo) and cancer molecular genetics (Dr. Brenneman) to develop and validate anti-KRAS U1 Adaptors in mouse models of pancreatic cancer. The era of targeted therapies and personalized/precision medicine is upon us, and patient genomic data is now driving the development of novel gene-targeted therapeutics. This an arena for which U1 Adaptor technology is highly suited. U1 Adaptor gene silencing technology, through rationale design, has potential to rapidly produce potent anti-KRAS U1 Adaptor oligonucleotides that will be lead compounds for further development towards human trials. In broad terms, our specific aims are: 1) design and confirm active anti- KRAS Adaptors targeting the mouse and human KRAS genes; (2) to develop methods for highly efficient delivery of the anti-KRAS U1 Adaptors through the stroma of pancreatic tumors, using the KPC mouse as a model, and (3) to assess in-vivo efficacy in the best available mouse models of pancreatic cancer, specifically to suppress tumor growth in the mouse KPC model and in patient-derived xenografts of pancreatic cancer. Our long term goal is to develop a revolutionary pancreatic cancer therapeutic. Success in this project will also enable application of KRAS U1 Adaptors to solid tumors arising in other sites such as lung and colon.
Mutations in one key gene, called KRAS, drive the growth of almost all pancreatic cancers. Our ongoing inability to combat the effects of mutated KRAS is a major part of what makes pancreatic cancer one of the most difficult-to-treat and deadly forms of cancer. This project will bring a new class of drug technology for targeted silencing of genes, U1 Adaptors, to bear on the problem of suppressing mutated KRAS genes and test them for ability to slow or stop tumor growth in pre-clinical (animal) models of pancreatic cancer.
| Tsang, Ashley T; Dudgeon, Crissy; Yi, Lan et al. (2017) U1 Adaptors Suppress the KRAS-MYC Oncogenic Axis in Human Pancreatic Cancer Xenografts. Mol Cancer Ther 16:1445-1455 |
| Boregowda, Rajeev K; Medina, Daniel J; Markert, Elke et al. (2016) The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma. Oncotarget 7:29689-707 |
| Goraczniak, Rafal; Wall, Brian A; Behlke, Mark A et al. (2013) U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo. Mol Ther Nucleic Acids 2:e92 |
