Selection-driven plant metabolites for treatment of CNS diseases

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a solid tumor and is the fourth leading cause of cancer-related death in the U.S. The 5-year survival rate of its victims is lt5%. There is increasing evidence that most solidtumors have a subpopulation of tumor-initiating cells termed cancer stem cells (CSCs). The inability to eradicate these CSCs is postulated to be the reason for tumor relapse and death following initial responses to the current standard therapeutic regimen. In addition to the existence of CSCs, a critical problem in combating solid tumors is the heterogeneity of cell types within the tumor microenvironment. This heterogeneity is further complicated by epithelial-mesenchymal transition (EMT), a process thatplays a key role in cancer invasion and metastasis. Thus successful treatment of pancreatic cancer requires the development of therapeutics that can attack multiple pro-tumorigenic pathways simultaneously. The COARE team has demonstrated that the putativestem cell protein DCLK1 is a central regulator of key stem cell and oncogenic PDAC pathways and EMT. COARE's pre-clinical experimental data shows that therapeutic targeting of cells that overexpress DCLK1 arrests tumor growth in animal models. DCLK1 signaling inhibition triggers the induction/activation of several critical endogenous tumor-suppressor pathways within the tumor, which in turn regulate several downstream oncogenes and cancer growth regulatory pathways and processes and EMT-related transcription factors. DCLK1 is overexpressed in many solid tumors. COARE has generated anti-human-DCLK1 mAbs that inhibit DCLK1 function upon binding. Thus, in this Phase I SBIR project we propose to prove the feasibility of optimizing CBT-1111 that targets DCLK1 asa next-generation treatment for eradicating PDAC. We will pursue three Specific Aims. Aim 1: Prove that we can identify a safe and effective dose of CBT-1111. Aim 2: Assess via mAb modifications if we can effectively deliver CBT-1111 to the animals and cells. Aim 3: Demonstrate the effects of CBT-1111 on suppressing primary and metastatic tumor growth in xenograft models using human pancreatic cancer cells, and assess the effects on candidate gene expression in vivo. Test of Feasibility: CBT-1111 should knock down at least 50% of DCLK1 mRNA and protein and their downstream oncogenic signaling proteins in vitro and in vivo with minimal/no toxicity effects. CBT-1111 tagged with Cy7 should be tracked once injected in animals/cells using whole-body and cellularlive imaging. Additionally, we must observe a significant reduction (gt3 fold) in tumor size of the CBT-1111 treated tumors vs. controls. We must observe a reduction in metastatic tumor uptake in the lungs and liver following treatment with CBT1111. Finally, we must observe a 2-fold increase in candidate tumor suppressor microRNAs and a corresponding gt40% reduction in downstream targets at the protein and mRNA level in xenograft residual tumors following treatment with CBT-1111. Phase I success will leadto a follow-on Phase II validation project and ultimate Phase III commercialization. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma is the nation's fourth leading cause of cancer-related death, and it's very poor response to treatment results in a 5-year survival rate of only a few percent. The COARE RandD team has identified a new approach that shows significant promise in eliminating the current barriers to successful treatment of pancreatic cancer. The SBIRproject proposed here is focused on proving the feasibility of pursuing this novel approach as a means of developing the first effective biologic treatment for this devastating disease.