Development of a DCLK1 siRNA Nanoparticle as Targeted Therapy to Treat Pancreatic Cancer

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Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating human cancers. It is the fourth leading cause of cancer-related deaths in the U.S. annually, with a <7% 5-year survival rate. Despite FDA-approved therapeutic regimens and marked improvements in medical and surgical care, no significant impact on PDAC patient survival has been achieved. In 2017, some 53,000 Americans are expected to be diagnosed, and ~43,000 are expected to die from PDAC. There is increasing evidence that most solid tumors such as PDAC have a subpopulation of tumor-initiating cells termed tumor stem cells (TSCs) that are involved in cancer invasion/metastasis through a process called epithelial-mesenchymal transition (EMT). Additionally, studies have demonstrated that DCLK1 marks TSCs in the Apcmin/+ mouse model of intestinal neoplasia. COARE has shown that the TSC marker DCLK1 is upregulated in PDAC and is a central regulator of key oncogenic, pluripotency pathways and EMT. Also, the Dclk1 role in PDAC initiation is demonstrated by lineage-tracing and TSC-initiating mouse models. COARE's pre-clinical data shows that targeting of cells that overexpress DCLK1 arrests xenograft tumor growth. DCLK1 signaling inhibition using DCLK1 specific siRNAs delivered via PLGA nanoparticles (NPs) triggers induction and activation of several critical endogenous tumor- suppressor pathways, which in turn regulate oncogenic pathways and EMT-related transcription factors. COARE, in collaboration with Bioneer Inc., has developed CBT-411E (DCLK1 siRNAs encapsulated into SAMiRNATM conjugated with EGFR antibodies), which has several advantages over PLGA NPs including enhanced efficacy, reduce off-target toxicity, increase siRNA half-life, and minimal cytokine or interferon induction in human PBMCs. The potential outcome of this Fast-Track SBIR project is improved inhibition of PDAC and preparation for human clinical trials and commercialization. We will pursue four Phase I/II Aims: Fast-Track Phase I: Aim 1: Formulate and standardize CBT-411E. Aim 2: Demonstrate effectiveness of CBT- 411E against PDAC in vitro and in vivo. Fast-Track Phase II: Aim 3: Obtain optimum pharmacokinetic (PK) and pharmacodynamic (PD) properties, and continued preclinical efficacy of CBT-411E in patient-derived tumor xenograft models of PDAC. Aim 4: Perform IND-enabling toxicity and immunogenicity studies for CBT- 411E in Sprague-Dawley rats (SDR) and non-human primates (NHPs). Milestones: CBT-411E will show >40% inhibition of DCLK1 activity (10 nM); a DCLK1 MOA (>50% reduction in EMT factors, oncogenes (NOTCH, MYC, VEGF, and COX2) and DCLK1 expression); continued preclinical efficacy incl. a >3-fold reduction in patient-derived model tumorigenesis; suitable PK/PD, and <5% measureable toxicity in SDR and NHPs. Desired Outcome: Phase I/II SBIR success will provide the results and data needed to engage private-sector investors/partners in funding the regulatory approval needed for clinical trials in PDAC patients. Success will lead to marketing CBT-411E as the first PDAC treatment for significantly increasing patient survival.