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., with a 5% 5-year survival rate. Despite FDA- approved therapeutic regimens and advances in medical and surgical care, no significant impact on PDAC patient survival has been observed. In 2013, an estimated 45,220 Americans were expected to be diagnosed, and 38,460 were expected to die from PDAC. There is increasing evidence that most solid tumors, including PDAC, have a sub-population of tumor-initiating cells termed tumor stem cells (TSCs) and that epithelial- mesenchymal transition (EMT), a key feature in cancer invasion and metastasis, is linked to a TSC phenotype. COARE has shown that the TSC marker DCLK1 is significantly upregulated in PDAC and is a central regulator of pluripotency and EMT. DCLK1 is overexpressed in PDAC epithelia and stroma, where it strongly correlates to pancreatic intraepithelial lesion stage, and inhibition of DCLK1 by siRNA triggers a signaling cascade that reduces stemness and EMT in PDAC cells. Recent studies definitively confirmed Dclk1's TSC status in the Apcmin/+ model of intestinal neoplasia, and a similar role for Dclk1 in PDAC initiation is indicated by lineage- tracing mouse models. Recent studies also indicate that Dclk1 marks a population of cancer-initiating cells with TSC characteristics that fuel pre-invasive/invasive cancer in multiple mouse models of PDAC. To date, experiments targeting DCLK1 in colorectal cancer and PDAC xenograft models have demonstrated inhibition of EMT and pluripotency factors, leading to reduced invasion and tumor growth arrest. DCLK1 is a unique TSC marker that contains an extracellular C-terminal domain expressed in the primary tumor and circulating tumor cells (CTCs). Antibody-drug conjugates (ADCs) allow the specific targeting of tumor cell-surface expressed antigens with cytotoxins, with the potential benefits of enhanced efficacy and reduced off-target toxicity. Recently, Abraxane(r) (a formulation based on Paclitaxel [PTX]) was FDA-approved for PDAC treatment in combination with gemcitabine. COARE's CBT-3112 is a PTX-based ADC targeting the DCLK1 TSC/CTC antigen in PDAC, with potential to improve outcomes in locally advanced/metastatic PDAC.
Two Specific Aims will be pursued: 1) demonstrate that CBT-3112 effectively delivers a cytotoxic payload to PDAC cells; and 2) demonstrate that CBT-3112 suppresses tumor growth in orthotopic PDAC models with or without gemcitabine and prevents in vivo metastasis. Test of Feasibility: CBT-3112 should induce cell death and inhibit proliferation comparable to PTX alone. It should also significantly inhibit cell invasiveness and demonstrate internalization of PTX. In in vivo models, CBT-3112 should clearly reduce tumor growth and metastasis and result in decreased DCLK1 expression due to DCLK1+ cell death, precipitating reduced expression of stemness and EMT factors regulated by DCLK1 compared to controls. Phase I success will lead to a follow-on Phase II validation project and ultimately Phase III commercialization.
Pancreatic cancer is the Nation's fourth leading cause of cancer-related death, and has a dismal 5-year survival rate of only a 5%. The COARE Biotechnology R&D team has identified a new antibody-drug conjugate based approach that shows significant promise in eliminating the current barriers to successful treatment of locally advanced and/or metastatic pancreatic cancer. This SBIR project is focused on proving the feasibility of pursuing this approach as a therapy for improving outcomes in advanced and metastatic pancreatic cancer.
