COARE BIOTECHNOLOGY, INC. — Department of Health and Human Services SBIR Phase I: 102

Description

DESCRIPTION provided by applicant 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 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 an estimated Americans were expected to be diagnosed and 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 DCLK is significantly upregulated in PDAC and is a central regulator of pluripotency and EMT DCLK is overexpressed in PDAC epithelia and stroma where it strongly correlates to pancreatic intraepithelial lesion stage and inhibition of DCLK by siRNA triggers a signaling cascade that reduces stemness and EMT in PDAC cells Recent studies definitively confirmed Dclk andapos s TSC status in the Apcmin model of intestinal neoplasia and a similar role for Dclk in PDAC initiation is indicated by lineage tracing mouse models Recent studies also indicate that Dclk 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 DCLK in colorectal cancer and PDAC xenograft models have demonstrated inhibition of EMT and pluripotency factors leading to reduced invasion and tumor growth arrest DCLK 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 COAREandapos s CBT is a PTX based ADC targeting the DCLK TSC CTC antigen in PDAC with potential to improve outcomes in locally advanced metastatic PDAC Two Specific Aims will be pursued demonstrate that CBT effectively delivers a cytotoxic payload to PDAC cells and demonstrate that CBT suppresses tumor growth in orthotopic PDAC models with or without gemcitabine and prevents in vivo metastasis Test of Feasibility CBT 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 should clearly reduce tumor growth and metastasis and result in decreased DCLK expression due to DCLK cell death precipitating reduced expression of stemness and EMT factors regulated by DCLK compared to controls Phase I success will lead to a follow on Phase II validation project and ultimately Phase III commercialization PUBLIC HEALTH RELEVANCE Pancreatic cancer is the Nationandapos s fourth leading cause of cancer related death and has a dismal year survival rate of only a The COARE Biotechnology Randamp 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