Development of ADC to Target Tumor Stem Cells In Colorectal Cancer

DESCRIPTION provided by applicant Colorectal cancer CRC is the third leading cause of cancer related death in the U S Although advances in CRC screening surgical therapies and medical management have improved clinical outcomes there still is a major need to develop better medical therapies for CRC particularly among those with advanced local or metastatic disease The year survival rate of victims with stage IV disease is a dismal There is increasing evidence that most solid tumors including CRC have a subpopulation of tumor initiating cells termed tumor stem cells TSCs Epithelial mesenchymal transition EMT is a key feature in cancer invasion and metastasis and is linked to a TSC phenotype in CRC The COARE team has demonstrated that the tumor stem cell marker DCLK is significantly upregulated in CRC and is a central regulator of key oncogenic pathways and EMT Recent studies have definitively confirmed DCLK andapos s TSC status in the Apcmin model of intestinal neoplasia COAREandapos s pre clinical experimental data shows that therapeutic targeting of cells that overexpress DCLK arrests tumor growth in xenografts and reduces the size and number of adenomas in Apcmin mice DCLK signaling inhibition triggers the induction activation of several critical endogenous tumor suppressor pathways within the tumor which in turn regulate oncogenic pathways and processes and EMT related transcription factors DCLK is a unique TSC marker because it contains an extracellular C terminal domain 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 COAREandapos s CBT is a Paclitaxel based ADC targeting the DCLK TSC CTC antigen in CRC with the potential to improve outcomes in locally advanced metastatic CRC We will pursue three Specific Aims Aim Demonstrate that CBT will effectively deliver a cytotoxic payload to CRC cells resulting in cell death Aim Demonstrate that CBT will suppress tumor growth in TSC derived tumor isografts Aim Demonstrate that CBT will suppress tumor growth in xenograft models of CRC with and without fluorouracil and prevent in vivo metastasis Test of Feasibility CBT should induce cell death and inhibit proliferation comparable to Paclitaxel PTX alone Additionally it should significantly inhibit cell invasiveness and demonstrate internalization of PTX In TSC isografts CBT treatment should precipitate a significant reduction andgt in tumor growth and andgt induction of tumor suppressors and loss of downstream oncogenic signaling compared to controls In the tumor xenografts CBT should significantly reduce tumor volume alone sensitize tumors to fluorouracil FU and prevent engraftment of metastatic CRC cells in an in vivo metastasis assay Phase I success will lead to a Phase II project focused on humanizing DCLK mAb completing detailed pharmacokinetics and in vivo toxicity analyses and preparing for IND clinical trial work to set th stage for ultimate commercialization PUBLIC HEALTH RELEVANCE Colorectal cancer is the Nationandapos s third leading cause of cancer related death and stage IV disease has a dismal year survival rate of only a The COARE 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 colorectal cancer This SBIR project is focused on proving the feasibility of pursuing this approach as a therapy for improving outcomes in advanced and metastatic colorectal cancer