Early Translational III
Despite advances in molecular medicine and technology, the majority of cancer patients with late-stage disease do not survive five years after diagnosis. A growing body of scientific and clinical research indicates that a subset of stem cells within a tumor, called cancer stem cells, play a critical role not only in tumor initiation but also in chemoresistance, tumor relapse and metastasis that eventually leads to cancer death. Scientists believe that selectively targeting these cancer stem cells is the key to significantly increasing survival for patients with late-stage and metastatic tumors. Our group has developed highly effective methods to identify drugs that specifically inhibit cancer stem cell growth, and generated a large panel of candidate antibody drugs targeting a cancer stem cell protein essential for the growth of colorectal and many other cancers. The research in this grant will focus on selecting a lead antibody drug to develop and prepare for human clinical trials in advanced cancer patients within 3 years. We will optimize anti-tumor activity of our drug, manufacture sufficient high quality drug material for these studies, and evaluate safety and potential toxicity. Finally, to reduce the time, costs and high risk of failure traditionally associated with cancer drug development, we will identify markers of drug activity and clinical efficacy, as well as patient subpopulations most likely to respond to our drug, prior to initiating human studies.
Statement of Benefit to California:
This project will benefit the citizens of California in three distinct ways. First, we are developing a novel drug that will target a group of cancers that significantly reduce the quality and duration of life for thousands of Californians each year. Significant improvement in cancer survival will benefit not only our citizens, and will also benefit the State through increased worker productivity and decreased financial burden on the health care system. Secondly, we will support the novel approach of targeting cancer stem cells in the clinical setting. This will benefit the California biotechnology industry by helping it maintain its standing as the pre-imminent state for developing novel therapeutics. By validating the concept of treating cancer by attacking cancer stem cells, our research may also lead to additional drugs in this category or in other indications in the future. Finally, this project will benefit the state of California through job creation. Continued advancement and development of our drug candidates will directly lead to increased jobs at our company.
The objective of this Development Candidate (DC) proposal is to select a lead development candidate and complete preclinical studies for an antibody targeting a protein expressed by cancer stem cells (CSC) in colorectal and other solid tumors. Toward that end, six milestones are proposed: 1) selection of lead and backup development candidate antibodies; 2) generation of sufficient antibody for translational studies; 3) identification of biomarkers for use in pharmacodynamic (PD) studies; 4) development of a scalable process and analytical methods that are GMP-compatible and production of lead antibody; 5) performance of preliminary pharmacology studies; 6) demonstration of efficacy and validation of PD markers in a preclinical primary human xenograft model. Objective and Milestones - The objective to target colorectal CSC is appropriate and the Target Product Profile is reasonable, although the desired activity should include in vivo reduction or inhibition of CSC. - In general, the milestones and success criteria are good and are clearly described. The proposal addresses all the antibody-selection/production related issues well. Rationale and Significance - The applicant proposes to target CSC in colorectal cancer, a disease that kills >50,000 patients/year. Current treatment options are ineffective, thus successful development of this DC has the potential for very significant benefit. Research Project Feasibility and Design - Preliminary data showing reduced xenograft tumor growth after treatment with an antibody to the target does not assess whether CSC are being targeted. Limiting dilution secondary transplantation assays that are required to assess the presence of CSC after antibody treatment haven’t been done, and aren’t proposed until year 2. - The overexpression of the target has been documented only in bulk tumors (containing CSC and non-CSC), so it isn't clear whether the CSC subcomponent has overexpression of the target relative to normal SC. Thus, there may not be a good therapeutic window between the desired target CSC and the normal tissue SC where this target is expressed. - The mechanism by which the target promotes tumor development is poorly understood. The favored hypothesis is that inhibition of the target will inhibit a key signaling pathway promoting cancer stem cell self-renewal. If the antagonistic nature of this antibody is critical to its success, then this activity should be among the first aspects evaluated. - The proposed approach for identification of biomarkers that could be used in pharmacodynamic (PD) assays is to study gene expression in tumorspheres. However, no enrichment for cancer stem cells will be employed so only total bulk population data will be obtained, and the relevance of that data to the CSC subpopulation is unclear. Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - While some reviewers felt that the investigators clearly understand the area of antibody development, others commented that the team has relatively limited experience in that area. - While some reviewers felt that the investigators have good expertise in stem cell biology and early translational research, others felt that the investigators are not strong in understanding the cancer stem cell theory and the expected biological outcomes/responses of that theory. - The advisory and consulting people listed in the proposal are well qualified and provide needed expertise. In addition, the team is aided by an excellent scientific advisory board. - The budget for certain subcontract and preclinical model expenses appears to be excessive. Collaborations, Assets, Resources and Environment - Laboratory facilities on-site are minimal, but arrangements have apparently been made to access nearby external resources. - It appears that work from humanization forward will be outsourced. This is likely to be important for success given that there appears be insufficient personnel on the proposed team with the depth of antibody development expertise to implement all the proposed research. - It isn't clear whether the IP position is strong for this target/mAbs since there are a number of issued patents and patent applications from other parties related to this target and therapeutic strategies. Responsiveness to the RFA - The proposed DC purports to target CSC in colorectal cancer, so meets the RFA objectives.
- A motion was made to move this application into Tier 3, Not Recommended for Funding. Reviewers were unconvinced that a mAb to the proposed target would target cancer stem cells. The motion carried.