Operational Milestone #1

Over the last several years, it has become increasingly clear that cancer is a diverse disease where the treatments must be individualized. More recently, there has been increased recognition that if we can identify a group of cancer stem cells and target them, we may be able to treat cancer more aggressively. This hypothesis has led to several FDA approvals to treat hematologic cancers that originate in the bone marrow (lymphoma, or myeloma) but no cancer stem cell based therapies have yet been approved in “solid” tumors (e.g. breast or lung cancer). Therefore, the idea of attacking the cancer stem cell in solid tumors has become a priority for the scientific community. The cancer stem cell model suggests that there is a class of cells that are the main drivers of tumor growth that are resistant to standard treatments.

In our proposal, we are conducting a first in human Phase 1 clinical trial of a first-in-class mitotic inhibitor. The target is a serine/threonine kinase that was originally selected because blocking this target affects both tumor cell lines and tumor initiating cells (TICs). But, compared to chemotherapy, it appears to decrease more of the tumor initiating cell population in many cancer models. The goal of our Phase 1 trial is to determine the maximum tolerated dose, the recommended Phase 2 dose, and any dose-limiting toxicities. We have now completed the first part of this clinical trial which has characterized the safety, pharmacokinetic, and pharmacodynamic profiles of this agent. We have recently opened the expansion phase of this trial which is examining patients with select cancers (colon cancer, pancreas cancer and certain types of breast cancer) and we have begun to enroll in this group. We are also performing careful genomic biopsy-driven analyses that will help guide the optimal clinical development. Now that the maximum tolerated dose has been identified, the biomarker expansion cohort has become the priority in order to determine whether appropriately selected biomarkers are associated with a predictable patient response. This will allow a rational approach to study single agent and combination studies and allow us the opportunity to facilitate a targeted clinical development plan.