New-Generation Precision Medicines: Biomarker-Targeted TR3 Biologics Overcome Treatment Resistance in Ovarian Cancer
Abstract
The ultimate goal in the field of cancer drug development is to generate therapeutics that will automatically find and destroy their intended cellular targets and spare healthy host tissues (magic bullets), leading to more efficient therapies and fewer off-site toxicities. Our current proposal will help getting a major step closer to this proclaimed goal. By combining an enhanced version of nature s own anti-cancer drug with ways to selectively deliver the therapeutic directly to the malignant cells, we developed a promising new platform technology featuring enhanced cancer cell death and reduced off-target toxicities. Ovarian cancer is uniquely suitable for a targeted drug development approach due to the high frequency and abundancy of the biomarkers mesothelin and CA125 (MUC16) present on the surface of the tumor cells with only limited presence on healthy host cells. We will use these tumor markers as docking sites for our recently redesigned therapeutic TR3, a functionally and structurally improved variant of the clinically explored but underperforming cancer therapeutic rhApo2L/TRAIL. Of note, the targeted delivery and cell surface attachment of TR3 is associated with an improved killing activity due to the induction of much stronger death signaling events compared to the non-targeted death ligand, capable of overcoming acquired or inherent resistance to TRAIL-based therapeutics. In contrast to non-targeted TR3, our targeted TR3 biologics are anticipated to rapidly accumulate at the tumor site in mouse models of ovarian cancer. According to our preliminary data, this cancer-selective delivery mode is expected to substantially enhance drug efficacies and result in better treatment outcomes alone and in combination with standard-of-care chemotherapy or other sensitizers of the TR3-induced, complementary intrinsic pathway of cell death, such as other tumor-targeted pathway enhancers (SW IV-134). Overall, we believe this to be a highly innovative and translational grant proposal that has the potential to make a difference in the treatment of ovarian cancer with reduced toxicities compared to currently available treatment regimens. We further believe that this approach will likely have a patient-related outcome in less than 5-6 years and will have a significant impact on finding a cure for women diagnosed with ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710102
Entities
People
- Dirk Spitzer
Organizations
- United States Army
- Washington University in St. Louis