Detection and Treatment of Advanced Prostate Cancer with Radiolabeled Transferrin Molecules
Abstract
The goal of this proposal is to develop a new therapy to treat castration-resistant prostate cancer, the most advanced and lethal form of the disease. Our new therapy is a radiolabeled version of a naturally occurring serum protein called transferrin. We decided to develop a transferrin-drug conjugate foremost because two common drivers of prostate cancer (MYC and mTOR) strongly upregulate transferrin uptake in a prostate cancer cell. Therefore, we hypothesize that virtually all castration-resistant prostate cancer patients will harbor disease with high avidity for transferrin. Moreover, MYC cannot be directly drugged, and mTOR inhibition slows tumor growth, but does not kill tumor cells. Consequently, there is an urgent need to develop therapeutic strategies targeting these prostate cancer drivers with agents capable of inducing tumor cell death. While using transferrin to bring a therapeutic radioisotope to prostate cancer is highly innovative, we anticipate a high likelihood of success. We are optimistic given that two radioisotopes (Xofigo®, Samarium lexidronam) that target remodeling bone were recently approved in the United States for the treatment of castration-resistant prostate cancer, showing that a tumor response can be affected with radiotherapy in spite of potential damage to normal tissue. Our transferrin-drug conjugate has the potential to be even more impactful, as it will address soft tissue and bony metastases, and our new human imaging data show clear resolution of prostate cancer lesions, with very little transferrin uptake in normal tissues (the historical drawback cited by the community against transferrin-drug conjugates). Another advantage of this approach is that human transferrin is commercially available and safe. Consequently, a transferrin-drug conjugate sidesteps two of the historical barriers to clinical translation of biomolecule-drug conjugates: the excessive cost of humanization and Good Manufacturing Practices (GMP) production of the biomolecule. This consideration elevates the likelihood of near-term clinical translation of a transferrin-drug conjugate. A final advantage is that the radionuclide we are proposing to work with also emits decays that can be detected with SPECT, a nuclear imaging modality in routine use worldwide for the management of castration-resistant prostate cancer. The implication for drug development is that efficacy can be predicted with a SPECT scan well prior to subjecting the patient to high dose targeted radiotherapy. A predictive biomarker of this type is also highly responsive to the major themes of the Precision Medicine Initiative. This training component of this proposal is an extension of the relationship I have built with Drs. Evans and Ruggero over the past year. This proposal will consolidate our collaboration, while further advancing my career to my ultimate goal of supervising an academic laboratory at a research center or university in the USA. Because of Dr. Evans s and Ruggero s expertise in preclinical pharmacology, imaging, and prostate cancer cell biology, I expect that their mentorship will round out my training, allowing me to become a leader in new biomarker and therapy development for prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610435
Entities
People
- Charles Truillet
Organizations
- United States Army
- University of California, San Francisco