Exploring CUB Domain-Containing Protein 1 as a Theranostic Target for Castration-Resistant Prostate Cancer
Abstract
Radioligand therapy (RLT), a treatment approach in which a radioactively labeled drug (e.g., small molecule, antibody) administered intravenously to a patient delivers ionizing radiation to multiple tumors within the body simultaneously, has shown promise in controlling and even curing many metastatic cancers. Although not a new therapeutic strategy (RLT with radioiodine has been used for decades to cure a form of thyroid cancer), RLT is undergoing a renaissance that has resulted in several recent FDA drug approvals for diverse cancers within the past 5 years (e.g., Lutathera, Azedra, Xofigo). Although it has not been extensively studied as a treatment for metastatic castration-resistant prostate cancer (mCRPC), the few RLTs that have been tested in these patients have shown encouraging clinical activity. Examples include bone-targeting RLTs like Xofigo, and 177Lu-PSMA 617, which targets the protein PSMA. These therapies come with caveats, most notably that treatment responses are temporary and neither therapy can treat the increasingly common neuroendocrine form of mCRPC, which has low PSMA expression and typically arises in soft tissues. Thus, identifying a protein that is more broadly present in mCRPC would likely provide a pathway to develop a more effective RLT. The hypothesis of this project is that CUB domain containing protein 1 (CDCP1) is one such protein. We and others have already shown that CDCP1 is widely present at high levels in biologically diverse prostate cancer tumors, which should enable effective tumor treatment via CDCP1-directed RLT. Moreover, an analysis of our mCRPC patient biopsies and tumor models has shown that CDCP1 is present in mCRPC tumors that would be expected to respond poorly to PSMA-directed RLT, including neuroendocrine prostate cancer. To treat tumors with CDPC1 expression, we developed first in class, highly potent and specific antibodies targeting CDCP1 and have already established proof of concept that they can be employed for RLT to eliminate other highly aggressive tumors (e.g., pancreatic cancer). Last, others have shown that standard of care therapies targeting the androgen receptor (e.g. enzalutamide) actually stimulate prostate cancer cells to produce more CDCP1, which raises the possibility that combining approved therapies like enzalutamide with CDCP1-directed RLT could result in more profound tumor cell death. Overall, we have strong foundational data showing that CDCP1 is a promising drug target for mCRPC, and we have unique technologies in place to begin testing this hypothesis immediately. The first phase of this project will establish proof of concept that CDCP1 directed RLT using either of two clinically active and human ready therapeutic isotopes (Lu-177 or Ac-225) can ablate prostate cancer tumors in mouse models. The second phase of this project will explore strategies to maximize tumor responses, both by tuning the dosing of CDCP1 directed RLT to increase tumor delivery of therapy, and by combining RLT with other therapies that we expect to improve tumor control, for example enzalutamide and apalutamide. During the final phase of this project, we will perform a deeper analysis of our tissue bank of over 300 mCRPC patient biopsies to (1) better define the average level of CDCP1 abundance, (2) determine whether CDCP1 is more abundant in certain subtypes of mCRPC like neuroendocrine prostate cancer, and (3) validate CDCP1 as a therapeutic target expressed at the surface of prostate cancer cells from newly obtained patient biopsies. Since this project is focused on validating CDCP1 a new drug target for patients with mCRPC, it is directly responsive to the overarching challenge to “Develop treatments that improve outcomes for men with lethal prostate cancer.” This project also studies the biological interactions between ionizing radiation and androgen receptor signaling, as well as the underlying prostate cancer biology that might promote high tumor
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110498
Entities
People
- Michael J. Evans
Organizations
- United States Army
- University of California, San Francisco