Targeting Neuroendocrine Prostate Cancer with Small-Molecule Drug Conjugates
Abstract
A significant number of patients with advanced prostate cancer who have failed anti-androgen and chemotherapies develop neuroendocrine prostate cancer (NEPC). NEPC is characterized by an aggressive clinical course. For men with prostate cancer, the development of NEPC is often a death sentence; the average survival for these patients from the time of diagnosis to death is less than 1 year. There is a clear need for effective therapeutic approaches against NEPC. We were intrigued by a recent study that identified a cell surface protein known as carcinoembryonic antigen-related cell adhesion molecule 5, or CEACAM5, in a majority of NEPCs. From experience and review of the literature, we knew that using antibodies directly conjugated to drugs would not work effectively against NEPC and would have significant toxicity. We thus devised an innovative strategy to use a bispecific antibody that would bind to CEACAM5 on NEPC tumors, as well as serve as a homing signal for other drugs. We reasoned that this approach would enable the bispecific antibody to target NEPC cells without the significant toxicity of antibody drug conjugates. We then developed a small molecule drug conjugate (SMDC) that could target the homing signal on bispecific antibody bound to NEPC cells. The SMDC would bind to the NEPC and then deliver a toxic payload to these cells. To further ensure the specificity of our SMDC for NEPC, our SMDC employed a drug that targets a protein expressed primarily in NEPC cells. Further, since our SMDC has a built-in imaging component, noninvasive and quantitative positron emission tomography imaging will be used, not only to ensure that the drug is taken up specifically in the NEPC tumors, but also to monitor therapeutic activity against NEPC tumors in animal models. We will systematically evaluate the optimal dosing regimen needed for the combination of the bispecific antibodies and SMDCs to ensure uptake within NEPC tumors and enable tumor regression. Importantly, our drugs have both therapeutic and diagnostic components and function effectively as a theranostic. These data will establish the preclinical rationale for the combination of bispecific monoclonal antibodies and SMDC in patients with NEPC. We believe that the proposed studies will offer significant hope for patients with lethal NEPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910363
Entities
People
- Ganesh V Raj
Organizations
- United States Army
- University of Texas Southwestern Medical Center