Target Neuroendocrine Differentiation for Nuclear Imaging Diagnosis and Targeted Radionuclide Therapy of CRPC
Abstract
The 5-year cancer-specific survival rate for patients with clinically localized and regional prostate cancer is nearly 100%, but the survival rate can drop to 31% when tumors acquire resistance to androgen deprivation therapies (ADT) and developing into lethal castration resistant prostate cancer (CRPC). The treatment induced neuroendocrine differentiation (NED) is believed to hold great accountability by producing and secreting a cocktail of neuronal mediators with mitogenic effects to sustain the growth and survival of adjacent cancer cells. Over 25% of the therapy-resistant patients on highly potent new-generation ADTs can end up with CRPC-NE showing focal NED. Neuroendocrine prostate cancer (NEPC) can also be de novo with pure/universal NED, also categorized as small cell carcinoma of the prostate, which is rare (~ 1%) but even more deadly. The diagnosis of NED in lethal CRPC has long been overlooked due to the intrinsic limitations from the biopsy procedures such as sampling bias and invasive nature. Even though there are several FDA-approved PET imaging radiopharmaceuticals out there for recurrent prostate cancer; none of them can specifically detect NED in vivo. The FDA-approved somatostatin receptors (SSTRs) PET radiopharmaceutical seems to be a viable option because of its success in neuroendocrine tumors (also featuring NED). However, recent case reports have given mixed results, from negative/weak to positive/strong prostate tumor imaging readouts, which makes SSTR-PET remain largely inconclusive to reliably represent NED in CRPC. A greater challenge is that there is no effective targeted and personalized treatment method available to directly tackle the NED-protected prostate cancer cell survival and recurrence. Therefore, an urgent unmet clinical need is to identify a new biomarker specific for NED targeted diagnosis and potentially targeted therapy. We have taken actions and demonstrated the great potential of applying synaptic vesicle protein 2 isoform A (SV2A) as a biomarker for noninvasive NED detection via nuclear imaging modality. In this project, we hypothesize that SV2A is a specific biomarker for NED targeted nuclear imaging and targeted radionuclide therapy (TRT) applications in CRPC. To validate our hypothesis, we will carry out more comprehensive experiments to verify the correlation among multiple variables including tumor imaging readouts, the SV2A levels, the NED levels (defined by chromogranin A and synaptophysin), and the questionable SSTRs levels. We expect to confirm the representability of SV2A-PET for NED in CRPC. Furthermore, we will apply our extensive experiences in multivalent radiopharmaceutical design to develop a novel peptidic multifunctional chemical platform. Arising from this platform, we aim to acquire 67Cu-radioligands to enable the NED targeted radionuclide therapy option for lethal CRPC. In combination with the radionuclide pair of 64Cu and 67Cu, we will generate a precision and personalized radiotheranostic tool to potentially revolutionize the management of lethal CRPC. This project addresses two PCRP overarching challenges of defining the biology of lethal prostate cancer to reduce death and developing treatments that improve outcomes for men with lethal prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210453
Entities
People
- Guiyang Hao
Organizations
- United States Army
- University of Texas Southwestern Medical Center