Integrative Analysis of Prostate-Specific Membrane Antigen and Amino Acid Transporter Cistromes for Precision Molecular Imaging of Metastatic Prostate Cancer
Abstract
Scientific Objectives and Rationale: In the last 5 years, molecular imaging by radioligands has transformed prostate cancer management. 18F-fluciclovine, and more recently prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) imaging, are used for accurate disease localization for men with high-risk or recurrent prostate cancer. The role of molecular imaging in advanced prostate cancer has not yet been established. PSMA is a prostate cancer cell surface protein that can be imaged and also targeted. The PSMA targeted radionuclide 177Lu-PSMA-617 is expected to be FDA-approved for men with advanced prostate cancer based on positive results in the Phase 3 VISION trial (Sartor et al. 2021 N Engl J Med). Inclusion on the VISION trial relied on confirmation of PSMA-PET imaging positivity. In general, 10-20% of patients have been excluded from PSMA-directed therapy trials based on the presence of PSMA-negative lesions. Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that most commonly arises in later stages of prostate cancer progression as a mechanism of treatment resistance. As prostate cancer transitions towards NEPC, tumors may heterogeneously express PSMA or become PSMA-negative. While this may manifest as PSMA-negativity on PSMA-PET, the prevalence of NEPC based on PSMA-imaging is not known. Detection of NEPC has clinical implications, as these patients do not respond well to traditional prostate cancer therapies. Based on an increased understanding of the biology of NEPC, there are several clinical trials testing new drugs in early development for patients with NEPC. Patient selection for these studies will be critical. Based on preliminary data, I hypothesize that a combination of 18F-fluciclovine and PSMA-PET imaging could be a non-invasive approach to identify PSMA-suppressed advanced prostate cancer such as NEPC. In this proposal, I will leverage our unique patient-derived models to systematically evaluate the expression, concordance, and heterogeneity of expression of the radioligands 18F-fluciclovine and 18F-PSMA. I will generate genomic uptake scores to be used for optimal application of fluciclovine and PSMA radioligands for monitoring of NEPC tumors. This work will serve as rationale for the incorporation of combined 18F-fluciclovine and PSMA -PET in trials geared at targeting NEPC. This work will also serve as a framework for the future incorporation of novel cell surface biomarkers for imaging NEPC such as DLL3 (Puca et al. 2019 Sci Transl Med). Applicability of the Research: The prognosis of NEPC is poor, in part due to late diagnosis and a lack of effective therapies. The current diagnosis of NEPC relies on metastatic tumor biopsy, which is invasive and challenged by tumor heterogeneity. A personalized non-invasive molecular imaging strategy would aid in the early diagnosis and treatment for men developing NEPC. This would improve morbidity and mortality for this subset of up to 20% of late-stage prostate cancer patients. In this proposal, I will address one of the FY21 PCRP Overarching Challenges: Define the biology of lethal prostate cancer to reduce death. By understanding the biology of molecular imaging targets in advanced prostate cancers such as NEPC, we can learn how to best utilize molecular imaging probes to delineate and treat tumors more accurately. In the near term, our fluciclovine and PSMA-radioligand uptake scores will estimate which radioligand should be used at which stages of prostate cancer. A longer-term goal of this work will be to develop a non-invasive companion diagnostic test using multiple radioligands to identify the onset of lineage plasticity and NEPC development. Such a companion diagnostic platform will facilitate the development of therapies to prevent progression toward NEPC. Career Goals in Prostate Cancer Research: My commitment to prostate cancer research began as a graduate student. At
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210010
Entities
People
- Mohamadreza Bakht
Organizations
- Dana–Farber Cancer Institute
- United States Army