A Peptide-Based Drug Delivery System to Target Metastatic Prostate Cancer
Abstract
Prostate cancer (PC) is the second leading cause of cancer death in American men. Various therapies for PC are available, such as androgen deprivation therapy, chemotherapy, radionucleotides, and immunotherapy. However, despite these therapies, PC often progresses and becomes lethal especially once it metastasizes. We hypothesize that a drug delivery system that efficiently and selectively targets metastatic PC will greatly improve PC management. In fact, 177LuLu-PSMA-617, a novel drug that targets prostate-specific membrane antigen (PSMA), showed prolonged progression-free and overall survival in the VISION trial, suggesting that selectively delivering drugs to PC can be a powerful way to improve the outcome of PC therapy. We recently discovered a peptide named CTK, which appears to efficiently target metastatic PC. We identified CTK through an extensive in vivo phage display screen in mice bearing metastatic PC tumors. Our preliminary data show that CTK homes efficiently to PC, especially to metastatic PC in various sites, such as the bone (e.g., tibia, ribs, jaw), brain, and lymph nodes. In contrast, CTK has not shown obvious homing to pancreatic and breast cancer in mice, suggesting that it targets a molecule selectively expressed in PC. Here, we will characterize the CTK peptide in detail to study its potential as a drug delivery scaffold for metastatic PC therapy. We will further confirm the PC-specific homing of CTK in humanized mice that carry human PC in the presence of human immunity (huPC mice) to study CTK biodistribution under a translational setting. We will also search for the receptor(s) of CTK that determines the in vivo biodistribution of the peptide. To study the significance of CTK in PC therapy, we will perform a proof-of-concept treatment study using CTK-coated docetaxel (Doc) liposomes in the huPC mice. We will apply various techniques we have developed through the studies of the iRGD peptide, another tumor-homing peptide that we had identified through phage display and is now in clinical trials for pancreatic cancer therapy. The Specific Aims and Study Design are: Specific Aim 1. To study the biodistribution of the CTK peptide in humanized prostate cancer mice. We will develop huPC mice using a human PC cell line and patient-derived PC tissue. Humanized mice bearing human leukocyte antigen (HLA) matched with their human immune cells and PC cells will be used. We will first characterize the huPC mice by various means including tissue staining, flow cytometry, and RNA-seq. Fluorescein-labeled CTK and control peptides such as scrambled CTK will be injected into the tail vein of the huPC mice, and the biodistribution will be studied by macroscopic and microscopic fluorescence imaging. Specific Aim 2. To identify the receptor(s) of the CTK peptide. Affinity chromatography coupled with mass spectrometry will be used to identify the receptor(s) of CTK expressed on the PC cells or in the PC microenvironment. We will then study the expression profile of the receptor(s) in the huPC tumors and a panel of patient-derived PC and normal tissue. To confirm the binding of CTK to the receptors, we will perform in vitro binding assays using purified receptor(s) and cells in which the receptor(s) was eliminated or forcefully expressed. The affinity between CTK and the receptor(s) will also be measured. Specific Aim 3. To perform a proof-of-concept treatment study to assess the therapeutic efficacy of CTK-coated docetaxel liposomes in humanized prostate cancer mice. We will treat huPC mice using Doc-loaded liposomes coated with either CTK or a control scrambled CTK. The liposomes will be prepared using our original protocol. Therapeutic efficacy based on the primary and metastatic tumor burden and the potential side effects will be studied. Its effect on the immune microenvironment of the tumors will also be studied for potential future development of synergistic immunothera
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311036
Entities
People
- Kazuki Sugahara
Organizations
- Columbia University
- United States Army