NIH grant: Targeting Lineage Plasticity in Prostate Cancer (1R01CA305895-01)

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NIH grant 1R01CA305895-01: Targeting Lineage Plasticity in Prostate Cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Aaron Matthew LeBeau. Award: $634791.
Start: 2026-07-03T00:00:00.
SUMMARY
 Androgen receptor (AR) pathway inhibitors (ARPIs) and the PSMA-targeted radiopharmaceutical (RPT)
Pluvicto have made an impact on the survival of men suffering from castration-resistant prostate cancer (CRPC).
All men fail these therapies, however, resulting in the deaths of nearly 30,000 men annually. Resistance can
occur through multiple mechanisms. Often poor response rates to Pluvicto are due to heterogenous PSMA
expression or the complete loss of PSMA on the cell surface. In a growing subset of men, genetic, epigenetic,
and transcriptomic alterations resulting from the ARPI therapeutic barrage promote cellular plasticity leading to
phenotypic changes. This phenomenon known as lineage plasticity describes acquired and diverse molecular
alterations that result in treatment resistance and differential antigen expression. The most common form of
disease resulting from this transition is neuroendocrine prostate cancer (NEPC), which has lost AR expression
and acquired neuroendocrine differentiation markers. It is possible for men to have heterogeneous disease
consisting of CRPC and NEPC lesions. Our goal is to combat heterogeneity and lineage plasticity in CRPC by
developing a novel class of therapies called Shark Antibody Radiopharmaceuticals (SHARPs). SHARPs are
bispecific antibody constructs that can engage two antigens on the same cell or adjacent cells. This strategy is
made possible by harnessing the unique properties of shark antibody binding domains called variable new
antigen receptors (VNARs). At ~11kDa in size, VNARs are the smallest naturally occurring variable domain.
VNARs have low to no immunogenicity and their hydrophilicity allows for high expression yields making them
readily translatable. Through the direct immunization of nurse sharks, we identified VNARs for the cell surface
antigens Trop2 (CRPC), DLL3 (NEPC), and the cancer-associated fibroblast (CAF) marker FAP. Using a human
IgG1 Fc scaffold, tetravalent-bispecific SHARPs that simultaneously target cancer cells and CAFs (Trop2xFAP,
DLL3xFAP), and two antigens on the surface of cancer cells (Trop2xDLL3) were developed. The objective of
this proposal is to evaluate the ability of our SHARPs to deliver the β-emitting radionuclide Lutetium-177 for
therapeutic benefit in vivo. The first specific aim will determine the maximum-tolerated dose, toxicity, and
dosimetry of our SHARPs in mouse models. In the second aim, we will evaluate their therapeutic efficacy in vivo
using multiple xenograft models and investigate their biological effect. Using spatial transcriptomics and T cell
imaging, we will also investigate the immunological mechanism of action in the tumor microenvironment. In the
third aim, we will conduct studies in non-human primates to determine the immunogenicity of our SHARPs in
addition to their pharmacokinetic and pharmacodynamic properties using PET imaging. Overall, this innovative
proposal has significant clinical potential and may serve as a critical milestone for nearing an important shift in
the development of biologic therapies in oncology. Animal use: We are using
mice in these studies because of their physiologic resemblance to humans and their ability to grow prostate
tumors. The NHPs (macaques) in Aim 3 are essential for understanding the behavior and safety of the SHARPs
before introducing them into human trials.

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