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NIH grant 1R43CA314905-01: De Novo Minibinder Radiotheranostics for Targeted Treatment of Prostate Cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: David Chmielewski. Award: $400000.
Start: 2026-09-18T00:00:00.
Project Summary/Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is responsible for the vast majority (80-90%) of prostate
cancer (PC) deaths and is characterized by rapid disease progression and limited treatment options. Since
mCPRC develops in response to standard androgen deprivation and androgen receptor (AR) signaling inhibition
treatment regimens, alternative therapeutic strategies beyond AR signaling modulation are required for mCRPC.
PSMA-targeted Lutetium-177–PSMA-617 (Pluvicto) is the first approved radiotherapeutic for mCRPC, yet its
effect is relatively modest (4 month OS increase) and most patients quickly progress, reportedly due to (1) PSMA
expression heterogeneity, both within and across individual metastases as well as between patients, which
results in suboptimal on-tumor radiation dose and ineligible patient groups, (2) dose-limiting systemic toxicities,
and (3) cancer cell resistance mechanisms such as antigen loss (VISION Trial). While Pluvicto has clinically
validated the radioligand approach in mCRPC treatment, next generation radiotheranostics can achieve more
significant and durable patient responses by improving on-tumor radiation delivery, increasing coverage across
heterogeneous tumors, and expanding biomarker-based targeting across PC disease stages and molecular
phenotype. To this end, we have developed targeted de novo designed minibinder (Mb) proteins in small format
(~7kDa) that bind diverse cancer targets with high affinity and specificity, can be efficiently radiolabeled, and can
be engineered for tunable pharmacokinetics in vivo to maximize tumor accumulation while minimizing
accumulation in radiation-sensitive normal tissues. Here we will apply our de novo Mb radioconjugate (MbRC)
platform to target non-enzyme PC biomarkers B7-H3 and STEAP1, traditionally not targetable by small molecule
ligands and peptides, which offers a promising approach for next-generation radiotheranostics in mCRPC.
In Aim 1 we will utilize state-of-the-art computational protein design methods to make de novo Mbs against
clinically validated PC targets B7-H3 and STEAP1. We will experimentally select hit Mbs from library scale
screening for each target with confirmed high affinity target binding and biochemical stability. In Aim 2, we will
radiolabel candidate Mbs, engineer half-life extension and analyze biodistribution (BioD) and pharmacokinetics
(PK) of candidate MbRCs in vivo using an antigen-specific xenograft mouse model (VCaP) of PC. We will
quantitatively compare BioD metrics for candidate MbRCs and select the Mb with highest tumor accumulation
(%IA/g) and tumor:normal organ ratios, with limited systemic exposure, as our lead molecule. Successful
completion of these aims will validate a novel lead Mb radiotheranostic and support future exploratory IND
submission. The work will position our validated lead molecule for private investment or future grant awards
supporting preclinical toxicology, anti-tumor efficacy studies and a Phase 0 first-in-human imaging trial in
mCRPC patients, the next critical scientific and commercial milestone for our novel technology.
Project Summary / Abstractdocument fetched 2026-09-27 02:45