[R01] Utilizing integrin-targeted PET imaging and therapeutics to predict and treat radiation-induced pulmonary fibrosis
Ente: National Cancer Institute
Scadenza: 2031-05-31
Importo max: 645.414 EUR
Paese: US
Descrizione
Project Summary/Abstract.
Lung cancer is the leading cause of cancer death in the US, with over 125,000 deaths annually. Radiation
therapy (RT) is a critical component of curative lung cancer treatment for many patients. However, radiationinduced pulmonary fibrosis (RIPF) is a common side effect that carries a poor prognosis with limited treatment
options. Up to 40% of patients with lung cancer who receive RT may experience RIPF. RIPF is a late effect of
RT, typically occurring 3 or more months after treatment. The symptoms of RIPF can include shortness of breath,
pleural effusions, decreased lung function, and respiratory failure. Cell surface integrin heterodimers play a key
role in the pathogenesis of RIPF. In particular, the integrin αvβ6, which is expressed at a low level in the alveolar
epithelium at baseline, is significantly upregulated upon RT damage. The key role of integrin αvβ6 in RIPF is
illustrated by studies in which mice lacking integrin αvβ6, or treated with an αvβ6-blocking antibody, do not develop
RIPF. Here, we propose to translate this mechanistic understanding of RIPF into novel approaches for monitoring
and treating RIPF. We hypothesize that non-invasive αvβ6 PET imaging will be safe and can specifically bind to
αvβ6 in patients with RIPF. Additionally, we hypothesize that a novel small-molecule integrin antagonist, IDL2965, can mitigate and treat RIPF in mice. In this project, we are utilizing mice to model RIPF, as mice develop
RIPF that mimics human disease. In addition, cellular and in vitro models do not approximate the complex biology
leading to the development of RIPF.
Our data using [64Cu]Cu-DOTA-αvβ6-BP to detect early RIPF in mice are compelling in both single-fraction
high-dose RT and lower dose-larger volume RT models (Lo et. al, IJROBP 2025). However, to progress to clinical
trials in patients with cancer, we will obtain data to submit an Investigational New Drug (IND) application to the
FDA. Importantly, we propose translating [64Cu]Cu-DOTA-αvβ6-BP PET imaging into patients with lung cancer,
allowing us to better identify RIPF and develop a tool to determine the efficacy of IDL-2965 in future clinical
studies. The specific aims of the proposal are: (1) Characterize the utility of [64Cu]Cu-DOTA-αvβ6-BP in mice with
conventionally fractionated RT and identify circulating biomarkers of RIPF, and determine the in vivo toxicology
of [64Cu]Cu-DOTA-αvβ6-BP to prepare and submit an exploratory Investigational New Drug (eIND) application to
the FDA, (2) Conduct a first-in-human clinical trial of [64Cu]Cu-DOTA-αvβ6-BP to determine its safety and human
dosimetry in patients with evidence of RIPF from computed tomography or in healthy controls, and (3) Determine
the effect of integrin antagonism using IDL-2965 on mitigating RIPF in preclinical mouse models.
The goals of this proposal are two-fold: (1) demonstrate safety and target specificity for [64Cu]Cu-DOTA-αvβ6-BP so that it can be used in future studies to identify
Istituzione: WASHINGTON UNIVERSITY
PI: Carmen Bergom, FARROKH DEHDASHTI, Buck E. Rogers, Pamela Parker Samson
Progetto: 1R01CA303248-01A1
Settori: National Cancer Institute
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