The Phoenix Children’s Research Institute (PCRI) is a partnership between Phoenix Children’s and the University of Arizona College of Medicine – Phoenix. PCRI facilitates translational research programs. The institute utilizes cutting-edge technologies to develop new therapies for pediatric patients. Under the direction of renowned physician-scientist Vladimir Kalinichenko, MD, PhD, this work elevates the rigor, excellence and inquiry to our research tradition and clinical programs.
A Collaborative and Multidisciplinary
Translational Research Program
Research scientists with PCRI engage in research across multiple clinical disciplines. In addition to the research topics highlighted below, more information about translational research within PCRI can be found on our Center for Cancer & Blood Disorders, Genetics and Center for Pediatric Orthopedics research pages. This diverse group of researchers and healthcare professionals develop innovative therapeutic approaches to the most challenging pediatric conditions.
Translational Neonatology Research
Dr. Kalinichenko leads a translational research laboratory to study the role of pulmonary vasculature during lung development and regeneration. His team uses innovative technologies, such as pluripotent embryonic stem cells, tissue bioengineering and nanoparticle-based gene therapies, to improve health outcomes of newborns and infants diagnosed with various pulmonary disorders. These disorders include bronchopulmonary dysplasia, congenital diaphragmatic hernia, alveolar capillary dysplasia, acute respiratory distress syndrome and others.
This $3 million NIH-funded research grant seeks to use mouse and rat models of bronchopulmonary dysplasia (BPD) to determine whether neonatal lung angiogenesis, pulmonary hypertension (PH), pathologic lung remodeling and lung regeneration in hyperoxia-injured animals can improve via nanoparticle-based gene delivery of Forkhead box F1 (FOXF1) transcription factor into the pulmonary circulation. Alternative therapies evaluated in this funding proposal include cell therapy with FOXF1+ endothelial progenitor cells (FOXF1+ EPCs). FOXF1+ EPCs serve as progenitors of pulmonary microvascular endothelial cells.
This manuscript, published in Nature Communications, demonstrates how frequent non-coding FOXF1 gene deletions that interfere with important DNA regulatory regions, called enhancers, can lead to Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV). ACDMPV is a rare, lethal, genetic lung disease that causes respiratory failure in newborns and infants. Many non-coding deletions in or near the FOXF1 gene locus cause ACDMPV. Identifying specific pathogenic FOXF1 enhancers – critical for lung development – is important to diagnose and treat ACDMPV. This work could also enable better genetic screening for the disease, which relies primarily on exome DNA sequencing.
This study utilized lung tissue and endothelial cell samples from hypoxia-treated mice and data from patients with hypoxemic respiratory failure. The study demonstrates that hypoxia inhibits FOXF1 expression in endothelial cells in a HIF-1α dependent manner. Results suggest we can achieve elevated FOXF1 expression and improved lung function in patients with lung injury via endothelial cell-specific inhibition of HIF-1α via gene therapy.
This study successfully developed non-toxic poly(β-amino) ester (PBAE) nanoparticles with specific structure design and fluorinated modification for high efficiency. PBAE nanoparticles deliver nucleic acids and hydrophobic small molecule compounds to pulmonary endothelial cells without affecting surrounding tissue or other lung cell types. These nanoparticles could be an ideal vehicle for future therapies for pulmonary disorders associated with vascular insufficiency.
Translational Oncology and Injury/Repair Research
Tanya Kalin, MD, PhD, leads a groundbreaking research laboratory that develops new therapies for patients with cancer and interstitial lung diseases. They are actively involved in drug development by screening for new therapeutic compounds to inhibit carcinogenesis. They are also working to alleviate the long-term complications after non-resolved lung injury caused by radiation treatment, chemotherapy or viral infections. Using clinical tissue samples, human ex vivo models and animal models, the lab aims to understand the complex signaling networks that regulate disease progression. The goal is to target abnormal signaling to improve patients’ survival and disease outcomes.
Dr. Kalin is developing innovative anti-cancer therapies for childhood sarcomas. This includes therapies directed at tumor cells using novel combinations of drugs. She is also researching therapies directed at tumor microenvironment with the focus of targeting cancer-associated angiogenesis and fibroblasts. In addition, Dr. Kalin is developing therapies to improve lung regeneration after lung injury, such as radiation, chemotherapy and viral injury. These therapies include nanoparticle anti-fibrotic treatments and cell therapy with transplantable endothelial progenitor cells (EPCs).
This published work demonstrated that combination treatment with low doses of vincristine and nanoparticle delivery of the FOXM1 inhibitor RCM1 in a pre-clinical model of rhabdomyosarcoma had superior anti-tumor effects while reducing vincristine toxicity. This combination treatment downregulated the expression of Chac1, a gene implicated in regulating cell death. It provides an additional area for future research into potential therapeutics for patients with rhabdomyosarcoma.
FOXM1 is an oncogenic transcription factor essential for cancer progression, metastases and chemotherapy resistance. The team developed RCM1, the small-molecule inhibitor of FOXM1. The combination therapies that include RCM1 are promising new approaches to treat cancers, especially childhood sarcomas. This project evaluates the synergistic role of FOXM1 inhibitors with chemotherapy and molecular-targeted therapies for cancer treatment. These compounds provide potential therapeutic benefits applicable to different pediatric and adult cancers.
The study published in EMBO Molecular Medicine identified FOXF1 as a critical novel regulator of tumor-associated angiogenesis and its role in preventing cancer growth and metastases. FOXF1 increases tumor vessel stability. It inhibits lung cancer progression by stimulating FZD4/Wnt/β-catenin signaling in tumor-associated endothelial cells. Nanoparticle delivery of FZD4 cDNA demonstrated a promising future therapy in non-small cell lung cancers.
Pulmonary fibrosis stems from dysregulated lung repair, but the role of endothelial cells in fibrosis remains unclear. In this study in Nature Communications, authors demonstrated that FOXF1/R-Ras signaling in endothelial cells inhibited profibrotic mediators. Also, endothelial cell-specific nanoparticle FOXF1 gene therapy decreased lung fibrosis in mice.
Find a Research Study
Patients and families can use the Find a Research Study tool or speak with their child’s doctor to learn about enrollment in current and upcoming clinical research studies at Phoenix Children’s.