Pilot Grants to Advance Innovative Precision Medicine Research

July 16, 2020

Five teams of researchers from Columbia University Irving Medical Center (CUIMC) have been awarded pilot grants to fund a diverse set of precision medicine research. 

Jointly awarded by the Columbia Precision Medicine Initiative (CPMI), the Herbert Irving Comprehensive Cancer Center (HICCC), and the Irving Institute for Clinical and Translational Research (Irving Institute), the Precision Medicine Pilot Awards underscore Columbia’s commitment to supporting research targeting the promise of precision medicine, across multiple diseases.

The winning proposals span a wide array of diseases and methods of tackling them, including: uveal melanoma, which occurs in the eye, and the use of exosomal proteins to indicate this cancer; a more streamlined way to identify low- and high-turnover renal osteodystrophy, a bone disorder common in patients with kidney disease; alternative splicing, a human genetic processing mechanism, and how RNA can play a role in that process; hidradenitis suppurativa, a chronic skin inflammatory condition, and the need for increased understanding of the disease and potential treatments; and the role the vaginal microbiome plays in spontaneous preterm birth, a leading cause of neonatal morbidity and mortality.

The five precision medicine pilot projects are being led by: Richard Carvajal, MD, co-director of the HICCC’s Precision Oncology and Systems Biology research program and associate professor of medicine at Columbia Vagelos College of Physicians & Surgeons (VP&S); Tal Korem, PhD, assistant professor of systems biology and of obstetrics and gynecology at VP&S; Thomas Nickolas, MD, associate professor of medicine at VP&S; Lynn Petukhova, PhD, assistant professor of dermatology at VP&S and of epidemiology at Mailman School of Public Health; and Chaolin Zhang, PhD, HICCC member and associate professor of systems biology at VP&S.

The Vagelos Precision Medicine Pilot Grant program is made possible by a generous donation from Roy and Diana Vagelos and is intended to support groundbreaking basic research in the field of precision medicine. This year, the program received 34 applications and for the first time leveraged a three-way partnership among the CPMI, the HICCC, and the Irving Institute to aid in new multi-disciplinary collaborations and increasing the number of awards granted.

Precision Medicine Resource of the Irving Institute seeks to facilitate research studies to improve diagnosis and treatment of disease, and ultimately improve maintenance of health through more accurate prediction of disease risk. HICCC is dedicated to understanding the biology of cancer and to applying that knowledge to the design of cancer therapies and prevention strategies.

The five teams will each receive $100,000 in funding for one year. The researchers will present their projects at an annual symposium for the precision medicine awards in fall 2021.

“Biological and Therapeutic Relevance of Exosomes in Uveal Melanoma”
Lead Investigator: Richard Carvajal, MD
Co-PIs: Alex Rai, MD; Grazia Ambrosini, PhD

Dr. Carvajal, alongside Drs. Rai and Ambrosini, are working towards identifying a treatment strategy that can prevent the development of metastatic uveal melanoma (UM). UM is a rare melanoma that is distinct from those that start in the pigment producing cells of the skin. Recent analyses of UM patients have shown an increase of proteins contained with exosomes, small vesicles or blisters released from the cell. Cancer-derived exosomes contribute to cancer development and progression, making them both a potential indicator of disease and an opportunity for intervention. The researchers will further assess the role of the exosomes in UM disease progression. The end goal is to identify one or more lead treatment strategies to prevent the development of metastatic disease and devise a clinical trial for patients at high risk for disease recurrence.

“Mechanistic Investigation of the Vaginal Microbiome in Different Manifestations of Spontaneous Preterm Birth”
Lead Investigator: Tal Korem, PhD
Co-PIs: Anne-Catrin Uhleman, MD, PhD; George Gallos, MD; Joy-Sarah Vink, MD

Spontaneous preterm birth (sPTB) is a leading cause of neonatal morbidity and mortality. The vaginal microbiome – the bacteria and other microorganisms that live in the vagina - is associated with sPTB, but the underlying mechanisms are largely unknown. This stems from the low resolution of current approaches to cataloging the microbes in the vaginal microbiome as well as the oversimplified clinical profiling of sPTB, which ignores the complexity of its pathophysiology. The team will optimize methods for bacterial DNA extraction and perform metagenomic sequencing of vaginal microbiome samples from a well characterized cohort of pregnant women. They will study how the microbiome interacts with the body in the context of sPTB and its clinical presentations, using microbiome analysis methods that provide biological insights to the link between microbial genomes and host outcomes. Their aim is that this research will lead to novel insights regarding the involvement of the microbiome in different manifestations of sPTB, addressing a critical gap in the field.

“A microRNA Approach to Identify Renal Osteodystrophy Sub-Type”
Lead Investigator: Thomas Nickolas, MD, MS
Co-PIs: Stavroula Kousteni, PhD; Krzysztof Kiryluk, MD, MS

Together, with his collaborators Drs. Kousteni and Kiryluk, Dr. Nickolas is tackling renal osteodystrophy (ROD), a disorder that weakens the skeleton, resulting in bone loss, fractures, and cardiovascular complications. ROD can be classified based on changes in bone turnover rates as high-turnover ROD (markedly elevated) or low-turnover ROD (markedly suppressed. Currently, treatment of ROD focuses on stopping high-turnover ROD, while also avoiding the development of low-turnover ROD that can occur through excessive use of these treatments. There currently is a strong need for a better system of diagnosing  bone turnover rate in patients in order to better manage disease treatment. The team believes circulating fragments of cellular RNA called microRNAs (miRNAs) can assess turnover types in ROD. They are looking to identify miRNA profiles in order to test them as biomarkers of ROD turnover-type, positively impacting the diagnosis and management of ROD.

“Deciphering Monogenic and Polygenic Etiologies of a Longitudinal Multi-Ethnic Hidradenitis Suppurativa Cohort”
Lead Investigator: Lynn Petukhova, PhD
Co-PI: Suzanne Leal, PhD

Drs. Petukhova and Leal are investigating the chronic skin disease, hidradenitis suppurativa (HS), aiming to find better ways to manage and hopefully prevent it. HS, which typically appears after puberty, causes painful lumps to form deep within the skin. The condition can persist for many years and get worse over time. There is currently a lack of therapies and understanding of HS, causing patients’ needs to remain unmet. The researchers believe that HS has a genetic architecture that is similar to other chronic inflammatory diseases. They will be studying a multi-ethnic group of participants with HS, with a goal of garnering new knowledge about the biological drivers of disease.

“Unbiased Screen of Proximal and Distal Splicing Regulatory Elements Towards Drug Discovery”
Lead Investigator: Chaolin Zhang, PhD
Co-PI: Samuel Sternberg, PhD

Numerous Mendelian diseases are caused by mutations that disrupt individual genes and could potentially be treated by modulating gene expression to restore normal protein production. A level of molecular regulation called alternative splicing occurs ubiquitously in human genes and frequently generates a combination of RNA isoforms that code for proteins or are noncoding. Modulation of alternative splicing using synthetic genetic strings called antisense oligonucleotides (ASOs) to target splicing regulatory elements has recently emerged as a powerful means of increasing gene expression levels. For example, SPINRAZA is an FDA-approved ASO drug that targets the SMN2 gene to treat spinal muscular atrophy. A critical challenge, however, is pinpointing the most effective regulatory RNA elements that can be targeted to modulate splicing. Drs. Zhang and Sternberg are proposing a high-throughput screening strategy to do just that—to exhaustively identify splicing-regulatory elements for any gene.