Awarded Grants

Awarded Grants

MDBR, DC Million Dollar Bike Ride MDBR, DC Million Dollar Bike Ride

Nucleoside therapy for telomere diseases

Agarwal Suneet

Boston Children's Hospital

$63,000.00

Awardee: Agarwal Suneet

Institution: Boston Children's Hospital

Grant Amount: $63,000.00

Funding Period: February 1, 2024 - January 31, 2025

Summary:

Telomere biology disorders (TBDs) are a spectrum of diseases characterized by life-threatening complications including bone marrow failure, liver and lung disease. Tissue and organ transplantation remain the primary treatments, but cures that address the underlying problem and restore telomere length to improve symptoms throughout the body are lacking. We recently discovered that molecules called nucleosides can increase telomere length in human cells, including those from patients with TBDs. This is exciting because nucleosides have already been used in children with another rare disease, and appear to be safe and effective for that disease. In this proposal, we will now rigorously test whether these same nucleosides can effectively increase telomere length in human stem cells, both in the dish and in animal models. If successful, these experiments will provide critical results that will help take nucleosides into clinical trials for patients with TBDs.

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Using TERT variant-to-function analysis to define cryptic telomere biology disorders in sporadic cancers

Coleman Lindsley

Dana-Farber Cancer Institute

$62,528.00

Awardee: Coleman Lindsley

Institution: Dana-Farber Cancer Institute

Grant Amount: $62,528.00

Funding Period: February 1, 2023 - January 31, 2024

Summary:

Impaired telomere maintenance is linked to development of cancer. Inherited mutations affecting telomerase cause short telomeres in all tissues and an increased risk of specific cancers. The goal of this proposal is to define the spectrum and functional impact of inherited TERT mutations in adults with cancer and analyze associations with clinical outcomes. To achieve this goal, we have assembled a cohort of 40,000 adult patients with various cancers, will identify TERT variants in existing DNA sequencing data, and perform comprehensive functional interrogation of cancer-associated TERT variants to define their effects on telomerase function.

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Targeting the shelterin component TINF2 in telomere diseases

Suneet Agarwal

Boston Children's Hospital

$65,445

Awardee: Suneet Agarwal

Institution: Boston Children's Hospital

Grant Amount: $65,445

Funding Period: February 1, 2022 - January 31, 2023

Summary:

Telomere biology disorders (TBDs) affect multiple parts of the body, including the blood, lungs, liver and bones. There are no effective treatments that address the life-threatening problems. Telomeres are the ends of chromosomes that ensure ability of cells to keep dividing to replace damaged cells with new healthy ones. In TBDs, genetic mutations reduce telomere length and thus cells cannot regenerate themselves, and the tissues fail causing disease. By studying a particular mutation, we have found that decreasing a protein called TIN2 can increase telomere length in TBD patient cells. In this proposal we will study in depth whether reducing TIN2 could be a viable strategy to restore telomeres in the setting of various mutations that cause TBDs, and also test whether chemicals can be used to achieve this effect. These studies could provide a new therapeutic strategy that could be applied throughout the body for patients with TBDs.

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Characterization of Telomere Maintenance in Tumor Models of Dyskeratosis Congenita

Judy Wong

University of British Columbia

$66,440

Awardee: Judy Wong

Institution: University of British Columbia

Award Amount: $66,440

Funding Period: February 1, 2021 - January 31, 2022

Summary:

Work in my laboratory and others had shown that telomere maintenance defects in the bone marrow failure syndrome dyskeratosis congenita (DC) contributed to an increased risk of developing cancers. Our long-term collaboration with the Inherited Bone Marrow Failure Syndrome (IBFMS) clinical group at the National Cancer Institute provided us with the opportunity to model and study the cancer development process in DC.  Using primary patient materials collected by the IBFMS group, my laboratory will develop DC cancer models in the laboratory and study how these DC tumors overcome the innate genetic restrictions on telomere maintenance and achieve immortal growth.  The long term goal of this project is to provide new screening paradigm and to stratify treatment options for DC tumors, an unmet clinical need in the battles against the spectrum of disorders associated with this Bone Marrow Failure Syndrome.

Final Report Lay Summary:

Dyskeratosis congenita (DC) was the first telomere maintenance disorder identified in humans. DC is an inherited disease of bone-marrow failure, with symptoms that include hematopoietic, epithelial and mucosal epithelial dysfunctions. In addition, DC patients have an increased risk of developing cancers from epithelial origin, believed to be a direct consequence of accelerated telomere attrition. With advancement in the clinical management of DC mortality due to hematopoietic system failure, DC patients are now faced with an estimated hundreds-fold increase in their risk of developing cancer, with HPV-negative Head and Neck Cancer (predominantly at the tongue) being the most prominent cancer type (Haematologica, 2018). My laboratory has ongoing interests in modeling the cancer development process in DC, using primary patient materials collected from the NIH National Cancer Institute’s Inherited Bone Marrow Failure Syndrome cohort study. With funding from the UPennMDBR award, we have optimized the sequential viral infection protocol for the delivery of oncogenic elements, and successfully created four X-DC tumor models and two corresponding controls. Currently, we are conducting mouse xenograft studies using these cell models to further characterize the in vivo behavior of these XDC tumors. Our project successfully optimized the in vitro transformation protocol and established viable DC tumor models for future research towards informed patient screening guidelines and the development for novel, targeted therapeutics.

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