Research

Extracellular Domain Shedding of the ALK Receptor Mediates Neuroblastoma Cell Migration (Cell)

Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ∼10% of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly expressed in most non-mutated cases, is unclear. Both WT and mutant proteins undergo ECD cleavage. In a recent study published in Cell, first author, Hao Huang, PhD, and senior author, Rani George, MD, PhD, show that extracellular domain (ECD) cleavage of the ALK cell surface tyrosine kinase receptor mediates neuroblastoma cell migration through induction of an epithelial-to-mesenchymal transition (EMT) gene signature. They also show that ECD cleavage is caused by matrix metalloproteinase 9 (MMP-9), whose inhibition leads to decreased NB cell migration. Proteolytic cleavage of the ECD of WT ALK, which is expressed in most NB cases, promotes metastasis. By targeting that process, these adverse cancer-associated features of ALK cleavage can be circumvented, raising the possibility of MMP-9 inhibition, either singly or in combination with that of ALK in patients with NB ...

Structure-Guided Design of a “Bump-and-Hole” Bromodomain-Based Degradation Tag (Journal of Medicinal Chemistry)

Targeted protein degradation offers the potential for rapid and dose-dependent protein depletion through the use of protein fusion tags toward which protein degraders have been established. In a recent article published in the Journal of Medicinal Chemistry, first author Radoslaw Nowak, PhD, and senior author Eric Fischer, PhD, present a newly developed protein degradation tag BRD4BD1L94V along with the corresponding cereblon (CRBN)-based heterobifunctional degrader based on a “bump-and-hole” approach. The resulting compound XY-06-007 binds to BRD4BD1L94V with increased selectivity over the wild-type bromodomain, which translates into potent and preferential degradation of the degron tag. Nowak, Fisher, et al. anticipate that the BRD4BD1L94V degradation system can be used in tandem with other ligand-induced degradation tags to assess the synergistic effect of degrading multiple targets in a chemically controlled manner, enabling investigation into the consequences resulting from rapid degradation of previously undruggable disease codependencies ...

Request for Applications: Innovations Research Fund (IRF) Basic Research Grants

Applications Due: November 1, 2021 at 5PM

Amount: $1,000,000 per grant which can be expensed over a period of time not to exceed three years

In order to enhance our ability to fund early stage research, Dana-Farber created a venture philanthropy project known as the Innovations Fund. The Innovations Funds are comprised of two separate funds, the Innovations Investment Fund (INV) and the Innovations Research Fund (IRF).

To fulfill the goals of the Innovations Funds, the resources provided in the IRF will be used to support basic discovery research that are high risk/high reward for which little preliminary data may exist. This support will take a few different forms including recruitment of junior faculty in the basic sciences and purchases of shared capital equipment. However, the majority of the resources will be used to support basic research projects proposed by Dana-Farber faculty.

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