Targeting Fusion Oncoproteins in Childhood Cancers (TFCC)

Progress in our understanding of fusion oncoprotein-driven cancer biology through investigator-initiated research and the Fusion Oncoproteins in Childhood Cancers (FusOnC2) Consortium, along with recent technological developments, provides an opportunity for collaborative efforts towards the development of new treatment approaches for childhood cancers.  

Advances in chemical biology have expanded the universe of “druggable” protein targets in pediatric cancers and new technological approaches provide strategies for the direct targeting of fusion oncoproteins and the proteins with which they interact within complexes. Progress in medicinal chemistry (such as PROTACs and molecular glues) provides a knowledge base for the design of new therapies for fusion-driven childhood cancers. 

While directly targeting fusion oncoproteins would be ideal because of their exclusivity in tumors, other targets (e.g., interacting proteins, synthetic lethal partners, mediators of fusion oncoprotein function) may be more amenable to these strategies. 

The TFCC aims to build on the progress of fusion oncoprotein research and translate preclinical discoveries into the development of effective treatments for fusion oncoprotein-driven childhood cancers.

Program Directors in DCB and DCTD discuss challenges and future opportunities for the development of therapies targeting fusion oncoproteins in childhood cancers in a JNCI Perspective. 

TFCC has added Research Advocates and scientific investigators as Associate Members of the Network. The Research Advocates are Sharon Hammond (Summer’s Way Foundation) and Craig and Suzanne Vincze (Max Vincze Foundation). The four investigators are Kris Wood (Duke University), Jeffrey Klco (St. Jude), Asmin Tulpule (MSKCC), and Srinivas Viswanathan (Dana-Farber).
 

TFCC UM1 principal investigators Corrine Linardic (Duke University) and Angela Koehler (MIT) and colleagues published a review article summarizing the history, contemporary application, clinical evaluation, and future of fusion positive-rhabdomyosarcoma (RMS) systemic therapy.

TFCC UM1 principal investigator Daniel Nomura (UC Berkeley) described the discovery and optimization of a lead compound bearing a unique sulfinyl aziridine warhead that engages MYC as a pure MYC/MAX protein complex, destabilizing MYC in cancer cells and degrading MYC in a proteasome-dependent manner. The authors demonstrate that it is possible to interrogate certain intrinsically disordered regions within transcription factors such as MYC, with implications for targeting proteins previously considered to be “undruggable."

TFCC UM1 principal investigator Angela Koehler (MIT) published a comprehensive evaluation of degradation versus inhibition of the transcription factor CDK9 to assess when degradation might offer superior therapeutic outcomes. The findings suggest that CDK9 degradation offers a more robust strategy to overcome limitations associated with its inhibition.

For additional information about TFCC, please contact Dr. Keren Witkin in DCB or Dr. Joseph Agyin in DCTD. 

Projects Investigating Mechanisms of Fusion-Driven Oncogenesis in Childhood Cancers (U01s)

Next Generation Chemistry Centers for Fusion Oncoproteins (UM1)

• Sharon Hammond (Summer’s Way Foundation) 
• Craig and Suzanne Vincze (Max Vincze Foundation).