Fusion oncoproteins are associated with childhood cancers and have proven challenging to target
Miguel Bronchud, Co-Founder of Regenerative Medicine Solutions, shared a paper by Sharad K Verma, et al on LinkedIn:
“Chromosome translocations have been associated with human malignancy (mainly blood leukemia like CML and Philadelphia chromosomes) for a long time.
Soft tissue human sarcomas have also been characterized by such chromosome abnormalities or fusions.
Sharad K Verma, PhD, Keren L Witkin, PhD, Anu Sharman, PhD, Malcolm A Smith, MD, PhD-JNCI: Journal of the National Cancer Institute, Volume 116, Issue 7, July 2024, Pages 1012–1018
Fusion oncoproteins are associated with childhood cancers and have proven challenging to target, aside from those that include kinases.
As part of its efforts for targeting childhood cancers, the National Cancer Institute recently conducted a series on Novel Chemical Approaches for Targeting Fusion Oncoproteins.
Key learnings on leading platforms and technologies that can be used to advance the development of molecular therapeutics that target fusion oncoproteins in childhood cancers are described.
Recent breakthroughs in medicinal chemistry and chemical biology provide new ground and creative strategies to exploit for the development of targeted agents for improving outcomes against these recalcitrant cancers?
Recurrent chromosomal translocations that produce fusion oncoproteins are a hallmark of selected cancers, particularly among those associated with childhood, and many are pathognomonic of specific cancer types.
These translocations generate fusions of normal genes that encode novel proteins that acquire oncogenic function, often by dysregulating protein complexes that control gene expression or chromatin state, thus altering developmental programs that lead to transformation of the unique cell of origin for each cancer.
Over the past 2 decades, there have been some clear success stories in improving outcomes in pediatric and adolescent and young adult cancers.
For example, mortality in the United States for acute lymphoblastic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma declined by approximately 40%, 60%, and 80%, respectively, between 2000 and 2022.
These successes at least partially result from the availability of new therapeutic agents for these cancers.
However, new active agents are lacking for other childhood-associated cancers, such as soft tissue sarcomas like rhabdomyosarcoma (frequently driven by the PAX3/7::FOXO1 gene fusion), bone cancers like Ewing sarcoma (frequently driven by the EWSR1::FLI1 gene fusion) and osteosarcoma, and many types of childhood brain tumors.
In these cancers that lack new therapeutic approaches, similar declines in mortality have not been observed and patients continue to be treated with toxic chemotherapy and radiation, leading to substantial acute and long-term morbidity.
Improving outcomes for recalcitrant cancers like these requires the development of new active drugs.”
Source: Miguel Bronchud/LinkedIn