Targeting mutant cohesin protein complex to treat relapsed pediatric Ewing Sarcoma
Project Goal: To develop a novel targeted therapy to address these clinical challenges in EWS by exploiting a synthetic lethal interaction between two cohesin complex proteins, STAG1(SA1) and its functional paralog STAG2 (SA2), a tumor suppressor.
Institution: Texas Children’s Cancer Center and Baylor College of Medicine
Researchers: Debananda Pati, PhD
Year Awarded: 2021
Type of Childhood Cancer: Ewing Sarcoma (EWS)
While rare, Ewing sarcoma (EWS) is the second most common type of bone cancer in children. Approximately 200-250 children and young adults are found to have EWS each year in the USA. Approximately half of all EWS tumors occur in children and young adults between the ages 10 and 20 years, and the remainder occur in adults. For the past 30 years, the 5-year survival rate for pediatric EWS remains <20% for patients with metastatic or recurrent tumors. Two overarching challenges for current treatments of EWS are development of resistance to stand of care chemotherapy and tumor metastasis. As a rare pediatric cancer, EWS has received considerably little attention from researchers and very little interest from pharmaceutical companies to develop new drugs. Identification of novel drug targets for the development of precision therapy while sparing normal developmental tissues in children is of highest priority. Also, there is a critical need to design targeted therapies for patients with resistant/relapsed disease.
The objective of this proposal is to develop a novel targeted therapy to address these clinical challenges in EWS by exploiting a synthetic lethal interaction between two cohesin complex proteins, STAG1(SA1) and its functional paralog STAG2 (SA2), a tumor suppressor. Numerous recent genomics studies have reported pathogenic mutations in SA2 in as many as 21% of relapsed EWS tumors, and SA2 is one of only 12 genes that are significantly mutated in four or more cancer types. Whereas SA2 is mutated frequently in human tumors, only rarely are mutations reported in the SA1 in EWS. siRNA knockdown of SA1 or SA2 has no significant effect on cell lethality, but knockdown of both SA1 and SA2 in the cells leads to cell death, indicating a synthetic lethal interaction between SA1 and SA2. Additionally, recent studies in our laboratory and others show that knockdown of SA1 and SA1-mutant tumor cells, but not in SA2 wild-type (WT) cells leads to significant cell death, suggesting that the SA pathway can be targeted. We hypothesize that inhibition of SA1-cohesin function in tumors with somatic mutations in the paralog of SA2-cohesin by small molecular inhibitors represents and effective and ingenious way to selectively inhibit proliferation of EWS. Our goals here to carry out a structure-based virtual screening (SBVS) and high throughput screening of large natural product library to identify potential SA1 inhibitors to treat drug-resistant relapsed Ewing sarcoma tumors. We hypothesize that SA1 activity can be targeted either by disrupting its function in the cohesin complex or by preventing its expression at the transcriptional level.
We propose three innovative strategies for the identification of potent SA1 inhibitors: 1) disrupting SA1-cohesin complex formation by preventing the binding of SA1 with Rad21, a major structural component of the tripartite cohesin ring; 2) inhibiting the SA1 interaction with cohesin loader, NIPBL, to prevent the loading of SA1-cohesin complex to chromatin; and 3) suppressing the transcription of SA1 gene expression, all resulting in synthetic lethality in SA2-mutant cells. Once the hit compounds are identified from the screen, we will validate their structure by independent synthesis then, further characterize their ADME properties and efficacy in vivo in EWS patient-derived xenograft models and ex vivo using three sets of isogenic EWS lines and mutant SA2 and knock-in WR SA2 generated in our lab.