Clinical & mechanistic underpinnings to reducing PAX:FOXO1 for alveolar rhabdomyosarcoma
Ended Project Grant Awarded Last action
- Award ID
- R01CA258720
- Recipient
-
Children's Cancer Therapy Development Institute UEI W1X1U9VLD9G4
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,685,416
Award facts
- Assistance listing
- 93.395 Cancer Treatment Research
- Completion date
- Funding
-
- $2,381,636.00 Federal
- $303,780.00 Non-federal
- Place of performance
- Beaverton, OR 97006, USA
Award details come from USAspending.gov.
Description
- Abstract
- The childhood muscle cancer alveolar rhabdomyosarcoma (arms) is generally not survivable when metastatic. However, arms does usually respond clinically to chemotherapy initially. With respect to the cause of recurrences, clinicians observe that the PAX3:FOXO1 oncogene present in most arms cases mediates treatment resistance, causing a 45% drop in 10-year survival. In explanation, we reported that PAX3:FOXO1 facilitates G2/m checkpoint adaptation (tolerance of DNA breaks & mitotic catastrophe). Thus, the driving clinical challenge is to overcome recurrence by counteracting PAX3:FOXO1. We published that PAX3:FOXO1 can be pharmacologically silenced by entinostat, a novel histone deacetylase inhibitor. We find entinostat dramatically improves arms sensitivity to frontline chemotherapy. Mechanistically, our recently published studies implicate an HDAC3 - SMARCA4 - MIR-27A - PAX3:FOXO1 regulatory circuitry in arms. In parallel we have uncovered that SMARCA4 expression is uniquely elevated in fusion positive arms, and that arms-selective SMARCA4 expression is a pivotal long-term susceptibility in tumor cell survival. These results point to SMARCA4 having a key role in fusion positive arms - controlling PAX3:FOXO1 and chemotherapy sensitivity in the short-term and tumor cell maintenance long-term. We hypothesize that PAX3:FOXO1+ arms can be made more chemosensitive at relapse and less likely to recur by epigenetically silencing PAX3:FOXO1. Thus, our aims are to: (1) delineate the atypical role of SMARCA4 as an oncogene in arms via the SWI/SNF BAF complex, and (2) test efficacy of direct PAX3:FOXO1 inhibition versus upstream SMARCA4/A2 inhibition versus entinostat when combined with relapse chemotherapy and non-chemotherapy agents. From these results, we hope to understand rhabdomyosarcoma molecular underpinnings.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $0 | $0 | |
| Amendment | $303,780 | $0 | |
| Amendment | $288,592 | $0 | |
| Amendment | $288,592 | $0 | |
| Amendment | $297,704 | $0 | |
| Amendment | $297,704 | $0 | |
| Amendment | $297,704 | $0 | |
| Amendment | $303,780 | $0 | |
| Original award | $303,780 | $303,780 |
Quick answers
Who received award R01CA258720?
R01CA258720 was awarded to Children's Cancer Therapy Development Institute by National Cancer Institute (National Institutes of Health) on May 14, 2021.
How much is award R01CA258720 worth?
$2,685,416 has been obligated on R01CA258720: $2,381,636 in federal funding and $303,780 in non-federal funding.
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