# Development of Mithramycin Analogues to Target Transcriptional Vulnerabilities in Rhabdoid Tumor

> **NIH NIH F31** · VAN ANDEL RESEARCH INSTITUTE · 2020 · $36,965

## Abstract

PROJECT SUMMARY
Rhabdoid tumor (RT) is a pediatric malignancy characterized by a single recurrent coding mutation in the
chromatin remodeling complex, SWI/SNF, leading to overactivation of polycomb repressive complex 2 (PRC2).
In normal cells these complexes oppose each other, however in RT, the defect in SWI/SNF and activation of
PRC2 establishes an imbalance that drives malignant transformation and progression. Therefore, the
dysregulated balance between SWI/SNF and PRC2 is widely regarded as the therapeutic vulnerability in
rhabdoid tumor. Our lab identified a unique sensitivity of rhabdoid tumor to the transcriptional inhibitor,
mithramycin. Due to the tumor’s dependence on SWI/SNF and PRC2, the overall hypothesis of this proposal
is that rhabdoid tumor sensitivity to mithramycin is due to disruption of the SWI/SNF-PRC2 axis.
Mechanistically, the SWI/SNF-PRC2 balance maintains a proliferative and pluripotent cellular status
suggesting modulation of this balance may lead to apoptosis or differentiation. Therefore, the goal of this study
is to define the optimal therapeutic endpoint of mithramycin in rhabdoid tumor. In aim 1, we will elucidate the
mechanism of rhabdoid tumor sensitivity to mithramycin. By understanding the mechanism of mithramycin in
RT, we can validate mithramycin as a targeted therapy for rhabdoid tumor. Our preliminary data indicates
mithramycin can induce both an apoptotic and differentiation phenotype depending on dose and exposure of
the drug. We will determine the transcriptional network responsible for the divergent phenotypes and correlate
the phenotypes with SWI/SNF-PRC2 dynamics. In aim 2.1, we will use second-generation analogues of
mithramycin as chemical probes to maximize the clinical potential of this compound. In this aim, we will
develop more potent and less toxic compounds that increase the penetrance of apoptosis and differentiation
endpoints. We will determine the mechanism responsible for their improved toxicity profile and directly
compare the therapeutic endpoints of apoptosis and differentiation in vitro and in vivo. In aim 2.2, we will
employ an unbiased screening approach to identify additional therapeutic targets in rhabdoid tumor that
cooperate with or are independent of SWI/SNF and PRC2. We will define novel differentiation targets that are
dependent on SMARCB1-deficiency and therefore specific to rhabdoid tumor. Further, we will define targets
that are dependent on SMARCB1 and mithramycin and therefore, are candidates for combination therapy
development. In summary, this study addresses the need for a targeted therapy in rhabdoid tumor. Specifically,
we will characterize apoptotic and differentiation endpoints by targeting the transcription of epigenetic
modifiers, thereby defining a novel approach to targeting epigenetics. Further, we will characterize the optimal
therapeutic endpoint for rhabdoid tumor to inform the clinical translation of the therapies developed in this
proposal.

## Key facts

- **NIH application ID:** 9830502
- **Project number:** 5F31CA236300-02
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Maggie Chasse
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,965
- **Award type:** 5
- **Project period:** 2018-12-01 → 2020-08-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830502

## Citation

> US National Institutes of Health, RePORTER application 9830502, Development of Mithramycin Analogues to Target Transcriptional Vulnerabilities in Rhabdoid Tumor (5F31CA236300-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9830502. Licensed CC0.

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