Histone Deacetylase Inhibitors Synergize with Catalytic Inhibitors of EZH2 to Exhibit Antitumor Activity in Small Cell Carcinoma of the Ovary, Hypercalcemic Type

Wang, Yemin; Chen, Shary Yuting; Colborne, Shane; Lambert, Galen; Shin, Chae Young; Santos, Nancy Dos; Orlando, Krystal A.; Lang, Jessica D.; Hendricks, William P.D.; Bally, Marcel B.; Karnezis, Anthony N.; Hass, Ralf; Underhill, T. Michael; Morin, Gregg B.; Trent, Jeffrey M.; Weissman, Bernard E.; Huntsman, David G.

doi:10.1158/1535-7163.mct-18-0348

Cited by 60 publications

(65 citation statements)

References 44 publications

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“…BIN67 (BIN-67), SCCOHT1 (SCCOHT-1), and COV434 are SCCOHT cell lines bearing mutations in SMARCA4 and lacking SMARCA2 expression [35][36][37] . SCCOHT1 and BIN67 cells were maintained in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 10% Fetal Bovine Serum (FBS) and 1% Penicillin/Streptomycin (PS).…”

Section: Methodsmentioning

confidence: 99%

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Raupach

Garcia-Mansfield

Sharma

et al. 2019

Preprint

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Chromatin remodeling plays a critical role in tumor suppression as demonstrated by 20% of human cancers bearing inactivating mutations in SWI/SNF chromatin remodeling complex members. Mutations in different SWI/SNF subunits drive a variety of adult and pediatric tumor types, including non-small cell lung cancers, rhabdoid tumors, medulloblastomas, and ovarian cancers. Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is an aggressive subtype of ovarian cancer occurring in young women. Nearly all (>98%) SCCOHTs have inactivating mutations in SMARCA4, which encodes 1 of 2 mutually exclusive catalytic subunits of the SWI/SNF complex. Less than half of SCCOHT patients survive 5 years despite aggressive surgery and multimodal chemotherapy. Empirical support for effective SCCOHT treatments is scarce, in part because of the poor understanding of SCCOHT tumorigenesis. To gain insight into the functional consequences of SWI/SNF subunit loss, we defined SWI/SNF composition and its protein-protein interactions (PPIs) by immunoprecipitation and mass spectrometry (IP-MS) of SWI/SNF subunits in 3 SCCOHT cell lines. Comparing these results to a cell line containing a wild-type SWI/SNF complex, the interaction of most canonical core SWI/SNF subunits was observed in all SCCOHT cell lines at a lower abundance. The SCCOHT SWI/SNF also lacked ATPase module subunits and showed a drastic reduction in PBAF-specific subunit interactions. The wild-type and SCCOHT SWI/SNF subunits immunoprecipitated a shared set of 26 proteins, including core SWI/SNF subunits and RNA processing proteins. We observed 131 proteins exclusively interacting with the wild-type SWI/SNF complex including isoform-specific SWI/SNF subunits, members of the NuRD complex, and members of the MLL3/4 complex. We observed 60 PPIs exclusive to the SCCOHT residual SWI/SNF shared in at least 2 of the 3 SCCOHT cell lines, including many proteins involved in RNA processing. Differential interactions with the residual SWI/SNF complex in SCCOHT may further elucidate altered functional consequences of SMARCA4 mutations in these tumors as well as identify synthetic lethal targets that translate to other SWI/SNF-deficient tumors.Introduction:

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Section: Methodsmentioning

confidence: 99%

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Raupach

Garcia-Mansfield

Sharma

et al. 2019

Preprint

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“…Preclinical studies conducted by Wang et al demonstrated the therapeutic potential of the combination of EZH2i and HDACi against small cell carcinoma of the ovary hypercalcemic type (SCCOHT), a rare but extremely lethal cancer that interests mainly young women. This kind of tumor shows a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin‐remodeling complex.…”

Section: The Mmt Approachmentioning

confidence: 64%

“…A combined treatment based on the use of quisinostat 13 and tazemetostat 19 (Combination K, Figure ) at sub‐lethal doses synergistically induced targeted gene expression (such as genes dysregulated by SWI/SNF remodeling complex in SCCOHT) as a result of H3K27 hyperacetylation at the promoter region of PRC2, by simultaneous inhibition of both deacetylase and methyltransferase enzymes. Such H3K27 hyperacetylation led to growth suppression and apoptosis of both SCCOHT cells and xenografted tumors …”

Section: The Mmt Approachmentioning

confidence: 99%

“…159 In addition, a substantial increase in caspase 3/7 activation was registered when the BETi JQ1 42 was combined with either romidepsin 4 or vorinostat 3, confirming that the observed synergies are mainly due to apoptosis induction. 159 Preclinical studies conducted by Wang et al 175 demonstrated the therapeutic potential of the combination of EZH2i and HDACi against small cell carcinoma of the ovary hypercalcemic type (SCCOHT), a rare but extremely lethal cancer that interests mainly young women. This kind of tumor shows a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex.…”

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confidence: 99%

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Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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“…SCCOHT is characterized by a dual loss of SMARCA2 and SMARCA4, two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex (12). Notable recent development in therapeutics for SCCOHT include EZH2 inhibitor (13), HDAC inhibitor (14),ponatinib (15), and a CDK4/6 inhibitor (16) which show promising efficacy in preclinical models. Clinical translation of these molecules is highly anticipated.…”

Section: Introductionmentioning

confidence: 99%

Arginine depletion through ADI-PEG20 to treat argininosuccinate synthase deficient ovarian cancer, including small cell carcinoma of the ovary, hypercalcemic type

Cochrane²,

Tessier‐Cloutier

et al. 2019

Preprint

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A conflict of interest disclosure statement: The authors do not have any conflict of interest. Translational relevanceMany rare ovarian cancers lack effective management strategies and are resistant to the standard platinum-and taxane-based chemotherapy. Thus, for a rare ovarian cancer subtype like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) -an aggressive malignancy affecting young women in their twenties, effective targeted therapeutics are urgently needed. We used global proteomics to identify a deficiency in arginosuccinate synthase (ASS1) as a common feature among some rare ovarian cancer subtypes. Using in-vitro and in-vivo models, we demonstrated that the arginine-depriving investigational agent ADI-PEG20 effectively inhibited cell growth in ASS1 deficient ovarian cancers including SCCOHT, establishing it as a potential therapeutic agent for rare ovarian cancer subtypes deficient in ASS1. Further clinical investigation is warranted. AbstractPurpose: Many rare ovarian cancer subtypes such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) have poor prognosis due to their aggressive nature and resistance to standard platinum and taxane based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targetable vulnerabilities in rare ovarian cancer subtypes. Experimental Design: We compared the global proteomic landscape of six cases each of endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), and SCCOHT to the most common subtype high grade serous ovarian cancer (HGSC) to identify potential therapeutic targets. Immunohistochemistry of tissue microarrays were used as validation of ASS1 deficiency. The efficacy of arginine-depriving therapeutic ADI-PEG20 was assessed in vitro using cell lines and patient derived xenograft mouse models representing SCCOHT. Results: Global proteomic analysis identified low ASS1 expression in ENOC, CCOC, and SCCOHT compared to HGSC. Low ASS1 levels were validated through IHC in a large patient cohort. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 2/15 cases, and expressed in less than 5% of the tumor cells in 8/15 cases. ASS1 deficient ovarian cancer cells were sensitive to ADI-PEG20 treatment regardless of subtype in vitro. Furthermore, in two cell line mouse xenograft models and one patient derived mouse xenograft model of SCCOHT, once a week treatment of ADI-PEG20 (30mg/kg and 15mg/kg) inhibited tumor growth in vivo. Conclusions: Preclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers including SCCOHT. Author's contributions Conception and design:

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Histone Deacetylase Inhibitors Synergize with Catalytic Inhibitors of EZH2 to Exhibit Antitumor Activity in Small Cell Carcinoma of the Ovary, Hypercalcemic Type

Cited by 60 publications

References 44 publications

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Arginine depletion through ADI-PEG20 to treat argininosuccinate synthase deficient ovarian cancer, including small cell carcinoma of the ovary, hypercalcemic type

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