HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC- Driven Medulloblastoma

Pei, Yanxin; Liu, Kun Wei; Wang, Jun; Garancher, Alexandra; Tao, Ran; Esparza, Lourdes Adriana; Maier, Donna L.; Udaka, Yoko T.; Murad, Najiba; Morrissy, Sorana; Şeker-Cin, Huriye; Brabetz, Sebastian; Qi, Lin; Kogiso, Mari; Schubert, Simone; Olson, James M.; Cho, Yoon Jae; Li, Xiao Nan; Crawford, John R.; Levy, Michael L.; Kool, Marcel; Pfister, Stefan M.; Taylor, Michael D.; Wechsler‐Reya, Robert J.

doi:10.1016/j.ccell.2016.02.011

Cited by 209 publications

(198 citation statements)

References 44 publications

(62 reference statements)

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“…In addition, because multiple aberrations affecting histone modifiers have been found in these tumors (98), drugs that target epigenetic regulators could also represent a viable option. Consistent with this, HDAC inhibitors have shown some efficacy in G4-MB patient-derived xenograft (PDX) lines (87). Although the absence of a faithful animal model that mimics human G4-MB has hindered the development of therapeutic strategies against tumors of this subgroup, the finding that G3-and G4-MBs share overlapping genetic alterations suggests that drugs targeting G3-MB might also represent candidate therapeutics for at least a subset of G4-MBs.…”

Section: Groupmentioning

confidence: 75%

“…Although these drugs prolonged survival of tumor-bearing mice, animals eventually succumbed, in part because of changes in the microenvironment that rendered tumors insensitive to the drugs (86). The MP mouse model has also been used for high-throughput drug screening (87). These studies demonstrated that the pan-HDAC inhibitor panobinostat was highly effective against G3-MB and cooperated with a PI3K inhibitor, BKM-120 (buparlisib), to block growth of murine and human G3-MB cells in vitro and in vivo.…”

Section: Groupmentioning

confidence: 99%

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Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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Brain tumors are among the leading causes of cancer-related deaths in children. Although surgery, aggressive radiation, and chemotherapy have improved outcomes, many patients still die of their disease. Moreover, those who survive often suffer devastating long-term side effects from the therapies. A greater understanding of the molecular underpinnings of these diseases will drive the development of new therapeutic approaches. Advances in genomics and epigenomics have provided unprecedented insight into the molecular diversity of these diseases and, in several cases, have revealed key genes and signaling pathways that drive tumor growth. These not only serve as potential therapeutic targets but also have facilitated the creation of animal models that faithfully recapitulate the human disease for preclinical studies. In this Review, we discuss recent progress in understanding the molecular basis of the three most common malignant pediatric brain tumors-medulloblastoma, ependymoma, and high-grade glioma-and the implications for development of safer and more effective therapies.

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Section: Groupmentioning

confidence: 75%

Section: Groupmentioning

confidence: 99%

Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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“…Synergistic antitumor effect between HDAC and PI3K inhibition has been reported in DLBCL xenograft tumors (34) and in MYC-driven mouse medulloblastoma cells in vitro (16). However, the impact of this combination approach on MYC regulation has not been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

“…For example, HDAC inhibitors have been shown to suppress MYC transcription, in part by upregulating the transcription of MYC suppressor genes, such as FOXO1, in some (14)(15)(16)(17) but not all cancer types (18). HDACs also facilitate MYC's oncogenic function as a transcription factor, as they are often recruited to the promoter regions of some MYC-targeted genes to facilitate MYC-mediated regulation of transcription.…”

Section: Introductionmentioning

confidence: 99%

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

Sun

Atoyan

Borek

et al. 2017

Molecular Cancer Therapeutics

115

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Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYCdriven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYCdependent cancers.

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“…There are an increasing number of choices of preclinical mouse models available for preclinical studies of brain tumors. These include orthotopic patient-derived xenografts (i.e., PDX models), GEMMs, and nongermline GEMMs (nGEMMs), in which tumors are generated by introduction of oncogenes or oncogene-expressing cells into the brain [27,28]. Each of these has been applied to medulloblastoma to evaluate therapies.…”

Section: Modeling Drug Effects and Tumor Growthmentioning

confidence: 99%

CNS Anticancer Drug Discovery and Development: 2016 conference insights

Levin

Abrey

Heffron³

et al. 2017

CNS Oncol.

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The 2016 second CNS Anticancer Drug Discovery and Development Conference addressed diverse viewpoints about why new drug discovery/development focused on CNS cancers has been sorely lacking. Despite more than 70,000 individuals in the USA being diagnosed with a primary brain malignancy and 151,669-286,486 suffering from metastatic CNS cancer, in 1999, temozolomide was the last drug approved by the US FDA as an anticancer agent for high-grade gliomas. Among the topics discussed were economic factors and pharmaceutical risk assessments, regulatory constraints and perceptions and the need for improved imaging surrogates of drug activity. Included were modeling tumor growth and drug effects in a medical environment in which direct tumor sampling for biological effects can be problematic, potential new drugs under investigation and targets for drug discovery and development. The long trajectory and diverse impediments to novel drug discovery, and expectation that more than one drug will be needed to adequately inhibit critical intracellular tumor pathways were viewed as major disincentives for most pharmaceutical/ biotechnology companies. While there were a few unanimities, one consensus is the need for continued and focused discussion among academic and industry scientists and clinicians to address tumor targets, new drug chemistry, and more time-and cost-efficient clinical trials based on surrogate end points.

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HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC- Driven Medulloblastoma

Cited by 209 publications

References 44 publications

Molecular mechanisms and therapeutic targets in pediatric brain tumors

Molecular mechanisms and therapeutic targets in pediatric brain tumors

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

CNS Anticancer Drug Discovery and Development: 2016 conference insights

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