Thymoliposarcoma with sebaceous differentiation and MDM2 amplification

Abstract Non-genotoxic reactivation of p53 by MDM2 inhibitors represents a promising therapeutic strategy for tumors with wild-type TP53, particularly tumors harboring MDM2 amplification. MDM2 controls p53 levels by targeting it for degradation, while disruption of the MDM2-p53 interaction causes rapid accumulation of p53 and activation of the p53 pathway. We examined the efficacy of the small molecule MDM2 inhibitor KRT-232, alone and in combination with radiation therapy (RT), in MDM2-amplified and/or p53 wildtype patient-derived xenograft (PDX) models of glioblastoma in vitro and in vivo. In vitro, glioblastoma PDX explant cultures showed sensitivity to KRT-232, both tumors with MDM2 amplification (GBM108 and G148) and non-amplified but TP53-wildtype lines (GBM10, GBM14, and GBM39), with IC50s ranging from 300-800 nM in FBS culture conditions. A TP53 p.F270C mutant PDX (GBM43) was inherently resistant, with IC50 >3000 nM. In the MDM2-amplified GBM108 line, KRT-232 led to a robust (5-6 fold) induction of p53-target genes p21, PUMA, and NOXA, with initiation of both apoptosis and senescence. Expression of p21 and PUMA was greater with KRT-232 in combination with RT (25-35 fold induction), while stable knock-down of p53 in GBM108 led to complete resistance to KRT-232. In contrast, GBM10 showed lower induction of p21 and PUMA (2-3 fold) and was more resistant to KRT-232. In an orthotopic GBM108 xenograft model, treatment with KRT-232 +/- RT for one week extended survival from 22 days (placebo) to 46 days (KRT-232 alone); combination KRT-232 + RT further extended survival (77 days) over RT alone (31 days). KRT-232 is an effective treatment in a subset of glioblastoma pre-clinical models alone and in combination with RT. Further studies are underway to understand the mechanisms conferring innate sensitivity or resistance to KRT-232.

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Prominent response to platinum‐based chemotherapy in a patient with BRCA2 mutant‐neuroendocrine prostate cancer and MDM2 amplification

IJU Case Reports ◽

10.1002/iju5.12287 ◽

2021 ◽

Author(s):

Tatsuaki Daimon ◽

Takeo Kosaka ◽

Hiroshi Hongo ◽

Eriko Aimono ◽

Kohei Nakamura ◽

...

Keyword(s):

Prostate Cancer ◽

Neuroendocrine Prostate Cancer ◽

Platinum Based Chemotherapy ◽

Prominent Response ◽

Mdm2 Amplification

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MDM2 Amplified Sarcomas: A Literature Review

Diagnostics ◽

10.3390/diagnostics11030496 ◽

2021 ◽

Vol 11 (3) ◽

pp. 496

Author(s):

Raf Sciot

Keyword(s):

Suppressor Gene ◽

Negative Regulator ◽

Low Grade ◽

P53 Mutations ◽

Lipomatous Tumor ◽

Double Minute ◽

Genetic Features ◽

Murine Double Minute ◽

Well Differentiated ◽

Mdm2 Amplification

Murine Double Minute Clone 2, located at 12q15, is an oncogene that codes for an oncoprotein of which the association with p53 was discovered 30 years ago. The most important function of MDM2 is to control p53 activity; it is in fact the best documented negative regulator of p53. Mutations of the tumor suppressor gene p53 represent the most frequent genetic change in human cancers. By overexpressing MDM2, cancer cells have another means to block p53. The sarcomas in which MDM2 amplification is a hallmark are well-differentiated liposarcoma/atypical lipomatous tumor, dedifferentiated liposarcoma, intimal sarcoma, and low-grade osteosarcoma. The purpose of this review is to summarize the typical clinical, histopathological, immunohistochemical, and genetic features of these tumors.

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MDM2 amplification is an independent prognostic feature of node-negative, estrogen receptor-positive early-stage breast cancer

Cancer Biomarkers ◽

10.3233/dma-2011-0806 ◽

2011 ◽

Vol 8 (2) ◽

pp. 53-60 ◽

Cited By ~ 16

Author(s):

Matthias Choschzick ◽

Uwe Heilenkötter ◽

Annette Lebeau ◽

Fritz Jaenicke ◽

Luigi Terracciano ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Early Stage ◽

Early Stage Breast Cancer ◽

Node Negative ◽

Estrogen Receptor Positive ◽

Prognostic Feature ◽

Mdm2 Amplification

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MDM2 amplification and immunohistochemical expression in sarcomatoid renal cell carcinoma

Human Pathology ◽

10.1016/j.humpath.2019.02.004 ◽

2019 ◽

Vol 87 ◽

pp. 28-36 ◽

Cited By ~ 1

Author(s):

David Suster ◽

Shira Ronen ◽

Jess F. Peterson ◽

Alexander C. Mackinnon ◽

Ondrej Hes ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Immunohistochemical Expression ◽

Sarcomatoid Renal Cell Carcinoma ◽

Mdm2 Amplification

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Analysis of MDM2 Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

JCO Precision Oncology ◽

10.1200/po.17.00235 ◽

2018 ◽

pp. 1-14 ◽

Cited By ~ 8

Author(s):

Shumei Kato ◽

Jeffrey S. Ross ◽

Laurie Gay ◽

Farshid Dayyani ◽

Jason Roszik ◽

...

Keyword(s):

Next Generation Sequencing ◽

Mapk Signaling ◽

Small Subset ◽

Next Generation ◽

Investigational Agent ◽

Mutation Burden ◽

Tumor Types ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Mdm2 Amplification

Purpose MDM2 amplification can promote tumorigenesis directly or indirectly through p53 inhibition. MDM2 has increasing clinical relevance because inhibitors are under evaluation in clinical trials, and MDM2 amplification is a possible genomic correlate of accelerated progression, known as hyperprogression, after anti–PD-1/PD-L1 immunotherapy. We used next-generation sequencing (NGS) to ascertain MDM2 amplification status across a large number of diverse cancers. Methods We interrogated the molecular profiles of 102,878 patients with diverse malignancies for MDM2 amplification and co-altered genes using clinical-grade NGS (182 to 465 genes). Results MDM2 amplification occurred in 3.5% of patients (3,650 of 102,878). The majority of tumor types had a small subset of patients with MDM2 amplification. Most of these patients (99.0% [3,613/3,650]) had co-alterations that accompanied MDM2 amplification. Various pathways, including those related to tyrosine kinase (37.9% [1,385 of 3,650]), PI3K signaling (25.4% [926 of 3,650]), TP53 (24.9% [910 of 3,650]), and MAPK signaling (23.6% [863 of 3,650]), were involved. Although infrequent, mismatch repair genes and PD-L1 amplification also were co-altered (2.2% [79 of 3,650]). Most patients (97.6% [3,563 of 3,650]) had one or more co-alterations potentially targetable with either a Food and Drug Administration–approved or investigational agent. MDM2 amplifications were less frequently associated with high tumor mutation burden compared with the MDM2 wild-type population (2.9% v 6.5%; P < .001). An illustrative patient who harbored MDM2 amplification and experienced hyperprogression with an immune checkpoint inhibitor is presented. Conclusion MDM2 amplification was found in 3.5% of 102,878 patients, 97.6% of whom harbored genomic co-alterations that were potentially targetable. This study suggests that a small subset of most tumor types have MDM2 amplification as well as pharmacologically tractable co-alterations.

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