Evaluating dose-limiting toxicities of MDM2 inhibitors in patients with solid organ and hematologic malignancies: A systematic review of the literature

Pi, Lebei; Rooprai, Jasjit; Allan, David S.; Atkins, Harold L.; Bredeson, Chris; Fulcher, AJ; Ito, Caryn Y.; Ramsay, Tim; Shorr,; Stanford, William L.; Sabloff, Mitchell; Christou, Grace

doi:10.1016/j.leukres.2019.106222

Cited by 14 publications

(9 citation statements)

References 32 publications

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“…The proposal has already shown promising preliminary results in some preclinical studies, such as the combination of MDM2 inhibitors with AURKA inhibitors (senescence inducers), which not only induced melanoma cell death but also promoted the expression of numerous immune factors, thereby enhancing the anti-tumor immune response ( 33 ). However, currently known senescence scavengers, such as MDM2 inhibitors and BCL-2 family inhibitors, are not cell specific, and, therefore, the removal of senescent anti-tumor immune cells will lead to unpredictable toxic side effects ( 34 , 35 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma

Zhou

Liu

et al. 2022

Front. Immunol.

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Accumulating evidence has suggested the impact of senescence on tumor progression, but no report has yet described how senescence shapes the tumor microenvironment of clear cell renal cell carcinoma (ccRCC). The objective of this study was to delineate the senescence features of ccRCC and its role in shaping the tumor microenvironment through a comprehensive analysis of multiple datasets, including 2,072 ccRCC samples. Unsupervised consensus clustering identified three senescence subtypes, and we found that the senescence-activated subtype survived the worst, even in the condition of targeted therapy and immunotherapy. The activated senescence program was correlated to increased genomic instability, unbalanced PBMR1/BAP1 mutations, elevated immune cell infiltration, and enhanced immune inhibitory factors (cancer-associated fibroblasts, immune suppression, immune exclusion, and immune exhaustion signaling). A senescence score based on nine senescence-related genes (i.e., P3H1, PROX1, HJURP, HK3, CDKN1A, AR, VENTX, MAGOHB, and MAP2K6) was identified by adaptive lasso regression and showed robust prognostic predictive power in development and external validation cohorts. Notably, we found that the senescence score was correlated to immune suppression, and the low-score subgroup was predicted to respond to anti–PD-1 therapy, whereas the high-score subgroup was predicted to respond to Sunitinib/Everolimus treatment. Collectively, senescence acted as an active cancer hallmark of ccRCC, shaped the immune microenvironment, and profoundly affected tumor prognosis and drug treatment response.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma

Zhou

Liu

et al. 2022

Front. Immunol.

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“…Treatment with MDM2 inhibitors can lead to stabilization of the p53 response and apoptosis, but it can also lead to hematologic defects ( 2 , 36 , 47 ). One of the major reported side effects of MDM2 inhibition across different cancers has been thrombocytopenia ( 2 ).…”

Section: Discussionmentioning

confidence: 99%

Milademetan is a highly potent MDM2 inhibitor in Merkel cell carcinoma

Ananthapadmanabhan¹,

Frost²,

Soroko³

et al. 2022

JCI Insight

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Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with 2 etiologies. Merkel cell polyomavirus (MCPyV) integration is present in about 80% of all MCC. Virus-positive MCC (MCCP) tumors have few somatic mutations and usually express WT p53 ( TP53 ). By contrast, virus-negative MCC (MCCN) tumors present with a high tumor mutational burden and predominantly UV mutational signature. MCCN tumors typically contain mutated TP53 . MCCP tumors express 2 viral proteins: MCPyV small T antigen and a truncated form of large T antigen. MCPyV ST specifically activates expression of MDM2, an E3 ubiquitin ligase of p53, to inhibit p53-mediated tumor suppression. In this study, we assessed the efficacy of milademetan, a potent, selective, and orally available MDM2 inhibitor in several MCC models. Milademetan reduced cell viability of WT p53 MCC cell lines and triggered a rapid and sustained p53 response. Milademetan showed a dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft models. Here, along with preclinical data for the efficacy of milademetan in WT p53 MCC tumors, we report several in vitro and in vivo models useful for future MCC studies.

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“…There were no new or unexpected safety findings observed, in line with prior experience with idasanutlin and with AEs considered class effects among MDM2 inhibitors. 31 Idasanutlin exposure in the MIRROS study was above that of the previous phase 1/1b study, in which clinical efficacy was seen, highlighting that the observed gastrointestinal side effects did not prevent the achievement of therapeutic levels despite the oral route of administration of idasanutlin. 32 …”

Section: Discussionmentioning

confidence: 80%

Idasanutlin Plus Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia: Results of the MIRROS Trial

et al. 2022

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The phase III MIRROS trial (NCT02545283) evaluated the efficacy and safety of the small-molecule MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Adults (N=447) with R/R AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment or following salvage chemotherapy regimen, with Eastern Cooperative Oncology Group performance status ≤2 were enrolled regardless of TP53 mutation status and randomly assigned 2:1 to idasanutlin 300 mg or placebo orally twice daily plus cytarabine 1 g/m2 intravenously on days 1 to 5 of 28-day cycles. At primary analysis (cutoff, November 2019), 436 patients were enrolled, including 355 in the TP53 wild-type intention-to-treat (TP53WT-ITT) population. The primary endpoint, overall survival in the TP53WT-ITT population, was not met (median, 8.3 vs 9.1 months with idasanutlin-cytarabine vs placebo-cytarabine; stratified hazard ratio, 1.08; 95% CI, 0.81-1.45; p = .58). The complete remission (CR) rate, a key secondary endpoint, was 20.3% vs 17.1% (odds ratio [OR], 1.23; 95% CI, 0.70-2.18). The overall response rate (ORR) was 38.8% vs 22.0% (OR, 2.25; 95% CI, 1.36-3.72). Common any-grade adverse events (≥10% incidence in any arm) were diarrhea (87.0% vs 32.9%), febrile neutropenia (52.8% vs 49.3%), and nausea (52.5% vs 31.5%). In summary, despite improved ORR, adding idasanutlin to cytarabine did not improve overall survival or CR rates in patients with R/R AML.

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Evaluating dose-limiting toxicities of MDM2 inhibitors in patients with solid organ and hematologic malignancies: A systematic review of the literature

Cited by 14 publications

References 32 publications

Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma

Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma

Milademetan is a highly potent MDM2 inhibitor in Merkel cell carcinoma

Idasanutlin Plus Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia: Results of the MIRROS Trial

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