Effect of murine double‐minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys

Kawata, Yoshimasa; Nagasaka, Kazunori; Oda, Katsutoshi; Makii, Chinami; Takeuchi, Makoto; Oki, Sadaaki; Honjo, Haruo; Kojima, Masahiro; Miyagawa, Yuko; Taguchi, Ayumi; Sone, Kenbun; Hiraike, Haruko; Matsumoto, Yōko; Wada‐Hiraike, Osamu; Ayabe, Tokiyoshi; Osuga, Yutaka; Fujii, Tomoyuki

doi:10.1111/cas.14583

Cited by 7 publications

(7 citation statements)

References 40 publications

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“…Milademetan (DS-3032, RAIN-32) is a highly potent, orally available, small-molecule inhibitor of the p53-MDM2 interaction. Prior data indicate that milademetan restored WT p53 activity in in vitro and in vivo cancer models with WT p53 (33)(34)(35)(36). Here, we demonstrate the activity of milademetan toward reactivating WT p53 in MCCP MCC using established MCC cell lines, patient-derived cell lines (PDCLs), and multiple patient-derived xenograft (PDX) models.…”

Section: Introductionmentioning

confidence: 58%

“…Milademetan is a novel, highly potent MDM2 inhibitor, with activity in restoring WT p53 response in several WT p53 in vitro and in vivo cancer models and in a phase I clinical study (33)(34)(35)(36). Clinical trials for milademetan efficacy in liposarcoma, acute myeloid leukemia, lymphoma, and advanced solid tumors have been completed or are in progress (NCT04979442, NCT01877382, NCT03671564).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 58%

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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“…VEGF expression is related to lymphatic metastasis and is important for predicting the prognosis of ovarian cancer patients . Moreover, the VEGF is highly expressed in the ascites of mice that are injected with ID8 cells …”

Section: Methodsmentioning

confidence: 99%

“…36 Moreover, the VEGF is highly expressed in the ascites of mice that are injected with ID8 cells. 37 IL-6 and VEGF concentrations were examined using the Quantikine ELISA kit according to the manufacturer's instructions. We also histologically analyzed the therapeutic effect on peritoneal dissemination on the visceral peritoneum and investigated whether free CDDP and the AL/CDDP/Ca hydrogels affected the normal visceral tissue.…”

Section: ■ Introductionmentioning

confidence: 99%

Intraperitoneal Administration of a Cisplatin-Loaded Nanogel through a Hybrid System Containing an Alginic Acid-Based Nanogel and an In Situ Cross-Linkable Hydrogel for Peritoneal Dissemination of Ovarian Cancer

et al. 2021

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Intraperitoneal chemotherapy demonstrates potential applicability in the treatment of peritoneally disseminated ovarian cancer because the disseminated tumors can directly receive exposure to high concentrations of anticancer drugs. However, a considerable proportion of drugs, particularly micromolecular and hydrophilic drugs, such as cisplatin (CDDP), are often excreted through glomerular filtration for a short period. To effectively deliver CDDP into peritoneally disseminated ovarian cancer tissues, we developed an alginate (AL)-based hybrid system in which a CDDP-loaded AL nanogel (AL/CDDP-nanogel) was encapsulated in an injectable AL-hydrogel cross-linked with calcium ions. This system enabled the sustained release of CDDP from the AL/CDDP-nanogel/AL-hydrogel hybrid for over a week. Herein, we constructed a peritoneally disseminated ovarian cancer mouse model using ovarian cancer cell lines with KRAS mutations (ID8-KRAS: KRASG12V). The AL/CDDP-nanogel/AL-hydrogel hybrid system showed significant antitumor activity in vivo. This therapy may be considered a novel strategy for the treatment of advanced-stage ovarian cancer with KRAS mutations.

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“…In this regard, the inhibition of MDM2 reduced tumor size in pre-clinical models for ccRCC. Furthermore, the combined treatment of MDM2 inhibitors and everolimus showed a synergistic effect decreasing cell growth in ccRCC for “in vitro” and “in vivo” models [ 57 ]. However, specific clinical trials targeting MDM2 in kidney cancer have to still be planned.…”

Section: Current and New Targeted Therapies For Rcc Treatmentmentioning

confidence: 99%

New Therapeutic Interventions for Kidney Carcinoma: Looking to the Future

Dell’Atti

Bianchi

Aguiari

2022

Cancers

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Patients suffering from metastatic renal cell carcinoma (mRCC) show an overall survival rate of lower than 10% after 5 years from diagnosis. Currently, the first-line treatment for mRCC patients is based on antiangiogenic drugs that are able to inhibit tyrosine kinase receptors (TKI) in combination with immuno-oncology (IO) therapy or IO-IO treatments. Second-line therapy involves the use of other TKIs, immunotherapeutic drugs, and mTOR inhibitors. Nevertheless, many patients treated with mTOR and TK inhibitors acquire drug resistance, making the therapy ineffective. Therefore, the research of new therapeutic targets is crucial for improving the overall survival and quality of life of mRCC patients. The investigation of the molecular basis of RCC, especially in clear cell renal cell carcinoma (ccRCC), has led to the identification of different signaling pathways that are involved in renal carcinogenesis. Most of ccRCCs are associated with mutation in VHL gene, which mediates the degradation of hypoxia-inducible factors (HIFs), that, in turn, regulate the pathways related to tumorigenesis, including angiogenesis and invasion. Renal tumorigenesis is also associated with the activation of tyrosine kinases that modulate the PI3K-Akt-mTOR pathway, promoting cell proliferation and survival. In ccRCC, the abnormal activity of mTOR activates the MDM2 protein, which leads to the degradation of tumor suppressor p53 via proteasome machinery. In addition, p53 may be degraded by autophagy in a mechanism involving the enzyme transglutaminase 2 (TG2). Suppression of wild-type p53 promotes cell growth, invasion, and drug resistance. Finally, the activation of ferroptosis appears to inhibit cancer progression in RCC. In conclusion, these pathways might represent new therapeutic targets for mRCC.

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Effect of murine double‐minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 7 publications

References 40 publications

Milademetan is a highly potent MDM2 inhibitor in Merkel cell carcinoma

Milademetan is a highly potent MDM2 inhibitor in Merkel cell carcinoma

Intraperitoneal Administration of a Cisplatin-Loaded Nanogel through a Hybrid System Containing an Alginic Acid-Based Nanogel and an In Situ Cross-Linkable Hydrogel for Peritoneal Dissemination of Ovarian Cancer

New Therapeutic Interventions for Kidney Carcinoma: Looking to the Future

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