The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Therapeutic inhibition of the MDM2-p53 interaction prevents recurrence of adenoid cystic carcinomas
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Abstract
Purpose: Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the antitumor effect of a novel small-molecule inhibitor of the MDM2–p53 interaction (MI-773) combined with cisplatin in patient-derived xenograft (PDX) ACC tumors. Experimental Design: Therapeutic strategies with MI-773 and/or cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A, -2B, -5, -6) in vitro. The effect of therapy on the fraction of cancer stem cells (CSC) was determined by flow cytometry for ALDH activity and CD44 expression. Results: Combined therapy with MI-773 with cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-xL, and active caspase-9 upon MI-773 treatment. Both single-agent MI-773 and MI-773 combined with cisplatin decreased the fraction of CSCs in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a postsurgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (P = 0.0097). Conclusions: Collectively, these data demonstrate that therapeutic inhibition of MDM2–p53 interaction by MI-773 decreased the CSC fraction, sensitized ACC xenograft tumors to cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2–p53 interaction. Clin Cancer Res; 23(4); 1036–48. ©2016 AACR.
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SAR405838 has demonstrated potent single-agent efficacy in various cell lines and xenograft tumor models and is being investigated in a Phase I clinical trial.
“SAR405838 has demonstrated potent single-agent efficacy in various cell lines and xenograft tumor models and is being investigated in a Phase I clinical trial [42].”
From Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells (2017) · cites this paper as [42]
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Cites
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“This small population of uniquely tumorigenic cells was also found in salivary gland tumors (25, 26), but their sensitivity to chemotherapy is not understood.”
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“This small population of uniquely tumorigenic cells was also found in salivary gland tumors (25, 26), but their sensitivity to chemotherapy is not understood.”
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“It has been shown that the combination ofMI-319 (an alternate small-molecule inhibitor of MDM2 from the class as MI-773) with cisplatin suppressed cell growth, colony formation, and induced apoptosis of pancreatic cancer cells (35).”
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Small-molecule inhibition of MDM2-p53 interaction augments radiation response in human tumors
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“ACCs are resistant to all conventional chemotherapeutic drugs available today.”
BackgroundInfluentialBH3-mimetic small molecule inhibits the growth and recurrence of adenoid cystic carcinoma
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MethodSelf-citation
Flagged first, then by citations
Cited by
Sorted by citations
MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future
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“A similar mechanism has been observed in models of adenoid cystic carcinomas, where treatment with MI-77301 to eliminate tumor recurrence apparently worked by reducing the population of cancer stem cells and sensitizing the cells to cisplatin (Nor et al., 2017).”
ResultZebrafish blastomere screen identifies retinoic acid suppression of MYB in adenoid cystic carcinoma
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“We are now developing a long-term study (1-y follow-up) testing the effect of neoadjuvant therapy with temsirolimus and cisplatin (the most promising drug combination unveiled here) on the recurrence/metastasis of MECs, as we did with an MDM2 inhibitor in models of adenoid cystic carcinoma (Nör et al. 2017).”
BackgroundMethodSelf-citationp53 Inhibits Bmi-1-driven Self-Renewal and Defines Salivary Gland Cancer Stemness
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Self-citationBmi-1: A master regulator of head and neck cancer stemness
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“Inhibition of MDM2-p53 triggered G1 cell cycle arrest, and sensitized tumors to Cisplatin chemotherapy (99, 100).”
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“This molecule has been used in preclinical trials and no recurrences were observed when this molecule was used as adjuvant therapy in mice, while 63% of the mice in the control group showed recurrence (72).”
MethodSurvival of salivary gland cancer stem cells requires mTOR signaling
de Andrade, N. P., Warner, K. A., Zhang, Z., Pearson, A. T., Mantesso, A., Guimarães, D. M., ALTEMANI, A. M. D. A. M., Mariano, F. V., Nunes, F. D., & Nor, J. E. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03391-7 · Cited by 16
Self-citationStawarz, K., Durzyńska, M., Galazka, A., Gorzelnik, A., Zwoliński, J., Paszkowska, M., Bieńkowska‐Pluta, K., & Misiak-Gałązka, M. (2025) · Oncology Letters · doi:10.3892/ol.2025.14899 · Cited by 15
“In the ACC PDX model, inhibiting the interaction between murine double minute 2 (MDM2) and p53 using MI‑733 led to apoptosis, tumor regression and the prevention of tumor recurrence (105).”
Survivin is critically involved in VEGFR2 signaling-mediated esophageal cancer cell survival
Meng, L., Fu-hao, Z., Xiaoming, Z., Yuxiu, Z., Zhaojun, D., Bingcheng, L., Meiling, X., & Shuyan, S. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.05.134 · Cited by 15
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Therapeutic inhibition of Bmi-1 ablates chemoresistant cancer stem cells in adenoid cystic carcinoma
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“MI‐773, an optimized and potent MDM2 antagonist, has high selectivity and affinity in binding to MDM2 and shows tumor suppressive activity in different types of tumor, including adenoid cystic carcinomas (54) and muco‐ epidermoid carcinoma (55).”
BackgroundSelf-citationShao, Y., Zhang, Y., Hou, Y., Tong, H., Zhuang, R., Ji, Z., Wang, B., Zhou, Y., & Lu, W. (2017) · Oncotarget · doi:10.18632/oncotarget.14814 · Cited by 8
“Importantly, p53 transcriptionally activates several of its own regulators, including MDM2, allowing for efficient feedback control to limit the p53 response [20].”
Molecular Aspects of Mucoepidermoid Carcinoma and Adenoid Cystic Carcinoma of the Salivary Gland
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“MI773 is a small molecule inhibitor of MDM2 and in combination with cisplatin leads to reactivation of p53 and induction of tumor regression [69].”
Zhang, X., Chang, L., Zhu, Y., Mao, Y., Zhang, T., Zhang, Q., & Wang, C. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1139222 · Cited by 6
APG-115 Induces SLC7A11-Mediated Ferroptosis and Upregulates PD-L1 Expression in Thyroid Cancer
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Warner, K. A., Sahara, S., Herzog, A. E., Nör, F., CASTILHO, R. M., Polverini, P. J., & Nor, J. E. (2025) · Frontiers in Oral Health · doi:10.3389/froh.2025.1570042 · Cited by 3
“…of the ALDH inhibitor diethylaminobenzaldehyde (DEAB) for 10 min at 37°C, directly stained with Alde fl uor (StemCell Technologies) for 30 min, CD44-APC (BD Pharmingen, Franklin Lanes, NJ, USA) for 10 min at 4°C, and DAPI (cell viability marker, Invitrogen) as previously described (25 – 31, 33, 34).”
Self-citationWarner, K. A., Herzog, A. E., Sahara, S., Nör, F., CASTILHO, R. M., Demirci, H., Chepeha, D. B., Polverini, P. J., & Nor, J. E. (2024) · Oral Surgery Oral Medicine Oral Pathology and Oral Radiology · doi:10.1016/j.oooo.2024.06.005 · Cited by 3
Self-citationOvercoming head and neck cancer stem cells
Oklejas, A. E., & Nor, J. E. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-817868-3.00007-x · Cited by 2
Pearson, A. T., Muzaffar, J., Kirtane, K., Bellile, E., Suresh, K., Rosenberg, A. J., Worden, F. P., Chung, C. H., Vokes, E., Brenner, J. C., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70653-3 · Cited by 1
“MI-773 previously was shown to mediate ACC tumor regression in patient-derived xenograft models of ACC as both a single agent as well as potential synergy when administered in combination with platinum chemotherapy 16,17 .”
Self-citationGonçalves, M. T., Lavareze, L., Egal, É. S. A., ALTEMANI, A. M. D. A. M., & Mariano, F. V. (2025) · Cytotechnology · doi:10.1007/s10616-025-00726-6
“In contrast, PTC596, a potential therapeutic agent, inhibits Bmi-1 and Oct4, leading to a decrease in CSC cancer stem cells (Nör et al. 2017; Sahara et al. 2023) and could sensitize cells to CT. Similarly, therapeutic agents like PTC596, MI-773, and Vorinostat inhibit CSC fraction and increase…”
Metadata
- Authors
- Nör, F., Warner, K. A., Zhang, Z., Acasigua, G. A., Pearson, A. T., Kerk, S. A., Helman, J. I., Sant'Ana Filho, M., Wang, S., & Nör, J. E.
- Affiliations
- Universidade Federal do Rio Grande do Sul (BR)
- University of Michigan (US)
- 2Department of Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
- 1Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2017-02-14
- Volume
- 23
- Issue
- 4
- Pages
- 1036-1048
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC5315632
- OpenAlex
- W2512554954
- Cited by
- 37
- References
- 38
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 4 · 2017: 4
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k08de026500-05)
- National Cancer Institute (P50CA097248)
- National Institute of Dental and Craniofacial Research (R01DE023220, K08-DE026500, R21DE019279, R01DE021139)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Surgery › Salivary Gland Tumors Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Keywords
- adenoid cystic carcinoma, p53-MDM2 interaction, cisplatin, combination therapy, tumor recurrence, cancer stem cells, patient-derived xenografts, apoptosis, p21, neoadjuvant therapy, ALDH activity, CD44
- MeSH terms
- Animals, Cisplatin, Carcinoma, Adenoid Cystic, Female, Humans, Male, Neoplasm Proteins, Neoplasm Recurrence, Local, Spiro Compounds, Tumor Suppressor Protein p53, Apoptosis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, Proto-Oncogene Proteins c-mdm2, Protein Interaction Maps
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