Therapeutic Inhibition of the MDM2–p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas

Nör, Felipe; Warner, Kristy A.; Zhang, Zhaocheng; Acasigua, Gerson A.; Pearson, Alexander T.; Kerk, Samuel A.; Helman, Joseph I.; Filho, Manoel Sant’Ana; Wang, Shaomeng

doi:10.1158/1078-0432.ccr-16-1235

Cited by 30 publications

(15 citation statements)

References 38 publications

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“…Progress has been made in identifying novel therapeutic targets ( e.g. MDM2) using low passage primary ACC cells and PDX models [17,18]. However, such studies are challenging due to the limited number of passages that primary cells typically grow in vitro .…”

Section: Introductionmentioning

confidence: 99%

UM-HACC-2A: MYB-NFIB fusion-positive human adenoid cystic carcinoma cell line

et al. 2018

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Objectives: Limited availability of validated human adenoid cystic carcinoma (ACC) cell lines has hindered the mechanistic understanding of the pathobiology of this malignancy and the development of effective therapies. The purpose of this work was to generate and characterize a human ACC cell line. Material and Methods: Immediately after surgery, a tumor fragment from a minor salivary gland from the tongue of a female Caucasian was minced, dissociated, and a single cell suspension was plated in fibronectin-coated flasks. A culture medium containing bovine brain extract and rhEGF was optimized for these cells. Whole exome sequencing was used to evaluate the presence of MYB-NFIB translocation. Results: The University of Michigan-Human Adenoid Cystic Carcinoma (UM-HACC)-2A cells showed continuous growth in monolayers for at least 180 in vitro passages while maintaining epithelial morphology. Short-tandem repeat (STR) profiling confirmed a 100% match to patient DNA. Whole exome sequencing revealed the presence of the MYB-NFIB fusion in UM-HACC-2A cells, which was confirmed by PCR analysis. Western blots revealed high expression of epithelial markers (e.g. E-cadherin, EGFR, pan-cytokeratin) and proteins associated with ACC (e.g. c-Myb, p63). Developmental therapeutic studies showed that UM-HACC-2A cells were resistant to cisplatin (IC50=44.7 µM) while more responsive to paclitaxel (IC50=0.0006 µM). In a pilot study, we observed that UM-HACC-2A cells survived orthotopic transplantation into the submandibular gland. Notably, one of the mice injected with UM-HACC-2A cells exhibited lung metastasis after 6 months. Conclusion: UM-HACC-2A is a MYB-NFIB fusion-positive ACC cell line that is suitable for mechanistic and developmental therapeutics studies.

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Section: Introductionmentioning

confidence: 99%

UM-HACC-2A: MYB-NFIB fusion-positive human adenoid cystic carcinoma cell line

et al. 2018

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“…MDM2 inhibitors can activate endogenous wildtype p53 146 and reduce tumor volume, rate of recurrence, and CSC population in SGC. 147,148 They can also sensitize HNSCC to chemotherapy. 149 MDM2 inhibitors are in Phase I and II clinical trials for the treatment of several malignancies.…”

Section: Resultsmentioning

confidence: 99%

p53 and Cell Fate: Sensitizing Head and Neck Cancer Stem Cells to Chemotherapy

Rodriguez-Ramirez

2018

Crit Rev Oncog

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Head and neck cancers are deadly diseases that are diagnosed annually in approximately half a million individuals worldwide. Growing evidence supporting a role for cancer stem cells (CSCs) in the pathobiology of head and neck cancers has led to increasing interest in identifying therapeutics to target these cells. Apart from the canonical tumor-suppressor functions of p53, emerging research supports a significant role for this protein in physiological stem cell and CSC maintenance and reprogramming. Therefore, p53 has become a promising target to sensitize head and neck CSCs to chemotherapy. In this review, we highlight the role of p53 in stem cell maintenance and discuss potential implications of targeting p53 to treat patients with head and neck cancers.

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“…The low rate of TP53 mutations seen in ACC has led other groups to investigate the efficacy of MDM2 inhibitors as potential systemic therapies given alone, or in combination with cisplatin. Nor and colleagues used PDXs established at their institution to demonstrate that a MDM2 inhibitor, MI-773, slowed growth of ACC both alone and when combined with cisplatin (26,27). They showed that MDM2 inhibition led to p53 activation, induction of apoptosis, tumor growth delay, and could prevent the recurrence of surgically resected xenografted tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Building on work the work by Nor and colleagues (26,27), and our success using AMG 232 to radiosensitize lung squamous cell carcinoma in addition to cell lines derived from colon, breast, sarcoma, and melanoma (31), we combined AMG 232 with RT in ACC. We hypothesized that radiation induced p53 activity would be enhanced by inhibiting MDM2, a negative regulator of p53.…”

Section: Discussionmentioning

confidence: 99%

“…MDM2 inhibitors are known to exhibit anti-tumor effects and are currently being studied in clinical trials (23–25). In ACC, the promising efficacy of an MDM2 inhibitor alone or in combination with cisplatin, has recently been demonstrated in the treatment of ACC patient derived xenografts (26,27). In this study, we investigated the radiosensitizing effect of AMG 232, a picomolar affinity piperidinone inhibitor of MDM2 that is currently in clinical trials for several tumor types.…”

Section: Introductionmentioning

confidence: 99%

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Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition

Prabakaran

Javaid

Swick

et al. 2017

Clinical Cancer Research

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Purpose Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACC contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition. Experimental Design We report the successful establishment and detailed characterization of a TP53-WT ACC patient derived xenograft (PDX) which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiation (RT). Results AMG 232 monotherapy induced modest tumor growth inhibition and RT monotherapy induced a transient tumor growth delay in a dose dependent fashion. Strikingly, combination treatment of AMG 232 with RT (including low dose RT of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates three months following treatment. Post treatment analysis revealed that while both AMG 232 and RT alone induced TP53 tumor suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment. Conclusions These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/RT combination may be warranted to improve local control in this challenging malignancy.

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Therapeutic Inhibition of the MDM2–p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas

Cited by 30 publications

References 38 publications

UM-HACC-2A: MYB-NFIB fusion-positive human adenoid cystic carcinoma cell line

UM-HACC-2A: MYB-NFIB fusion-positive human adenoid cystic carcinoma cell line

p53 and Cell Fate: Sensitizing Head and Neck Cancer Stem Cells to Chemotherapy

Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition

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