Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors

Werner, Lauryn R.; Huang, Shyhmin; Francis, David M.; Armstrong, Eric A.; Ma, Fengwang; Li, Chunrong; Iyer, Gopal; Canon, Jude; Harari, Paul M.

doi:10.1158/1535-7163.mct-14-1056-t

Cited by 37 publications

(38 citation statements)

References 43 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, temozolomide was previously shown to act synergistically with RG7112 [37]. Other MDM2 inhibitors were shown to enhance sensitivity to radiation in human xenografts [38, 39]. In addition to confirming our data using other in vivo models, future studies will include testing of such combinations, as well as the evaluation of more potent MDM2 inhibitors including those in clinical trials (RG7388) [40, 41].…”

Section: Discussionsupporting

confidence: 57%

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Verreault

Schmitt

Goldwirt

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Rationale p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. Methods We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCLs), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. Results MDM2-amplified PDCLs were 44 times more sensitive than TP53 mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 μM vs 21.9 μM). MDM4 amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 μM), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 μM). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. Conclusion These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2 amplified models suggests that additional markers of response to MDM2 inhibitors must be identified.

show abstract

Section: Discussionsupporting

confidence: 57%

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Verreault

Schmitt

Goldwirt

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…The MDM2-p53 complex is currently intensely investigated as a potential drug target for cancer therapy1617. A number of inhibitors of the MDM2-p53 interaction have recently been tested both in vitro and clinically as potential cancer therapeutics1819202122232425.…”

mentioning

confidence: 99%

Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

Ciemny

Dębiński

Paczkowska

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Protein-peptide interactions are often associated with large-scale conformational changes that are difficult to study either by classical molecular modeling or by experiment. Recently, we have developed the CABS-dock method for flexible protein-peptide docking that enables large-scale rearrangements of the protein chain. In this study, we use CABS-dock to investigate the binding of the p53-MDM2 complex, an element of the cell cycle regulation system crucial for anti-cancer drug design. Experimental data suggest that p53-MDM2 binding is affected by significant rearrangements of a lid region - the N-terminal highly flexible MDM2 fragment; however, the details are not clear. The large size of the highly flexible MDM2 fragments makes p53-MDM2 intractable for exhaustive binding dynamics studies using atomistic models. We performed extensive dynamics simulations using the CABS-dock method, including large-scale structural rearrangements of MDM2 flexible regions. Without a priori knowledge of the p53 peptide structure or its binding site, we obtained near-native models of the p53-MDM2 complex. The simulation results match well the experimental data and provide new insights into the possible role of the lid fragment in p53 binding. The presented case study demonstrates that CABS-dock methodology opens up new opportunities for protein-peptide docking with large-scale changes of the protein receptor structure.

show abstract

“…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%

“…RT at the specified dose (2Gy, 5Gy or 8 Gy per fraction) was delivered twice per week for four weeks for a total of eight fractions. AMG 232 was delivered every day concurrent with RT for four weeks by oral gavage at 50mg/kg, a level that fell within the range of doses used in prior studies in the same mouse strain (31). Additional earlier unpublished work had highlighted the clinical relevance of this dose showing that 50mg/kg produced drug exposure level in mice that is similar to the exposure level observed in human trials at well tolerated doses.…”

Section: Methodsmentioning

confidence: 99%

“…AMG 232 and other MDM2 inhibitors have been shown to radiosensitize non-small cell lung cancer, breast cancer, colon cancer, melanoma, and prostate cancer cell lines that are p53 wild type, with more modest efficacy in models that harbor p53 mutations (31,32). Given the low rate of TP53 mutation in ACC and promising preclinical data demonstrating a role for MDM2 inhibition in ACC, we hypothesized that the combination of AMG 232 and RT would result in improved tumor control than either treatment alone.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition

Prabakaran

Javaid

Swick

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors

Cited by 37 publications

References 43 publications

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition

Contact Info

Product

Resources

About