Acute myeloid leukemia patients clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts

Reis, Bernhard; Jukofsky, Lori; Chen, Gong; Martinelli, Giovanni; Zhong, Hua; So, W. Venus; Dickinson, Michael; Drummond, Mark; Assouline, Sarit; Hashemyan, Maneja; Theron, Michel; Blotner, Steven; Lee, Je Hwan; Kasner, Margaret; Yoon, Sung Soo; Rueger, Ruediger; Seiter, Karen; Middleton, Steven A.; Kelly, Kevin R.; Vey, Norbert; Yee, Karen; Nichols, Gwen; Chen, Lin-Chi; Pierceall, William E.

doi:10.3324/haematol.2015.139717

Cited by 75 publications

(68 citation statements)

References 8 publications

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“…The clinical trial of RG7388 in relapsed/refractory AML assessed at the recommended dose revealed clinical activity in two out of nine patients [34, 67]. One patient achieved a complete response and another partial response, and a response rate of 30% in combination with AraC.…”

Section: Development Of Mdm2 Inhibitorsmentioning

confidence: 99%

“…The three major biomarkers that have been proposed to determine responses to MDM2/X inhibitors are p53 status, MDM2 levels, and MDMX levels [32–34, 70]. Interestingly, MDM2 overexpression, MDMX overexpression, or p53 mutation are often mutually exclusive in various solid tumors including liposarcoma, glioblastoma, melanoma, bladder, prostate, lung, and breast cancers [71].…”

Section: Predictive Biomarkers For Response To Mdm2 Inhibitorsmentioning

confidence: 99%

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Pharmacological activation of wild-type p53 in the therapy of leukemia

Kojima

Ishizawa

Andreeff

2016

Experimental Hematology

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The tumor suppressor p53 is inactivated by mutations in a majority of human solid tumors. Conversely, in leukemias p53 mutations are rare since they are only observed in a small fraction of the patient population, predominately in patients with complex karyotype acute myeloid leukemia or hypodiploid acute lymphoblastic leukemia. However, the loss of p53 function in leukemic cells is often caused by abnormalities in p53-regulatory proteins, including overexpression of MDM2/MDMX, deletion of CDKN2A/ARF, and ATM alterations. For example, MDM2 inhibits p53-mediated transcription, promotes its nuclear export, and induces proteasome-dependent degradation. The MDM2 homolog MDMX is another direct regulator of p53, which inhibits p53-mediated transcription. Several small molecule inhibitors and stapled peptides targeting MDM2 and MDMX have been developed and have recently entered clinical trials. The clinical trial results of the first clinically used MDM2 inhibitor, RG7112, illustrated promising p53 activation and apoptosis induction in leukemia cells as proof of concept. Side effects of RG7112 were most prominent in suppression of thrombopoiesis and gastrointestinal symptoms in the leukemia patients. Predictive biomarkers for response to MDM2 inhibitors have been proposed, but they require further validation both in vitro and in vivo such that the accumulated knowledge concerning pathological p53 dysregulation in leukemia, and novel molecular targeted strategies to overcome this dysregulation, can be translated safely and efficiently in to novel clinical therapeutics.

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Section: Development Of Mdm2 Inhibitorsmentioning

confidence: 99%

Section: Predictive Biomarkers For Response To Mdm2 Inhibitorsmentioning

confidence: 99%

Pharmacological activation of wild-type p53 in the therapy of leukemia

Kojima

Ishizawa

Andreeff

2016

Experimental Hematology

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“…The reason for this synergy with DNA hypomethylating agents is hypothesized to relate to changes in expression of other Bcl-2 family genes, tipping the balance in favor of apoptosis. Recognizing that the vast majority of AMLs retain wild-type p53, and following impressive preclinical data 54 , clinical trials are also underway in AML to explore the combination of Venetoclax with p53 activator idasanutlin (Roche), a small molecule inhibitor of Mdm2 (E3 ligase that mediates degradation of p53 protein) 55 . However, since Bcl-2 inhibition causes neutropenia as well as lymphopenia, it remains to be seen whether a p53 stimulator such as idasanutlin can be safely combined given the potential for overlapping hematotoxicity.…”

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confidence: 99%

Finally, An Apoptosis-Targeting Therapeutic for Cancer

2016

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Summary Resistance to cell death represents one of the hallmarks of cancer. Various genetic and epigenetic changes in malignant cells afford cytoprotection in the face of genomic instability, oncogene activation, microenvironment stress, chemotherapy, targeted anticancer drugs and even immunotherapy. Central among the regulators of cell life and death are Bcl-2 family proteins, with the founding member of the family (B-cell lymphoma/leukemia-2) discovered via its involvement in chromosomal translocations in lymphomas. The quest for therapeutics that target cell survival protein Bcl-2 represents a long road traveled, with many dead-ends, disappointments, and delays. Finally, a Bcl-2-targeting medicine has gained approval as a new class of anticancer agent.

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“…Ding et al, 2013). RG7338 has completed phase I clinical trials for AML as a single agent or in combination with cytarabine (NCT01773408) and advanced malignancies (NCT01462175), with one report correlating patient response to MDM2 protein expression (Reis et al, 2016). In addition to preclinical assessment of RG7338 as therapy for neuroblastoma (L.…”

Section: Small Molecule Wild-type P53 Activatorsmentioning

confidence: 99%

Reviving the guardian of the genome: Small molecule activators of p53

Nguyen

Liao

Zeng

et al. 2017

Pharmacology & Therapeutics

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The tumor suppressor p53 is one of the most important proteins for protection of genomic stability and cancer prevention. Cancers often inactivate it by either mutating its gene or disabling its function. Thus, activating p53 becomes an attractive approach for the development of molecule-based anti-cancer therapy. The past decade and half have witnessed tremendous progress in this area. This essay offers readers with a grand review on this progress with updated information about small molecule activators of p53 either still at bench work or in clinical trials.

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Acute myeloid leukemia patients clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts

Cited by 75 publications

References 8 publications

Pharmacological activation of wild-type p53 in the therapy of leukemia

Pharmacological activation of wild-type p53 in the therapy of leukemia

Finally, An Apoptosis-Targeting Therapeutic for Cancer

Reviving the guardian of the genome: Small molecule activators of p53

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