idasanutlin (RG7388)

The debate regarding whether allogeneic stem cell transplant should be offered to these patients is summarized. Finally, this review explores the recent unfortunate news of pauses in clinical trials for the leading investigational agents - eprenetapopt, magrolimab, sabatolimab, and idasanutlin - and offers solutions toward re-invigorating the pipeline of precision therapeutics in 2025.

In this research, RG7388 was investigated with pre-clinical methods in ALL cells as a novel treatment strategy. This study suggests further functional research and in-vivo evaluation, and it highlights the prospect of treating p53-functional ALL with MDM2 inhibitors.

P1/2, N=33, Completed, Mayo Clinic | Active, not recruiting --> Completed

This mutation abated its transcriptional activity via destabilization of the tetrameric p53-DNA complex and was observed in many cancer types. Finally, we found that Cisplatin and various BH3-mimetics could enhance RG7388-mediated apoptosis in RG7388-resistant neuroblastoma cells, thereby partially overcoming resistance to MDM2 inhibition.

Interestingly, other combinations of drugs, e.g., etoposide + nutlin-3a, actinomycin D + RG7112, and actinomycin D + idasanutlin had a similar effect. Moreover, normal human fibroblasts are less sensitive to death induced by ActD + Nut3a + FASLG. Our findings create the opportunity to revive the abandoned attempts of cancer immunotherapy employing the recombinant FAS ligand.

We demonstrated for the first time that mRNA expressed from this promoter actually produces the protein, which can be detected with Western blotting, in all examined cancer cell lines with wild-type p53 exposed to A + N. In some cell lines, it is also induced by clinically relevant camptothecin, by nutlin-3a acting alone, or by a combination of actinomycin D and other antagonists of p53-MDM2 interaction-idasanutlin or RG7112. This isoform, fused with green fluorescent protein, localizes in the perinuclear region of cells.

Furthermore, differential expression of certain genes was detected, which could serve as the backbone for novel combination treatment approaches. This research provides preclinical data to guide the exploration of drug combination strategies with MDM2 inhibitors, leading to future clinical trials and associated biomarkers that may improve outcomes for CLL patients.

P1/2, N=38, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> May 2024

Current treatments, i.e. the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation...Overall, the most efficient/selective single-agents and combinations (in vitro and in mice) in-cluded Cladribine, Romidepsin ((H)DAC), Venetoclax (BCL2), and/or Idasanutlin (MDM2)...Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.

P1/2, N=38, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Dec 2025 --> Jun 2024

Utilizing high-throughput combination screening of 1971 FDA-approved and clinically advanced compounds, we identified BCL-xL/BCL-2 inhibitor navitoclax as the most promising idasanutlin combination partner. We demonstrate a preferential engagement of cell death over G1 cell cycle arrest, mechanistically implicating MCL-1-binding pro-apoptotic sensitizer NOXA. The proposed combination of two clinical-stage compounds independently under clinical evaluation for ALL is of high clinical relevance and warrants consideration for the treatment of patients with high-risk and relapsed ALL.

P1/2, N=38, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | N=183 --> 38

P1, N=0, Withdrawn, St. Jude Children's Research Hospital | N=52 --> 0 | Not yet recruiting --> Withdrawn

Although two MDM2-recruiting heterobifunctional molecules reduced HDAC1 and HDAC2 abundance with complete selectivity over HDAC3 and reduced HDAC1/2 corepressor components LSD1 and SIN3A, we were surprised to observe that idasanutlin alone was also capable of this effect. This finding suggests an association between the MDM2 E3 ligase and HDAC1/2 corepressor complexes, which could be important for designing future dual/bifunctional HDAC- and MDM2-targeting therapeutics, such as PROTACs.

P1, N=52, Not yet recruiting, St. Jude Children's Research Hospital

In the context of acute myeloid leukemia (AML) specifically, several efficacious combination therapies have been approved for specific patient subsets, such as all-trans retinoic acid (ATRA) plus arsenic trioxide in the PML-RARA fusion acute promyelocytic subtype and Midostaurin plus Cytarabine and Daunorubicin in FLT3-mutant AML. Strong established hits in our screen include ATR inhibition plus Gemcitabine treatment as well as several combinations involving the BCL-2 inhibitor Venetoclax with chemotherapies (Decitabine and Daunorubicin), Quizartinib, Idasanutlin, and mTOR inhibitors. Thus, we have developed an efficient and cost-effective high throughput drug combinations profiling system that has uncovered candidate therapies that may expand treatment options for patients afflicted by AML.

Combination treatment with idasanutlin and navitoclax, a potent Bcl-2/Bcl-xL inhibitor, induces more consistent and potent synergistic killing of T-ALL PDX lines in vitro than venetoclax, a Bcl-2 specific inhibitor. Moreover, a marked synergic response to combination treatment with idasanutlin and navitoclax was seen in vivo in all four T-ALL xenografts tested, with a significant increase in overall survival in the combination treatment group. Collectively, these preclinical data show that the combination of idasanutlin and navitoclax is highly active in T-ALL and may merit consideration in the clinical setting.

P1, N=52, Not yet recruiting, St. Jude Children's Research Hospital | Phase classification: P1b --> P1

To exploit our mechanistic knowledge on TRIP13 ablation-mediated P53 activation, we further combined DCZ0415 with the MDM2 inhibitor Idasanutlin. In line with our mechanistic data, a high synergy (Bliss synergy score = 9.7) of TRIP13 and MDM2 inhibition was observed. In conclusion, our study uncovers TRIP13 as a fetal-enriched vulnerability in NJ-driven non-DS-AMKL, mechanistically acting through P53, which we leveraged for a mechanism-driven treatment approach with dual TRIP13/MDM2 inhibition as a potential therapeutic strategy for the treatment of high-risk pediatric non-DS-AMKL.

HDM2 antagonist therapy represents a rational and highly effective treatment approach in PV. The durable effects of idasanutlin on phlebotomy requirements and splenomegaly persist even after treatment discontinuation. Additionally, the lack of appearance of TP53 mutations or loss of TP53 in those who progress suggest that the previously-described transient TP53 mutations do not have long-term clinical implications.

In summary, we have described a positive feedback loop between CEBPB, IL-1/TNFα, and monocytic differentiation in monocytic leukemia that contributes to intrinsic and extrinsic drug resistance against BCL2 and MDM2 inhibitors. This crosstalk and the consequent drug resistance are further reinforced by venetoclax/MDM2 inhibition treatment. Combining venetoclax or idasanutlin with IL-1/TNFα antagonists or an IRAK inhibitor can abrogate the feedback loop and induce synergistic cytotoxic effects, offering promising therapeutic strategies to enhance the treatment efficacy of venetoclax and MDM2 inhibitors for monocytic leukemia.

A proof-of-concept study with idasanutlin (idasa), a first-generation MDM2 inhibitor and ven demonstrated manageable safety and encouraging efficacy in relapsed/refractory AML patients (Daver et al. Nvtm, a potent second-generation MDM2 inhibitor, rapidly restored p53 function, induced apoptosis in p53WT AML MOLM-13 by impeding cell cycle, viability, clonogenicity potential, and reducing both glycolysis and oxidative phosphorylation. Nvtm combined with ven significantly enhanced these effects. Importantly, this combination blocked stromal cell-mediated (contact and soluble factors) cytoprotection.

Venetoclax showed an additive benefit in 3 lines, but was only synergistic in 1 of 5 lines tested...We also evaluated ruxolitinib in combination with idasanutlin, as recent work has shown overlapping responses to inhibitors of Jak/Stat or Bcl-2 (Yuan et al...Idasanutlin and combination therapy samples clustered closely in PCA analysis, with p53 response a strongly-induced pathway, as expected. Our data suggest that the rational combination of idasanutlin and navitoclax is highly active against T-ALL, with greater synergic opportunity compared to other available idasanutlin combination treatments, through induction of a p53-dependent apoptotic cell death.

Our study identifies the combination of entinostat with olaparib as a new potential therapeutic approach for MYC-driven Group 3 MB.

P1/2, N=228, Completed, University Hospital Heidelberg | Recruiting --> Completed | N=350 --> 228 | Trial completion date: Sep 2024 --> Feb 2023 | Trial primary completion date: Sep 2023 --> Feb 2023

Furthermore, activation of the unfolded protein response using tunicamycin and thapsigargin was sufficient to activate the ATF4/CHOP stress response axis and sensitize to nutlin-3. Finally, cell line and patient-derived xenograft models demonstrated combinatorial effects of treatment with idasanutlin and carfilzomib on liposarcoma growth in vivo. Finally, cell line and patient-derived xenograft models demonstrated combinatorial effects of treatment with idasanutlin and carfilzomib on liposarcoma growth in vivo. Together, these data indicate that targeting of the proteasome could improve the efficacy of MDM2 inhibitors in liposarcoma.

The novel striking finding of this study was an independent link between SF3B1 mutational status and poor response to RG7388. Overall, SF3B1 mutations in CLL patient samples were associated with resistance to treatment with RG7388 ex vivo, and patients with the wild type for both SF3B1 and TP53 are more likely to benefit from treatment with MDM2 inhibitors.

While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.

P1b, N=40, Not yet recruiting, St. Jude Children's Research Hospital

This is the first study indicating the mechanistic importance of miR-16-5p overexpression in chALL and its inhibitory role in leukemia treatment when combined with the p53-Mdm2 antagonist, RG7388. These findings might be useful for researchers and clinicians to pave the way for better management of chALL.

P1/2, N=33, Active, not recruiting, Mayo Clinic | Trial completion date: May 2023 --> Dec 2023

P1/2, N=183, Recruiting, Hoffmann-La Roche | Trial completion date: May 2024 --> Dec 2025 | Trial primary completion date: May 2024 --> Dec 2025

In a selection of 166 compounds we showed that inhibitors of ATR and WEE1 were cytotoxic against a panel of OCCC cell lines. These two drugs are already in other clinical trials, making them ideal candidates for treatment of OCCC.

In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.

Our results confirmed that the combination treatment with RG-7388 (1M) and Selinexor (1M), which has never been investigated before for treating ovarian cancer cells, reduced the cell viability, upregulated apoptotic proteins, and induced cell death through activation of caspase-mediated apoptotic mechanisms.Grants: The Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida, provided the funds for this study.

Furthermore, the scratch assay showed inhibition of migration of the PCa cells, particularly after the combination treatments. Our results have confirmed that RG7388, simvastatin, and their combination treatments can reverse EMT, inhibit migration, and reduce cancer stemness in p53 mutant prostate cancer cells.

E7107 synergized with the MDM2 inhibitor RG7388, via dual MDM2 inhibition; by E7107 at the transcript level and by RG7388 at the protein level, producing greater p53 stabilisation and apoptosis. This study provides evidence for a synergistic MDM2 and spliceosome inhibitor combination as a novel approach to treat CLL and potentially other haematological malignancies.

We performed small RNA sequencing on longitudinally collected serum samples from mice carrying orthotopic neuroblastoma xenografts that were exposed to treatment with idasanutlin or temsirolimus. We identified idasanutlin-induced serum miRNA expression changes upon one day and 11 days of treatment. By limiting to miRNAs with a tumour-related induction, we put forward hsa-miR-34a-5p as a potential pharmacodynamic biomarker of p53 activation in serum.

We screened 2300 articles and included articles citing novel therapies such as "Venetoclax" (VEN), "Hypomethylating agents (HMA), 5-azacytidine (5-AZA), "checkpoint inhibitors, and "MDM2 inhibitors"...VEN with low-dose cytarabine (LDAC) had 27% CR, whereas LDAC alone had 7%.Checkpoint inhibitors such as nivolumab showed favorable responses, as in the phase II study of nivolumab in combination with azacitidine in relapsed/refractory (R/R) AML; it demonstrated acceptable toxicity and an overall response rate (ORR) of 33%. However, increased response rates were seen in HMA-naïve patients.HDAC inhibitors : In two phase II trials incorporating AZA vs AZA + entinostat, the CR was 46% vs 44%..., the combination therapy of Decitabine and valproic acid showed CR of 34% and mOS of 11.9 months...described a remission of 82% with a median OS of 14.7 months in Eprenetapopt + 5-AZA. The most common grade ≥ 3 hematological adverse events were anemia, neutropenia, thrombocytopenia, and leukopenia.MDM2 Inhibitors : In the MIRROS trial, a phase III trial incorporating idasanutlin + cytarabine + placebo + cytarabine in R/R AML; 436 patients were enrolled...Still a daunting challenge, a combination of these therapies may ultimately be necessary to obtain adequate and sustained responses. Participation in clinical trials for all newly diagnosed AML patients should be encouraged to promote the development of innovative therapeutics.