A revolutionary approach to reactivate p53 and overcome treatment resistance in MDM2-overexpressing solid tumors
Published: June 2023 | Last updated: September 2023
Imagine your body has a sophisticated defense system against cancer, with a key protein called p53 acting as a master guardian of your genome. This protector normally prevents damaged cells from turning cancerous by triggering repair or self-destruction.
Functions as the "master guardian" of the genome, preventing cancer development by triggering cell repair or death.
Overproduced in many cancers, MDM2 neutralizes p53's protective function, allowing tumors to grow unchecked.
But what happens when cancer disables this guardian? In approximately 50% of all cancers, the p53 protein remains perfectly functional, yet it's held hostage by another protein called MDM2—a molecular inhibitor that silences our natural protection system 3 8 .
The relationship between p53 and MDM2 represents one of biology's most delicate balancing acts. Under normal conditions, MDM2 regulates p53 activity, preventing excessive cell death. But cancers exploit this relationship—many tumors overproduce MDM2, effectively neutralizing p53's protective function and allowing cancer to grow unchecked 2 . For decades, scientists have sought ways to reawaken p53 in these cancers, and recent breakthroughs in MDM2 inhibition have brought this goal within reach.
Now, emerging research points to an even more powerful strategy: combining MDM2 inhibitors with a novel class of drugs called imipridones, led by the pioneering compound ONC201.
Preclinical studies presented at the 2023 AACR Annual Meeting revealed that this combination creates a synergistic effect that could potentially overcome treatment resistance in various solid tumors 1 .
The MDM2 gene, discovered in 1987, encodes a protein that functions as a master regulator of p53 4 . Under normal physiological conditions, MDM2 and p53 engage in an intricate feedback loop: p53 stimulates MDM2 production, while MDM2 in turn inhibits p53 activity—a carefully balanced system that maintains cellular equilibrium 2 3 .
MDM2 primarily controls p53 through two mechanisms:
MDM2-p53 Interaction Diagram
Visual representation of how MDM2 binds to and inhibits p53 function in cancer cells.
This relationship becomes dangerous when cancer cells exploit it. Approximately 40-60% of human sarcomas and significant percentages of other solid tumors show MDM2 amplification or overexpression, effectively shutting down p53's tumor-suppressing capabilities 2 4 . This MDM2 overexpression has been linked to chemotherapy resistance, radiotherapy insensitivity, and poorer clinical outcomes across multiple cancer types 2 .
The logical solution seemed straightforward: develop drugs that block MDM2 from interacting with p53. Since the early 2000s, several small-molecule MDM2 inhibitors have been developed, including nutlin, idasanutlin, milademetan, and others 4 8 . These compounds work by occupying the p53-binding pocket on MDM2, preventing the physical interaction between the two proteins and thereby freeing p53 to perform its protective functions 3 9 .
In theory, this approach should selectively target cancer cells with MDM2 overexpression while sparing normal cells, creating a therapeutic window. However, the clinical reality has proven more complex. As Dr. Ecaterina Dumbrava of MD Anderson Cancer Center explains, while MDM2 inhibitors have shown "promising clinical efficacy" in certain cancers like liposarcoma and hematologic malignancies, "primary and acquired resistance have limited their potential clinical benefit" 8 .
ONC201 (dordaviprone/TIC10/Modeyso™) represents a first-in-class imipridone compound that recently gained FDA approval for recurrent H3K27M-mutant diffuse midline glioma, marking it as the first and only treatment for this aggressive brain cancer 5 . Originally identified as a TRAIL-inducing compound (TIC10), ONC201 has a unique multi-mechanistic approach to attacking cancer cells.
For recurrent H3K27M-mutant diffuse midline glioma
Acts as a selective antagonist of dopamine receptor DRD2, which is implicated in various malignancies.
Activates caseinolytic protease P (ClpP), a mitochondrial serine protease that disrupts cancer cell metabolism.
Induces the integrated stress response (ISR) pathway, leading to cancer cell death through ATF4 and CHOP activation.
Inactivates both AKT and ERK signaling pathways, crucial survival pathways for cancer cells 5 .
This multifaceted mechanism allows ONC201 to selectively target cancer cells while largely sparing healthy cells. Particularly noteworthy is its ability to penetrate the blood-brain barrier, making it valuable for treating brain tumors 5 . However, as a single agent, ONC201 has demonstrated limitations—it sometimes exerts only cytostatic (growth-stopping) effects rather than cytotoxic (killing) effects, prompting researchers to explore combination approaches 5 .
The combination of MDM2 inhibitors with ONC201 emerged from both theoretical reasoning and observed limitations of each approach individually. While MDM2 inhibitors successfully stabilize and activate p53, they trigger a problematic feedback mechanism: the newly freed p53 stimulates increased MDM2 production, potentially counteracting the treatment's benefits over time 1 .
This is where ONC201 enters the picture. Researchers discovered that ONC201 has a previously unrecognized ability to suppress MDM2 levels, independently of its other mechanisms 1 . As Dr. Ilyas Sahin explained in an interview, "When you use these drugs together, [the] increase in MDM2 levels that is usually seen with MDM2-p53 inhibition was abolished" 1 .
Releases p53, allowing it to activate cell cycle arrest and apoptosis programs
Suppresses cancer cells' survival signaling while independently reducing MDM2 levels
Prevents the compensatory MDM2 increase that typically limits MDM2 inhibitor therapy
This synergistic relationship potentially addresses a critical challenge in cancer treatment: the development of resistance. As noted in recent research, "cancer cells often depend on multiple pathways for their growth and survival, resulting in therapeutic resistance and the limited effectiveness of treatments" 4 . By attacking multiple vulnerabilities simultaneously, the combination therapy may overcome the resistance mechanisms that often render single-agent therapies ineffective.
The groundbreaking preclinical study investigating the MDM2 inhibitor milademetan in combination with ONC201 was presented at the 2023 AACR Annual Meeting by researchers from Brown University 1 . The study employed a multi-faceted approach to evaluate the combination's potential:
Across multiple MDM2-overexpressing solid tumor cell lines to quantify synergistic effects
To examine protein expression changes, particularly focusing on p53 stabilization and MDM2 levels
To understand how the combination affects key pathways, including FOXO3a phosphorylation
The researchers tested various dosing regimens, including low-dose monotherapies, high-dose monotherapies, and combination approaches, to distinguish between additive and truly synergistic effects 1 .
The findings demonstrated compelling evidence of synergy between the two compounds:
| Parameter Measured | Milademetan Alone | ONC201 Alone | Combination Therapy |
|---|---|---|---|
| Cell Viability | Moderate reduction | Moderate reduction | Significantly greater reduction |
| p53 Stabilization | Increased | Minimal effect | Enhanced stabilization |
| MDM2 Levels | Feedback increase | Reduced | Abolished feedback increase |
| FOXO3a Activation | Moderate effect | Moderate effect | Enhanced effect |
Table 1: Key Findings from the Preclinical Study 1
The implications of these results are significant. As Dr. Sahin noted, "These findings are very promising and suggest that these 2 drugs can be used in future studies, especially for patients with cancer who have MDM2-overexpressed tumors" 1 . The combination effectively addresses the primary limitation of MDM2 inhibition—the compensatory rise in MDM2—while simultaneously activating multiple cell death pathways.
"When you use these drugs together, [the] increase in MDM2 levels that is usually seen with MDM2-p53 inhibition was abolished."
| Reagent/Solution | Function/Application | Key Features |
|---|---|---|
| MDM2-p53 inhibitors (Milademetan) | Disrupts MDM2-p53 interaction, stabilizing p53 | Small molecule; binds MDM2 p53-binding pocket; phase 3 clinical candidate |
| Imipridones (ONC201) | Activates integrated stress response and ClpP, reduces MDM2 | First-in-class; blood-brain barrier penetration; FDA-approved for glioma |
| Cell Viability Assays | Quantifies synergistic anti-cancer effects | Measures metabolic activity; determines IC50 values |
| Western Blot Analysis | Detects protein expression changes (p53, MDM2, FOXO3a) | Uses protein-specific antibodies; 48-hour treatment standard |
| MDM2-overexpressing Cancer Cell Lines | Models human tumors with MDM2 amplification | Represents clinical scenario; predicts patient response |
Table 2: Essential Research Reagents for Studying MDM2-ONC201 Combination Therapy
The promising preclinical data has opened several exciting avenues for future research and clinical development. Based on these findings, further investigations are underway to explore this combination more extensively in animal models, with the hope of eventually progressing to human trials 1 .
Researchers are particularly interested in how this combination might enhance response to immunotherapy. As MDM2 overexpression has been implicated in resistance to immune checkpoint inhibitors, there's growing interest in triple-combination approaches that would add PD-1/PD-L1 inhibitors to the MDM2 inhibitor-ONC201 backbone 1 7 .
A recent study published in Molecular Cancer Research demonstrated that "MDM2-inhibition represents a novel strategy to enhance IL-15 and MHC-II-production, which disrupts the immunosuppressive tumor microenvironment" 7 .
The translation of these findings to clinical application will require careful consideration of dosing schedules and toxicity management. As with many targeted therapies, MDM2 inhibitors have shown characteristic side effects, including gastrointestinal toxicities and bone marrow suppression (thrombocytopenia and anemia) 8 .
Researchers are exploring altered dosing strategies—reducing either the daily dose or the number of treatment days—to mitigate these side effects while maintaining efficacy 8 .
| Cancer Type | Rationale for MDM2-ONC201 Combination | Current Development Status |
|---|---|---|
| Dedifferentiated Liposarcoma | High frequency of MDM2 amplification | MDM2 inhibitors in phase 3 trials |
| Melanoma | MDM2 overexpression in subset; immunotherapy synergy potential | Preclinical validation |
| Glioblastoma | ONC201 crosses blood-brain barrier; MDM2 often amplified | ONC201 approved for related CNS cancer |
| Solid Tumors with MDM2 Overexpression | Broad applicability across tumor types | Preclinical stage |
Table 3: Potential Clinical Applications and Development Status
Initial in vitro and in vivo studies demonstrating synergistic effects of MDM2 inhibitors with ONC201 in various cancer models.
Presentation of compelling preclinical data at the 2023 AACR Annual Meeting, generating significant interest in the field.
Further validation in advanced animal models to establish optimal dosing regimens and confirm efficacy.
Design and initiation of clinical trials to evaluate safety and efficacy in patients with MDM2-overexpressing tumors.
The combination of MDM2 inhibitors with ONC201 represents a compelling example of how understanding cancer biology at the molecular level can lead to rational, effective treatment strategies.
By targeting complementary pathways and overcoming the limitations of each single agent, this approach may potentially help patients with MDM2-overexpressing tumors that have proven resistant to conventional therapies.
As the field advances, the key challenges will include identifying the patients most likely to benefit, optimizing dosing schedules to maximize efficacy while minimizing toxicity, and potentially expanding the approach to include third agents such as immunotherapies. The journey from this promising preclinical research to clinical application will require careful validation, but the synergistic combination of MDM2 inhibition with ONC201 offers new hope for overcoming cancer's defense mechanisms and reactivating the body's natural tumor suppressor systems.
As Dr. Sahin aptly concluded, "I would ask my colleagues to watch for MDM2-related research in the [future]" 1 . Indeed, this research avenue represents a frontier in our ongoing battle against cancer, potentially turning the tables on tumors that have learned to disable our most fundamental protective mechanisms.