MRS studies with the cell perfusion system revealed elevated creatine levels in senescent cells on Day 4, confirming the 1H-NMR results. These senescence-associated changes in metabolism and ECM degradation strongly impact growth and redox metabolism and reveal potential MRS signals for detecting senescent cancer cells in vivo.

RITA, a p53 inducer, attenuated Cr(VI)-induced HIF-1α and LC3-II in A549 cells, suggesting that p53 might be the mechanism underlying the different effects of Cr(VI) on HIF-1α in A549 and HELF cells. Thus, p53-dependent HIF-1α / autophagy-mediated glycolysis plays a role in facilitating Cr(VI)-induced carcinogenesis.

DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue.

The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance.

High levels of ROS can result in off-target effects and general toxicity, and thus, careful tuning of ligand Zn affinity, in comparison to the affinity for other endogenous metals, is important for selective mutant p53 targeting. In this work we show that by using carboxylate donors in place of pyridine we can change the relative Zn/Cu binding ability in a series of ligands, and we investigate the impact of donor group changes on metallochaperone activity and overall cytotoxicity in two mutant p53 cancer cell lines (NUGC3 and SKGT2).

We further discovered the positive feedback loop between THBS1 and the TGF-β pathway as the main source of resistance. This study enhances our understanding of p53 regulation and offers insights into overcoming drug resistance.

The molecular target agents eprenetapopt, tazemetostat, and vorinostat efficiently induced apoptosis in ENKL-J1 cells in vitro. Furthermore, GD2-directed chimeric antigen receptor T cells showed cytotoxicity against ENKL-J1 cells in vivo. These findings not only contribute to understanding the molecular and genomic characteristics of ENKL; they also suggest new treatment options for patients with advanced or relapsed ENKL.

The progress of developing a cancer treatment that may successfully and efficiently target mutant p53 is on the verge of development. Mutant p53 proteins not only initiate oncogenesis but also cause resistance in cancer cells to certain chemo or radiotherapies, further endorse cancer cell survival and promote migration as well as metastasis of cancerous cells. With this regard, many mutant p53 inhibitors have been developed, some of which are currently being evaluated at the pre-clinical level and have been identified and discussed. To date, APR-246 is the most prominent one that has progressed to the Phase III clinical trial.

We also found that while wt-p53 expression contributes to 5-FU sensitivity in colon cancer cells, the RITA p53 reactivating molecule counteracted the resistance against 5-FU in cells expressing mut-p53. Our results indicate that mut-p53 GOF acts as a positive regulator of canonical Wnt signaling and participates in the induction of resistance to 5-FU in colon cancer cells.

Mechanism-based combinations with XPO-1, MDM2, and Bcl-2 inhibitors induce massive apoptosis. PC14586 is presently in early clinical trials.

A novel Y220C-targeted small molecule (PC14586) has shown preliminary efficacy and safety in patients with solid tumors (Dumbrava, E., ASCO 2022)... TP53 Y220C mutations are present in malignant blood disorders and are particularly more common in myelodysplastic syndromes and acute myeloid leukemia, with associated poor outcomes. Novel targeted therapies for this TP53 variant (Y220C) would be of interest for this patient population.

We propose that the immunogenic effect of MQ can be linked to its thiol-reactive alkylating ability as we observed similar immunogenic effects with the broad-spectrum cysteine-reactive compound, iodoacetamide. Our results thus indicate that combination of APR-246 with immunomodulatory agents may elicit effective antitumor immune response irrespective of the tumor's p53 mutation status.

Promisingly, in vitro MDM2 inhibition with Idasnutlin and TP53 reactivation via Eprenetapopt was able to renew TNFRSF10B protein expression. Additionally, applying the BRD4-degrading PROTAC ARV-825 and the CDK4/6 inhibitor Abemaciclib as single-agents and in synergistic combination significantly reduced TP53-altered DLBCL cell line viability. Our analysis presents key associations within a genomic network of actionable targets capable of providing clarity within the evolving precision CAR-T treatment landscape.

DN TP53 mutations were associated with poorer survival outcomes for mCSPC patients. DN TP53 mutations also promoted prostate cancer pro-metastatic behaviors in vitro, which was effectively counteracted by APR-246, making it a promising treatment option that should be explored further in early-phase clinical studies.

The triple combination of azacitidine and venetoclax with either magrolimab or eprenetapopt have demonstrated safety in early trials, with phase III trials currently underway, and promising interim clinical results. This review compiles background on TP53 biology, available and emerging therapies along with their mechanisms of action for the TP53m disease entity, current treatment challenges, and recently published data and status of ongoing clinical trials for TP53m AML/MDS.

No abstract available

The synergism of the combination was associated with significant apoptosis induction through p53-dependent and p53-independent pathways. Preclinical confirmation of these data in in vivo models is highly recommended.

DN TP53 mutations were associated with poorer survival outcomes for mCSPC patients. DN TP53 mutations also promoted prostate cancer pro-metastatic behaviors in vitro , which was effectively counteracted by APR-246, making it a promising treatment option that should be explored further in early-phase clinical studies.

Simultaneously, inverse changes occurred at Serine S4 of the NPM. These new findings of RITA mechanism of action could establish the NPM pT199/pS4 ratio as a marker for suitability of RITA treatment of AML cells.

P1/2, N=1, Terminated, Aprea Therapeutics | N=100 --> 1 | Suspended --> Terminated; Sponsor decision

APR-246 mediated radio-sensitization effects through p53-dependent and -independent ways. The results may provide evidence for a clinical trial of the combination in rectal cancer patients.

Loss of BAP1 results in the sensitivity of cutaneous melanoma cells to p53 activator RITA. In melanoma cells, the activity of ubiquitinase in BAP1 is directly related to their sensitivity to RITA. An increased expression of p53 protein induced by BAP1 knockout is probably a key reason for RITA sensitivity of melanoma cells, suggesting the potential of RITA as a targeted therapeutic agent for cutaneous melanoma carrying BAP1-inactivating mutations.

Drugs that target the p53 pathway (mutant p53 re-activator PRIMA-1MET, dual MDM2/MDMX inhibitor RO-5963, and LEM3, a new molecule targeting interactions of MDM2/p53 family proteins) markedly inhibited viability of tumorigenic Ewing's sarcoma cells, demonstrating their increased vulnerability to restoring the p53 activity compared with nontumorigenic cells. Treatment with RO-5963 and LEM3 in tumorigenic cells stabilized p53 and induced apoptosis in a dose-dependent manner.ConclusionSOX2 expression and the p53 pathway deregulation are associated with sarcoma stemness. Our results indicate that enhanced p53 activity might effectively target aggressive stem-like childhood sarcomas, therefore showing promising clinical potential for p53 pathway re-activation in sarcoma therapy.

A significant decrease in intracellular ROS was observed and resulted in disruption of mitochondrial transmembrane potential. This study uncovers the underlying mechanism of Prima-1 and could be helpful to design further leads against lung cancers.Communicated by Ramaswamy H. Sarma.

Proteasome-mediated degradation was determined using the proteasome, inhibitor MG-132, while MYC half-life was measured using pulse chase experiments in the presence of cycloheximide. Co-treatment with COTI-2 and the MYC inhibitor, MYCi975 resulted in synergistic growth inhibition in all 4 mutant p53 cell lines investigated. The dual ability of COTI-2 to reactivate mutant p53 and degrade MYC should enable this compound to have broad application as an anticancer drug.

Pevonedistat (NEDD-8 inhibitor) and APR-246 (TP53 reactivator) both did not meet trial endpoints. Due to intolerance, primary, and secondary resistance to HMA, there is a large unmet need to develop new safe and effective therapies for patients with MDS. In this review, we focus on the current management strategies and novel therapies in development for treatment of high-risk MDS.

This discovery revealed the specific mechanism of ferroptosis induced by apatinib combined with olaparib in p53 wild-type ovarian cancer cells and provided a theoretical basis for the clinical combined use of apatinib and olaparib in p53 wild-type ovarian cancer patients.

DN TP53 mutations were associated with poorer survival outcomes for mCSPC patients. DN TP53 mutations also promoted prostate cancer pro-metastatic behaviors in vitro, which was effectively counteracted by APR-246, making it a promising treatment option that should be explored further in early-phase clinical studies.

P1/2, N=181, Recruiting, PMV Pharmaceuticals, Inc | Trial completion date: Dec 2025 --> Jul 2026 | Trial primary completion date: Nov 2024 --> Mar 2026

The sensitivity of non-transformed cells to APR-246 also depended on the cell type. These findings reveal that the clinical testing of APR-246 should not be limited to cancers expressing mutant TP53 but expanded to cancers that express wt TP53 or are TP53-deficient.

Eprenetapopt and venetoclax with azacitidine had an acceptable safety profile and encouraging activity, supporting further frontline evaluation of this combination in the treatment of TP53-mutated acute myeloid leukaemia.

COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. Cisplatin synergy is consistent with P53's role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting.

The MDM2 inhibitor Navtemadlin arrests mouse tumor growth and potentiates radiotherapy. Our results support a threshold model for apoptosis induction that requires a high, prolonged p53 signaling for cancer cells to become apoptotic.

This work presented a novel strategy to restore p53 activity for the treatment of gastric cancers via chemically targeting hnRNPA2B1. DATA AVAILABILITY STATEMENT: The data that support the findings of this study are available from the authors upon reasonable request.

To further evaluate for a time-dependent effect, 2 representative variants (R248Q and R273C) after 6 and 24 hours of incubation with 50μM APR-246 and 10μM of Nutlin-3. APR-246 demonstrated a negative, dose-dependent effect on cell viability in all EC cell lines. Our results demonstrate that APR-246's cytotoxic effects in EC seem to be p53-independent. Potential mechanisms for the anti-neoplastic effects of APR-246 include activity targeting antioxidant pathways demonstrated in other solid tumors and provides an area for further investigation in TP53mut EC.

On the other hand, p53 reactivation therapies have not been well established, as few of the p53-MDM2 complex inhibitors such as Nutlin-3 induces mutation in p53 gene upon prolonged usage...Collectively, CopA3 affected the MDM2-p53 interaction, which suppressed tumor development. This study may provide a novel inhibitor candidate for the MDM2-p53 complex, which could ultimately suppress the growth of colorectal cancer cells without being cytotoxic to the healthy neighboring cells present around the tumor microenvironment.

Cotreatment of THP-1 cells with venetoclax and a TP53 activator NSC59984 downregulated DRP1 expression and increased apoptosis. These findings suggest that DRP1 is functionally associated with venetoclax sensitivity in TP53-mutated AML cells. Targeting DRP1 may represent an effective therapeutic strategy for overcoming venetoclax resistance in TP53-mutated AML.

Overall, these findings demonstrate p53-dependent effects of NSC59984 on cellular metabolism, with increased activity in cells harboring the p53 R248W mutation. This research highlights the importance of defining the mutational status of a particular cancer to create a patient-centric strategy for the treatment of p53-driven cancers.

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.

Recent data indicate that the TP53 allelic state, co-occurring somatic mutations, and the position of the TP53 mutation within the clonal hierarchy define genetic heterogeneity among TP53-mutated MDS and acute myeloid leukemia that may influence clinical outcomes, thereby informing the selection of patients most suitable for transplantation. Further, novel therapeutic methods such as antibody-based agents (monoclonals or dual-affinity retargeting antibodies), cellular therapies (natural killer cells, chimeric antigen receptor T cells), or targeted agents (eprenetapopt) may offer opportunities to modify the approach to pretransplant conditioning or posttransplant maintenance and improve clinical outcomes.

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.

Recently, a Phase 1 clinical trial studying the novel Y220C-targeted small molecule PC14586, has shown preliminary safety and efficacy in patients with heavily treated solid tumors...Conclusion s : TP53 Y220C mutation is present in hematologic diseases, primarily in myeloid neoplasms (MDS and AML) and with higher frequency in therapy-related disease. Targeted therapies for this specific TP53 mutation would be of interest in this difficult to treat patient population.