Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor–suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations ( www.rescuep53.net ) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.
Background: In recent years, chimeric antigen receptor-modified T (CAR-T) cell therapy for B-cell leukemia and lymphoma has shown high clinical efficacy. Similar CAR-T clinical trials have also been carried out in patients with refractory/relapsed multiple myeloma (RRMM). However, no systematic review has evaluated the efficacy and safety of CAR-T cell therapy in RRMM. The purpose of this study was to fill this literature gap.Methods: Eligible studies were searched in PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, and WanFang from data inception to December 2019. For efficacy assessment, the overall response rate (ORR), minimal residual disease (MRD) negativity rate, strict complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) were calculated. The incidence of any grade cytokine release syndrome (CRS) and grade ≥3 adverse events (AEs) were calculated for safety analysis. The effect estimates were then pooled using an inverse variance method.Results: Overall, 27 studies involving 497 patients were included in this meta-analysis. The pooled ORR and MRD negativity rate were 89% (95% Cl: 83–94%) and 81% (95% Cl: 67–91%), respectively. The pooled sCR, CR, VGPR, and PR were 14% (95% Cl: 5–27%), 13% (95% Cl: 4–26%), 23% (95% Cl: 14–33%), and 15% (95% Cl: 10–21%), respectively. Subgroup analyses of ORR by age, proportion of previous autologous stem cell transplantation (ASCT), and target selection of CAR-T cells revealed that age ≤ 55 years (≤55 years vs. > 55 years, p = 0.0081), prior ASCT ≤70% (≤70% vs. > 70%, p = 0.035), and bispecific CAR-T cells (dual B-cell maturation antigen (BCMA)/BCMA + CD19 vs specific BCMA, p = 0.0329) associated with higher ORR in patients. Subgroup analyses of remission depth by target selection suggested that more patients achieved a better response than VGPR with dual BCMA/BCMA + CD19 CAR-T cells compared to specific BCMA targeting (p = 0.0061). In terms of safety, the pooled incidence of any grade and grade ≥ 3 CRS was 76% (95% CL: 63–87%) and 11% (95% CL: 6–17%). The most common grade ≥ 3 AEs were hematologic toxic effects.Conclusion: In heavily treated patients, CAR-T therapy associates with promising responses and tolerable AEs, as well as CRS in RRMM. However, additional information regarding the durability of CAR-T cell therapy, as well as further randomized controlled trials, is needed.
Targeting cancer metabolism has emerged as an attractive approach to improve therapeutic regimens in acute myeloid leukaemia (AML). Mitochondrial proteases are closely related to cancer metabolism, but their biological functions have not been well characterized in AML. According to different categories, we comprehensively review the role of mitochondrial proteases in AML. This review highlights some ‘powerful’ mitochondrial protease targets, including their biological function, chemical modulators, and applicative prospect in AML.
Background: The TP5 gene is by far the most frequently mutated gene in human cancer. Some studies have shown that TP53 should be used as an independent prognostic biomarker in the prognostic stratification of myelodysplastic syndromes(MDS) and acute myeloid leukemia (AML). In this study, we want to explore the effects of different TP53 mutation status on clinical outcomes in AML and MDS. Method and Results: We retrospectively collected and analyzed 51 patients with TP53 mutation from Jan 1st , 2015 to May 1st , 2019 in West China Hospital, Sichuan University, China. Among 51 patients, 27 patients were diagnosed as MDS,11 were diagnosed as AML. Then average age is 55.7(15-77). According to IPSS-R of MDS, there are 18 out of 27 patients in the high-risk and very high-risk groups, only 1 patient in the intermediate risk group and 8 patients lost follow up. 10 out of 11 AML patients were in the high risk group according to the NCCN guideline. In our analysis, the incidences of complex karyotype and additional gene mutations were 86.67% and 36.84% in MDS and AML patients. AML evolution was 40.74% in MDS patients. The median follow-up time was 16 months (4-51 months) and the median overall survival was 7.61 months (range, 2-17 months). So far, 28.95% patients are still being treated, of which 9 have been treated with hypomethylating agents. To compare the clinical outcome with different TP53 mutations status, firstly, we identified the mutation types and various mutants activity. We counted 62 TP53 mutations in 51 patients and marked their sites at the transcriptional level in Fig1 . Codons 248, 273, 175, 282, 245, and 249 are most common somatic mutations in TP53. Herein, the TP53 mutation hot spots found in 38 AML or MDS patients are clustered in the DNA-binding domain. Then we used the luciferase reporting system to test the p53 mutant activity with missense mutations in the DNA-binding domain as a transcription factor. The results in Fig2 showed that with the exception of R158H, M237V , V143M , Q136E and H178Q, almost all the other mutation types have no activity. And we demonstrated these TP53 hotspot mutations in the structure ( Figure 3). The overall survival time of patients with residual P53 mutant activity (except for the compound mutation) far exceeded the median overall survival(7.61months). For the other patients with mutants which almost completely lost the activity of p53 protein as a transcription factor, two patients were treated with hypomethylating agents followed by hematopoietic stem cell transplantation have survived for 14 and 11 months after diagnosis, respectively. As shown in Fig4 and Fig 5, we compared the OS of these two group patients with different P53 mutant activity and different function areas for 6 months and 12 months, respectively. The results showed that the patients with residual P53 activity survived better Conclusion: Patients with different TP53 mutations do have different clinical outcomes. Patients with residual P53 mutant activity do respond better to treatment, and the final clinical outcome of patients who lose P53 activity completely is poor, but hypomethylating agents and hematopoietic stem cell transplantation can also ppropriately prolong survival time. Legends to the figures Figure1: 62 TP53 mutations in 51 patients with hematological neoplasms. The TP53 mutation hot spots found in 38 AML or MDS patients are clustered in the DNA-binding domain. There were 9 patients with multiple TP53 mutations. The black label represents somatic mutation, and the red label represents germline mutation. Missense mutations account for 61.70%(29/47) of all the TP53 mutations in 38 patients. Figure 2: The p53 mutant activity with missense mutations in DNA binding domain tested by the luciferase reporting system. We compared the normalized RLU on PUMA of P53 mutant with wild type. Figure 3: The structure of the p53 core domain bound to DNA. We marked the residues affected by the TP53 hotspot mutations . The deeper the red, the higher the mutation frequency and the more the mutation clustered Figure 4 : The overall survival of 30 follow-up patients. We use a bar chart to show the clinical outcome(OS) of 30 patients with different mutation types and P53 structure affected by different p53 domains. Figure 5 : The probability of overall survival of 30 follow-up patients. They are divided in two groups: patients with residual P53 activity VS patients with inactive P53 mutant. Disclosures No relevant conflicts of interest to declare.
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