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1
Gener-Ricos, Georgina, Jan Philipp Bewersdorf, Sanam Loghavi, Aaron D. Goldberg, Christopher Famulare, Ghayas C. Issa, Gautam Borthakur, et al. "TP53 Y220C Mutations in Patients with Myeloid Malignancies." Blood 142, Supplement 1 (November 28, 2023): 1477. http://dx.doi.org/10.1182/blood-2023-189343.
Abstract:
Background: TP53 gene mutations lead to inactivation of the protein p53, causing genome instability, oncogenesis, and treatment resistance conferring an unfavorable prognosis. TP53 Y220C missense mutations in exon 6 (p.659A>G) are described as a frequent ‘hot spot’ mutation in solid tumors. A novel Y220C-targeted small molecule (PC14586) has shown preliminary efficacy and safety in patients with solid tumors (Dumbrava, E., ASCO 2022). No data has been reported about TP53 Y220C in hematologic malignancies to date. We set out to evaluate the clinicopathologic characteristics of TP53 Y220C in hematologic malignancies and particularly, myeloid neoplasms. Methods: We identified all patients with hematologic neoplasms with TP53 Y220C mutations at University of Texas MD Anderson Cancer Center and Memorial Sloan-Kettering Cancer Center, detected by standard next generation sequencing assays, and focused on patients with myeloid malignancies; summarizing the patient characteristics, disease features and outcomes for patients with this specific TP53 mutation. Overall survival (OS) was assessed by the Kaplan-Meier method from date of diagnosis to date of death from any cause or date of last follow-up. Leukemia-free survival (LFS) was calculated from time to diagnosis of TP53 Y220C mutated myelodysplastic syndrome (MDS) to date of transformation to acute myeloid leukemia (AML) or death. Survival analysis was conducted only for newly diagnosed patients with available follow-up data. Results: We identified 143 patients (pts) with hematologic malignancies harboring a TP53 Y220C mutation. MDS and AML were the most frequent diagnoses (MDS, n=66; AML, n=48). Median age was 69 years (range, 32-92) and 56% of patients were male (Table 1). We then analyzed in more detail patients with MNs, including CHIP/CCUS, MDS, AML and MDS/MPN. Among those, in 76 (64%) pts the TP53 Y220C mutation was detected at initial diagnosis and in 43 (36%) pts, TP53 Y220C was identified in the relapsed/refractory setting. Therapy-related myeloid neoplasms (MNs) accounted for 51 of 119 pts (41%). Complex karyotype was frequent (n=88/119, 74%) in the setting of TP53 Y220C. Median TP53 Y220C variant allele frequency (VAF) was 32% (range, 1%-96%). Eighty-two patients (69%) had additional co-mutations: 24 (20%) pts had additional (non-Y220C) TP53 mutations only; 34 (29%) pts had only non- TP53 co-mutations (most frequently DNMT3A and TET2) and 24 (20%) pts had additional TP53 mutations in the setting of other co-mutations. With a median follow-up of 9 months, median OS for patients with newly diagnosed TP53 Y220C MDS (n=39) and AML (n=23) was 13.1 months (95% CI, 7.6 to 18.7) and 8 months (95% CI, 5.6 to 13.4), respectively ( p=0.06) (Figure 2). For the TP53 Y220C MDS cohort, AML transformation occurred in 13 (33%) patients, after a median of 14.3 months. Median LFS for these patients was 12.2 months (95% CI, 7.9 to 16.5). Modest and non-statistically significant differences in median LFS for MDS patients who did and did not receive stem cell transplant (SCT) were identified; MDS+SCT (n=12) 14.5 months (95% CI, 4 to 25) vs MDS+no-SCT (n=27) 9.3 months (95% CI, 4.6 to 14), p=0.18. Interestingly, four patients diagnosed with TP53 Y220C mutated CHIP/CCUS with a median VAF of 2% were identified, and with a median follow-up of 34.6 months, none have developed dysplastic changes or progression to MDS or AML at the time of cut off. Additional outcomes data will be forthcoming in the analysis of this cohort of patients with TP53 Y220C mutated myeloid neoplasms. Conclusions: 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.
2
Carter, Bing Z., Po Yee Mak, Baozhen Ke, Yuki Nishida, Steffen Boettcher, Andrea Bedoy, Lauren B. Ostermann, et al. "Selective Targeting of TP53-Y220C Mutant AML By PC14586 Results in TP53 Wild-Type Conformation and Synergistical Apoptosis Induction By Concomitant Inhibition of Xpo-1, MDM2, or Bcl-2." Blood 142, Supplement 1 (November 28, 2023): 2261. http://dx.doi.org/10.1182/blood-2023-181186.
Abstract:
Patients with TP53-mutant acute myeloid leukemia (AML) constitute the worst outcome group with a survival of only several months. TP53 mutations frequently become dominant following exposure to chemotherapeutic agents, Bcl-2 or MDM2 inhibitors, and confer resistance to multiple other therapies. Y220C is a recurrent hotspot TP53 mutation observed in solid tumors and hematological malignancies, predominantly in AML and MDS (Gener-Ricoset al., ASH 2022). PC14586 (PMV Pharmaceuticals) is designed to bind to the p53-Y220C mutant and restore wild-type (WT) p53 protein conformation and function. PC14586 has been shown to convert Y220C-p53 mutant into WT-p53 protein conformation, induce the activation of p53 transcriptional pathways resulting in selective inhibition of proliferation ofTP53-Y220C mutant solid tumor cell lines and achieved partial responses and stable disease in an ongoing phase I clinical trial in solid tumors (Dumbrava, ASCO 2022, NCT04585750). However, the activity of PC14586 in TP53-Y220C mutated AML/MDS has not been investigated, either as monotherapy or in mechanism-based drug combinations. We investigated the mechanisms of action of PC14586 in AML using cells with TP53-WT, knockout (KO), and mutations (one allele with Y220C or R175H and the other truncated) generated by CRISPR (Boettcher et al., Science 2019) and found that PC14586 converts Y220C mutant p53 to the active form of p53 and selectively activates p53 signaling proteins including MDM2 and p21 in TP53-Y220C AML cells. PC14586 decreased cell viability but had limited apoptogenic activities in the TP53-Y220C AML cells . In primary AML cells with Y220C mutations, PC14586 induced cell death in bulk AML cells and, importantly, also in stem/progenitor cells in 2/3 samples. We reported previously that sustained nuclear retention of p53 by XPO-1 inhibition greatly enhances the transcriptional activity of activated p53 and that activation of p53 by inhibiting its negative regulator MDM2 effectively induces cell death in TP53-WT AML (Kojima et al., Blood 2013, 2005), and that XPO-1 inhibition vastly increased apoptosis induced by MDM2 inhibition through 20-60-fold increased p53 transcriptional activities. We also reported that combined Bcl-2 inhibition and p53 activation is synthetically lethal in TP53-WT AML (Pan et al., Cancer Cell 2017). We hypothesized that XPO-1 synergizes with PC14586 by retaining PC14586-activated p53 in the nucleus and that inhibition of MDM2 induced by PC14586-mediated p53 activation or inhibition of Bcl-2 synergizes with PC14586 in TP53-Y220C AML cells. Indeed, we found that PC14586-induced p53 target proteins were further upregulated when PC14586 was combined with XPO-1 or MDM2 inhibition. Inhibition of XPO-1, MDM2, or Bcl-2 synergistically induced massive apoptosis and decreased cell viability in PC14586 treated TP53 Y220C mutant AML cells (Fig.1), in primary AML blasts, and in CD34+CD38- stem/progenitor cells but not in normal bone marrow cells or stem/progenitor cells through conformational changes of mutant p53 to p53-WT. While PC14586 had limited activity on proliferation in TP53-Y220C AML cells, the combination with Bcl-2 inhibition largely blocked G1-S transition and enhanced apoptosis. The G1-S transition block and apoptosis induction were even more pronounced when PC14586 was combined with XPO-1 or MDM2 inhibitors as determined by flow cytometry measurement of DNA content, and PARP cleavage. Experiments in TP53-Y220C AML PDX models are ongoing and will be reported. In summary, PC14586 converts Y220C-mutant p53 into WT-p53 conformation and induces p53 target proteins. Mechanism-based combinations with XPO-1, MDM2, and Bcl-2 inhibitors induce massive apoptosis. PC14586 is presently in early clinical trials.
3
Puzio-Kuter, Anna M., Chris Mulligan, Brandon Russo, Amy Wiebesiek, Lizhong Xu, Hong Yang, Binh Vu, and Melissa Dumble. "Abstract 1295: Small molecule reactivators of Y220C mutant p53 modulate tumor infiltrating leukocytes and synergize with immune checkpoint inhibitors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1295. http://dx.doi.org/10.1158/1538-7445.am2022-1295.
Abstract:
Abstract Half of human cancers possess mutations in the TP53 gene, with most clustering as hotspots in the DNA binding domain. A tyrosine to cysteine substitution at amino acid 220 of the p53 protein (Y220C) is one such hotspot mutation (~1% of all solid tumors). Small molecules that reactivate Y220C mutant p53 activity to be like wild type have been developed at PMV Pharmaceuticals and the lead compound PC14586 is in Phase I clinical development. The molecules were designed to bind tightly to a crevice within the Y220C p53 mutant protein and stabilize it to a wild type conformation allowing reactivation of p53 transcriptional activity and expression of target proteins (e.g. p21, MDM2), resulting in tumor regression in Y220C p53 mutant xenograft models grown in immunocompromised mice. p53 has been documented to contribute to immune responses by activating regulators of immune signaling pathways and to result in T-cell exclusion in tumor models. To investigate the role of p53 and the immune system in tumorigenesis, a Y220C human p53 knock-in (HUPKI) mouse was generated. Mice that are homozygous mutant for the Y220C humanized alleles succumbed to lymphomas and sarcomas within 6 months and cell lines generated from these tumors were shown to be sensitive in an in vitro proliferation assay to Y220C p53 reactivators (IC50 ~ 192-722 nM) and used to generate Y220C mutant syngeneic mouse models. Administration of Y220C p53 reactivators in Y220C p53 syngeneic mouse models resulted in a dose responsive anti-tumor effect, with maximally efficacious doses resulting in durable cures in nearly all animals, more than observed in immunocompromised mouse models. Addition of checkpoint agents with sub-efficacious administration of Y220C reactivating compounds resulted in synergistic increases in mean survival time of mice, longer than with either single agent. Immunophenotyping analysis of HUPKI Y220C mutant tumors exposed to p53 reactivator compounds showed modulation of the tumor immune environment. Changes include dose responsive increases in T-cells (CD4+, CD8+), T-regulatory cells, natural killer T cells and dose responsive decreases in macrophages (M2) and g-MDSC cells. The synergy observed with an anti-PD-1 combination appears driven by an increase in CD8+ T cells, given a decrease in efficacy in mice depleted of CD8+ T cells, following exposure to anti-CD8. Further investigation into the role of Y220C p53 reactivation in immune modulation showed decreased cytokines and chemokines involved in inflammation (i.e. CXCL10, Ccl2) and an increase in a Tumor Inflammation Signature (nanoString) in a dose and time dependent manner. Taken together, these data suggest a role for p53 signaling in encouraging an immunologically hot tumor microenvironment and provide support for testing small molecule reactivators of mutant p53 in combination with immune checkpoint inhibitors. Citation Format: Anna M. Puzio-Kuter, Chris Mulligan, Brandon Russo, Amy Wiebesiek, Lizhong Xu, Hong Yang, Binh Vu, Melissa Dumble. Small molecule reactivators of Y220C mutant p53 modulate tumor infiltrating leukocytes and synergize with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1295.
4
Zheng, Qian, Peng Wang, Chen Liang, Yao Li, Xin Sun, Amin Li, Wei Zhang, Wei Long, and Yanping Wang. "Abstract 5940: JAB-30355: A highly potent, orally bioavailable p53-Y220C reactivator." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5940. http://dx.doi.org/10.1158/1538-7445.am2024-5940.
Abstract:
Abstract Background: As a key tumor suppressor, p53 precisely regulates cellular events such as cell cycle arrest, apoptosis, senescence, and DNA repair under physiological conditions. In 50-60% of human cancers, TP53 gene is mutated. The TP53 Y220C is a hotspot loss-of-function mutation occurring in around 1% of solid tumors. Application of p53-Y220C reactivator for restoration of p53 function represents a promising treatment strategy for patients with this mutation. Methods: The Induced Allosteric Drug Discovery Platform (IADDP), which integrates medicinal chemistry, biochemical and biophysical studies, and computational techniques, was applied for the development of JAB-30355. The proportion of p53-Y220C with wild-type protein-like structure after JAB-30355 treatment was determined by immunoprecipitation. Thermal shift assay was applied to assess the thermal stability of JAB-30355-reactivated p53-Y220C protein. DNA binding assay was developed to evaluate the in vitro DNA binding activity. p53-luciferase reporter system was developed to evaluate the cellular transcriptional activity. qPCR and Western blotting were performed to evaluate the transcriptional and translational levels of p53 downstream targets, respectively. CellTiter-Glo assay was performed to evaluate the inhibitory activity of JAB-30355 on the viability of tumor cell lines harboring wild-type or Y220C mutated TP53. In vivo PK-PD study was conducted to evaluate the relationship between JAB-30355 concentration and expression of p53 target genes. Multiple CDX and PDX mouse models harboring TP53 Y220C were used to evaluate the antitumor activity of JAB-30355. Results: Immunoprecipitation assay and thermal shift assay results demonstrated that JAB-30355 efficiently restored the wild-type p53-like structure and enhanced protein stability of p53-Y220C in a dose-dependent manner. In addition, JAB-30355 significantly enhanced the DNA binding activity of p53-Y220C and subsequently increased the expression of p53 target genes, such as CDKN1A, MDM2 and PUMA. JAB-30355 inhibited cell viability of multiple TP53 Y220C-mutated cancer cell lines with IC50s ranging from 0.2 to 0.7 μM, and exhibited good selectivity against TP53 wild-type cells. Overall, the in vitro data demonstrated that JAB-30355 is a potent and selective p53-Y220C reactivator. In vivo PK-PD study showed good correlation between JAB-30355 exposure and activation of p53 target genes. Furthermore, JAB-30355 exhibited dose-dependent anti-tumor activity, inducing tumor stasis or regression in multiple CDX and PDX models of ovarian cancer, pancreatic cancer, gastric cancer, and small cell lung cancer, with overall good tolerability. Conclusions: JAB-30355 is a highly potent, selective, and orally bioavailable p53-Y220C reactivator that will be tested in clinical space soon. Citation Format: Qian Zheng, Peng Wang, Chen Liang, Yao Li, Xin Sun, Amin Li, Wei Zhang, Wei Long, Yanping Wang. JAB-30355: A highly potent, orally bioavailable p53-Y220C reactivator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5940.
5
Liu, Meng, Kaijun Geng, Biao Lu, Yuanfeng Xia, and Fanglong Yang. "Abstract 7275: GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7275. http://dx.doi.org/10.1158/1538-7445.am2024-7275.
Abstract:
Abstract As a tumor suppressor, p53 can prevent tumor development through multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumor cell death and rapid tumor progression. The oncogenic Y220C mutation is the ninth most frequent p53 missense mutation in cancer. Y220C mutation creates a narrow, hydrophobic pocket on the surface of the p53 DBD that reduces its thermal stability. As a result, the Y220C mutation causes a rapidly unfold of the p53 protein under physiological conditions, abrogates p53 signaling and drives tumorigenesis. There are approximately 100,000 new Y220C mutation cancer cases per year worldwide with limited treatment choices. The initial clinical evaluation of PC14586 that can restore missense-mutant p53 protein has seen efficacy in patients harboring p53 Y220C mutation even though there is still room for improvement. Here we report a brain-penetrable, highly potent p53 Y220C reactivator which has great in vitro activity as well as induce tumor shrinkage in multiple tumor models at a much lower systematic exposure comparing to PC14586. In vitro, GS-P-328 could bind to p53 Y220C protein with a single nM potency and potently induce cell death in a wide range of p53 Y220C tumor cells while have no anti-proliferative effects with p53 WT cells. GS-P-328 is also active in patient-derived cell (PDC) models in various tumor background including SCLC, gastric, ovarian and colon. In vivo, GS-P-328, at approximately 1/3 of systematic exposure comparing to a leading clinical reactivator, causes tumor shrinkage in multiple CDX models. GS-P-328 could induce MDM2/p21 upregulation in cell systems. In vivo, GS-P-328 could induce 2 fold and more increase in MDM2/p21 protein levels in tumor tissues at approximately 1/3 of plasma concentrations comparing to PC14586. More importantly, in a NUGC3-luc intracranial model, GS-P-328 could strongly inhibit growth of cancer cells in the mouse brain. GS-P-328 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GS-P-328 is now under IND-enabling study and P1 study is planned in early 2025. Citation Format: Meng Liu, Kaijun Geng, Biao Lu, Yuanfeng Xia, Fanglong Yang. GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7275.
6
Valenzuela-Chavira, Ignacio, Salvador Meneses-Sagrero, Aldo A. Arvizu-Flores, Javier Hernández-Paredes, Luisa Rascón-Valenzuela, Carlos A. Velázquez-Contreras, and Ramón E. Robles-Zepeda. "Molecular Docking of the Cardenolides of Asclepias subulata in the Human p53 Protein Reveals an Interaction in the Cleft of the Y220C Mutant." Current Chemical Biology 15, no. 3 (September 2021): 222–33. http://dx.doi.org/10.2174/2212796815666211026112056.
Abstract:
Background and Objective: The objective of the present study is to use docking and ADME analysis to determine if the cardenolides of Asclepias subulata are potential stabilizing drugs of the p53-Y220C mutant. Materials and Methods: Two different receptors, wild-type p53, and the mutant p53-Y220C, were used for docking. Three independent stochastic series were performed, with 60,000 poses considered, and the 30 best poses were selected. ADME analysis was performed using SwissADME. Results: Docking experiments revealed that corotoxigenin 3-O-glucopyranoside and calotropin interact with the cleft, so they were considered potential stabilizers of the p53-Y220C mutant comparable to the control drug 9H5, which was able to predict a position very similar to that already reported in the crystallographic structure. The ADME predicted that calotropin and desglucouzarin have more favorable pharmacokinetic parameters. Both molecules are predicted to be absorbed from the GIT. Conclusion: Calotropin of A. subulata is predicted to be a potential drug for p53-Y220C, because it binds to the cleft of the mutant and has favorable pharmacokinetic parameters. Corotoxigenin 3- O-glucopyranoside also binds to the Y220C cleft, but had less favorable pharmacokinetic parameters. These results have a future impact since calotropin could be used for the treatment of some types of cancer.
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Bauer, Matthias R., Rhiannon N. Jones, Raysa K. Tareque, Bradley Springett, Felix A. Dingler, Lorena Verduci, Ketan J. Patel, Alan R. Fersht, Andreas C. Joerger, and John Spencer. "A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C." Future Medicinal Chemistry 11, no. 19 (October 2019): 2491–504. http://dx.doi.org/10.4155/fmc-2019-0181.
Abstract:
Aim: The p53 cancer mutation Y220C creates a conformationally unstable protein with a unique elongated surface crevice that can be targeted by molecular chaperones. We report the structure-guided optimization of the carbazole-based stabilizer PK083. Materials & methods: Biophysical, cellular and x-ray crystallographic techniques have been employed to elucidate the mode of action of the carbazole scaffolds. Results: Targeting an unoccupied subsite of the surface crevice with heterocycle-substituted PK083 analogs resulted in a 70-fold affinity increase to single-digit micromolar levels, increased thermal stability and decreased rate of aggregation of the mutant protein. PK9318, one of the most potent binders, restored p53 signaling in the liver cancer cell line HUH-7 with homozygous Y220C mutation. Conclusion: The p53-Y220C mutant is an excellent paradigm for the development of mutant p53 rescue drugs via protein stabilization. Similar rescue strategies may be applicable to other cavity-creating p53 cancer mutations.
8
Baud, Matthias G. J., Matthias R. Bauer, Lorena Verduci, Felix A. Dingler, Ketan J. Patel, Deeptee Horil Roy, Andreas C. Joerger, and Alan R. Fersht. "Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines." European Journal of Medicinal Chemistry 152 (May 2018): 101–14. http://dx.doi.org/10.1016/j.ejmech.2018.04.035.
9
Schram, Alison M., Geoffrey I. Shapiro, Melissa L. Johnson, Anthony W. Tolcher, John A. Thompson, Anthony B. El-Khoueiry, Andrae L. Vandross, et al. "Abstract LB_A25: Updated Phase 1 results from the PYNNACLE Phase 1/2 study of PC14586, a selective p53 reactivator, in patients with advanced solid tumors harboring a TP53 Y220C mutation." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): LB_A25. http://dx.doi.org/10.1158/1535-7163.targ-23-lb_a25.
Abstract:
Abstract Background: Mutations in the TP53 gene leading to p53 inactivation are the most common mutational event across human cancers. PC14586 is a first-in-class p53 reactivator that selectively binds to the mutated p53 Y220C protein and restores p53 wild-type activity. Preclinical data support potential for activity of PC14586 across TP53 Y220C-bearing tumors, with enhanced activity in KRAS wild-type (WT) models, consistent with the important parallel roles for p53 inactivation and oncogenic KRAS in tumorigenesis. Preliminary analysis of Phase 1 data from the Phase 1/2 PYNNACLE trial (NCT04585750) evaluating PC14586 in patients with advanced TP53 Y220C solid tumors showed that PC14586 was well tolerated with preliminary clinical activity across multiple tumor types in the efficacious dose range (1150 mg QD to 1500 mg BID). This updated Phase 1 analysis assesses PC14586 in patients treated across the efficacious dose range. Methods: Eligible patients (≥12 years) with locally advanced or metastatic solid tumors with a TP53 Y220C mutation received increasing oral doses of PC14586 to evaluate safety, PK, and preliminary efficacy via RECIST v1.1, and to determine the Recommended Phase 2 Dose (RP2D). Tumor molecular profiling was assessed for the impact of KRAS status on response. Results: As of 1 May 2023, 61 patients were treated in the efficacious dose range (safety population): median age 63 (range 32-84) years, 62% female, and median of 3 (range 1–9) prior lines of systemic therapy. The most frequent treatment-related adverse events (TRAEs) (≥10%) were nausea (42.3%), vomiting (35.2%), diarrhea (19.7%), increased creatinine (18.3%), fatigue (14.1%), and increased AST and ALT (12.7% each); 3% of patients discontinued PC14586 due to TRAEs. Most TRAEs were grade 1 or 2; the most common grade 3 TRAEs were anemia (4.2%) and increased ALT (2.8%). PC14586 administered with food led to improvement in nausea and vomiting. Dose proportional and linear PK was observed with a median half-life of 19 hours. Among patients with measurable disease, 36 patients had KRAS WT and 15 patients had KRAS mutated tumors. A total of 12 PRs (ORR 33.3%) were observed (9 confirmed and 3 unconfirmed - pending confirmation) in patients with KRAS WT disease across multiple tumor types including ovarian, breast, prostate, small-cell lung, and endometrial cancer. The median duration of confirmed response was 7 months. In patients with a KRAS mutation, there were no confirmed responses, although clinical activity was observed. At 2000 mg QD, the ORR was 46.2% in patients with TP53 Y220C and KRAS WT tumors (n=13). A RP2D of 2000 mg QD was selected based on overall safety, PK and preliminary efficacy. Conclusions: PC14586 was well-tolerated with a favorable safety profile. Efficacy was achieved in heavily pre-treated patients across multiple tumor types. The PYNNACLE registrational Phase 2 trial will assess PC14586 as monotherapy at the RP2D of 2000 mg QD in patients with TP53 Y220C and KRAS WT advanced solid tumors. Additional/updated data will be presented at the conference. Citation Format: Alison M Schram, Geoffrey I Shapiro, Melissa L Johnson, Anthony W. Tolcher, John A Thompson, Anthony B El-Khoueiry, Andrae L Vandross, Shivaani Kummar, Aparna R Parikh, Dale R Shepard, Ursula Garczarek, Kim LeDuke, Lisa Sheehan, Marc Fellous, Leila Alland, Ecaterina E Dumbrava. Updated Phase 1 results from the PYNNACLE Phase 1/2 study of PC14586, a selective p53 reactivator, in patients with advanced solid tumors harboring a TP53 Y220C mutation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A25.
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Lane, David P., and Chandra S. Verma. "Covalent Rescue of Mutant p53." Cancer Discovery 13, no. 1 (January 9, 2023): 14–16. http://dx.doi.org/10.1158/2159-8290.cd-22-1212.
Abstract:
Summary: p53 mutant proteins are widely expressed in human cancer. In this issue, Guiley and Shokat describe the development of compounds that rescue the function of the Y220C mutant p53 protein by forming covalent complexes with the target protein. See related article by Guiley and Shokat, p. 56 (3).
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Rockwell, Nathan, Nicole Warrington, and Joshua Rubin. "CBIO-22. p53 GAIN-OF-FUNCTION MUTATIONS DRIVE SEX SPECIFIC EFFECTS ON GLIOMA TUMORIGENESIS." Neuro-Oncology 22, Supplement_2 (November 2020): ii20. http://dx.doi.org/10.1093/neuonc/noaa215.082.
Abstract:
Abstract Sex differences in malignant brain tumors are well-established: Males exhibit greater incidence and poorer survival. Understanding the biology behind these sex differences requires investigation of the pathways known to drive gliomagenesis. The transcription factor TP53 (p53) is one of the most commonly mutated genes in glioblastoma. Most p53 mutations are missense mutations in the DNA-binding domain that lead to the expression of a full length mutant p53 protein. These mutations can endow p53 with oncogenic gains-of-function through aberrant DNA binding and regulation of noncanonical cancer-promoting target genes. Previously, we analyzed patient mutation data and identified six p53 mutations with sex differences in prevalence. In this study, we developed an in vitro mutant p53 glioma model to investigate the sex specific effects of three p53 point mutations: R175H, Y205C, and Y220C (Mm R172H, Y202C, and Y217C respectively). Male and female astrocytes isolated from p53flox/- mouse pups were transduced with a retrovirus expressing mutant p53, followed by a lentivirus expressing CRE recombinase to remove the endogenous WTp53. We then assessed cell proliferation, clonogenicity, and in vivo tumorigenesis in these cells. All three mutations assayed displayed sex differences in proliferation, with male cells overexpressing p53:Y202C and p53:Y217C growing faster than female cells, and female cells overexpressing p53:R172H growing faster than male cells. Male Y202C and Y217C expressing astrocytes also exhibited a trend toward greater clonogenicity compared to female astrocytes. This observation is supported by higher expression of the stem cell markers SOX2 and NESTIN in the male cells. We performed parallel flank injections of male and female astrocytes expressing each mutation or p53 KO. Only male astrocytes expressing p53:Y202C or p53:Y217C and female astrocytes expressing p53:R172H mutation were able to form tumors in vivo. Together, these data support a sex specific gain-of-function phenotype for three different p53 mutations observed in glioma.
12
Gomes, Sara, Bartolomeo Bosco, Joana B. Loureiro, Helena Ramos, Liliana Raimundo, Joana Soares, Nair Nazareth, et al. "SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma." Cancers 11, no. 8 (August 10, 2019): 1151. http://dx.doi.org/10.3390/cancers11081151.
Abstract:
Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structural mutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.
13
Gori, M., B. Barbaro, R. Maggio, M. Arciello, C. Viscomi, and C. Balsano. "Protective effect of the Y220C mutant p53 during steatosis: Good news?" Digestive and Liver Disease 45 (October 2013): e368-e369. http://dx.doi.org/10.1016/j.dld.2013.09.010.
14
Miller, Jessica J., Christophe Orvain, Shireen Jozi, Ryan M. Clarke, Jason R. Smith, Anaïs Blanchet, Christian Gaiddon, Jeffrey J. Warren, and Tim Storr. "Multifunctional Compounds for Activation of the p53-Y220C Mutant in Cancer." Chemistry - A European Journal 24, no. 67 (November 9, 2018): 17734–42. http://dx.doi.org/10.1002/chem.201802677.
15
Gori, Manuele, Barbara Barbaro, Mario Arciello, Roberta Maggio, Carmela Viscomi, Alessia Longo, and Clara Balsano. "Protective Effect of the Y220C Mutant p53 Against Steatosis: Good News?" Journal of Cellular Physiology 229, no. 9 (May 23, 2014): 1182–92. http://dx.doi.org/10.1002/jcp.24550.
16
Gori, M., B. Barbaro, M. Arciello, R. Maggio, C. Viscomi, A. Longo, and C. Balsano. "Protective Effect of the Y220C Mutant p53 Against Steatosis: Good News?" Journal of Cellular Physiology 230, no. 6 (February 25, 2015): 1400. http://dx.doi.org/10.1002/jcp.24874.
17
Dixit, Updesh, Ashutosh K. Pandey, Zhihe Liu, Sushil Kumar, Matthew B. Neiditch, Kenneth M. Klein, and Virendra N. Pandey. "FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53." Journal of Virology 89, no. 15 (May 20, 2015): 7905–21. http://dx.doi.org/10.1128/jvi.00729-15.
Abstract:
ABSTRACTHepatitis C virus (HCV) is a leading cause of chronic hepatitis C (CHC), liver cirrhosis, and hepatocellular carcinoma (HCC). Immunohistochemistry of archived HCC tumors showed abundant FBP1 expression in HCC tumors with the CHC background. Oncomine data analysis of normal versus HCC tumors with the CHC background indicated a 4-fold increase in FBP1 expression with a concomitant 2.5-fold decrease in the expression of p53. We found that FBP1 promotes HCV replication by inhibiting p53 and regulating BCCIP and TCTP, which are positive and negative regulators of p53, respectively. The severe inhibition of HCV replication in FBP1-knockdown Huh7.5 cells was restored to a normal level by downregulation of either p53 or BCCIP. Although p53 in Huh7.5 cells is transcriptionally inactive as a result of Y220C mutation, we found that the activation and DNA binding ability of Y220C p53 were strongly suppressed by FBP1 but significantly activated upon knockdown of FBP1. Transient expression of FBP1 in FBP1 knockdown cells fully restored the control phenotype in which the DNA binding ability of p53 was strongly suppressed. Using electrophoretic mobility shift assay (EMSA) and isothermal titration calorimetry (ITC), we found no significant difference inin vitrotarget DNA binding affinity of recombinant wild-type p53 and its Y220C mutant p53. However, in the presence of recombinant FBP1, the DNA binding ability of p53 is strongly inhibited. We confirmed that FBP1 downregulates BCCIP, p21, and p53 and upregulates TCTP under radiation-induced stress. Since FBP1 is overexpressed in most HCC tumors with an HCV background, it may have a role in promoting persistent virus infection and tumorigenesis.IMPORTANCEIt is our novel finding that FUSE binding protein 1 (FBP1) strongly inhibits the function of tumor suppressor p53 and is an essential host cell factor required for HCV replication. Oncomine data analysis of a large number of samples has revealed that overexpression of FBP1 in most HCC tumors with chronic hepatitis C is significantly linked with the decreased expression level of p53. The most significant finding is that FBP1 not only physically interacts with p53 and interferes with its binding to the target DNA but also functions as a negative regulator of p53 under cellular stress. FBP1 is barely detectable in normal differentiated cells; its overexpression in HCC tumors with the CHC background suggests that FBP1 has an important role in promoting HCV infection and HCC tumors by suppressing p53.
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Gener-Ricos, Georgina, Koji Sasaki, Sanam Loghavi, Abhishek Maiti, Nicholas Short, Fadi Haddad, Naval Daver, et al. "A Descriptive Analysis of TP53 Y220C Mutations in Patients with Hematologic Malignancies." Blood 140, Supplement 1 (November 15, 2022): 11830–32. http://dx.doi.org/10.1182/blood-2022-167923.
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Rauf, Shah Md Abdur, Akira Endou, Hiromitsu Takaba, and Akira Miyamoto. "Effect of Y220C Mutation on p53 and Its Rescue Mechanism: A Computer Chemistry Approach." Protein Journal 32, no. 1 (January 2013): 68–74. http://dx.doi.org/10.1007/s10930-012-9458-x.
20
SHEN, Hong-Chen, Ji-Yong DING, Li LI, and Fu-Feng LIU. "Effect of Y220C Mutant on the Conformational Transition of p53C Probed by Molecular Dynamics Simulation." Acta Physico-Chimica Sinica 32, no. 10 (2016): 2620–27. http://dx.doi.org/10.3866/pku.whxb201606224.
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van Kempen, Pauline M. W., Froukje J. Verdam, Eyleen de Poel, Weibel W. Braunius, Roel A. de Weger, Robert J. J. van Es, Wilko Grolman, and Stefan M. Willems. "TP53 Y220C Is a Hotspot Mutation in Oropharyngeal Squamous Cell Carcinoma." Pathobiology 82, no. 1 (2015): 21–27. http://dx.doi.org/10.1159/000369102.
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Khadiullina, Raniya, Regina Mirgayazova, Damir Davletshin, Elvina Khusainova, Vitaly Chasov, and Emil Bulatov. "Assessment of Thermal Stability of Mutant p53 Proteins via Differential Scanning Fluorimetry." Life 13, no. 1 (December 22, 2022): 31. http://dx.doi.org/10.3390/life13010031.
Abstract:
The p53 protein is a transcription factor that preserves the integrity of the genome. The TP53 gene has inactivating mutations in about 50% of all human cancers. Some missense mutations lead to decreased thermal stability in the p53 protein, its unfolding and aggregation under physiological conditions. A general understanding of the impact of point mutations on the stability and conformation of mutant p53 is essential for the design and development of small molecules that target specific p53 mutations. In this work, we determined the thermostability properties of some of the most common mutant forms of the p53 protein—p53(R273H), p53(R248Q), p53(R248W) and p53(Y220C)—that are often considered as attractive therapeutic targets. The results showed that these missense mutations lead to destabilization of the p53 protein and a decrease in its melting temperature.
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Bauer, Matthias R., Rhiannon N. Jones, Matthias G. J. Baud, Rainer Wilcken, Frank M. Boeckler, Alan R. Fersht, Andreas C. Joerger, and John Spencer. "Harnessing Fluorine–Sulfur Contacts and Multipolar Interactions for the Design of p53 Mutant Y220C Rescue Drugs." ACS Chemical Biology 11, no. 8 (June 21, 2016): 2265–74. http://dx.doi.org/10.1021/acschembio.6b00315.
24
Accordino, Sebastián R., J. Ariel Rodríguez Fris, and Gustavo A. Appignanesi. "Wrapping Effects within a Proposed Function-Rescue Strategy for the Y220C Oncogenic Mutation of Protein p53." PLoS ONE 8, no. 1 (January 24, 2013): e55123. http://dx.doi.org/10.1371/journal.pone.0055123.
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Basse, Nicolas, Joel L. Kaar, Giovanni Settanni, Andreas C. Joerger, Trevor J. Rutherford, and Alan R. Fersht. "Toward the Rational Design of p53-Stabilizing Drugs: Probing the Surface of the Oncogenic Y220C Mutant." Chemistry & Biology 17, no. 1 (January 2010): 46–56. http://dx.doi.org/10.1016/j.chembiol.2009.12.011.
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Shokat, Kevan M. "Abstract IA08: Direct covalent inhibitors of mutant K-Ras." Molecular Cancer Research 21, no. 5_Supplement (May 1, 2023): IA08. http://dx.doi.org/10.1158/1557-3125.ras23-ia08.
Abstract:
Abstract Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to directly target this oncogene have faced difficulties due to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. I will discuss the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras G12C. These compounds rely on the mutant cysteine for binding and therefore do not affect the wild type protein (WT). New covalent molecules targeting K-Ras G12S and G12D are currently under development and will be discussed. I will also discuss reactivation of mutant p53 (Y220C) to leverage the natural anti-tumor effects of tumor suppressors. Citation Format: Kevan M. Shokat. Direct covalent inhibitors of mutant K-Ras [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA08.
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Yu, Camilla, Aaron Petty, and Roberto Vargas. "Abstract 4885: APR-246 cytotoxic effects are TP53 independent in endometrial cancer cell lines." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4885. http://dx.doi.org/10.1158/1538-7445.am2023-4885.
Abstract:
Abstract Background: The majority (80%) of endometrial cancer (EC) related mortality is due to high-grade tumor histology, which harbor high rates of TP53 mutations. APR-246 is a small-molecule drug designed to restore WT p53 signaling in TP53-mutant cancers and has yet to be explored in EC. We aimed to test the cytotoxic potential for APR-246 in EC and its downstream impact. Methods: Using 3 parental EC cell lines with differing TP53 statuses, JHUEM2 (WT), Hec108 (hetero P151H), and Hec1B (R248Q), we generated dose-response curves for APR-246. Cells were treated for 24 hours and viability assessed with CellTiter-Glo after 9 days. To assess for mutation specific effect, we generated dose-response curves using a WT non-targeting control (NTC), CRISPR/Cas9 KO of TP53, and five KO cell lines complemented with 5 common TP53 mutations (R248Q, R248W, R273C, R273H, Y220C). Western blot analysis was performed to assess for p53, p21, PUMA, GADD45, and NOXA using whole-cell lysates, after treatment with 20μM of APR-246 for 24 hours. 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. Results: APR-246 demonstrated a negative, dose-dependent effect on cell viability in all EC cell lines. IC50s for JHUEM2, Hec108, and Hec1B were 2.5μM, 4.3μM, and 4.5μM respectively. For NTC, the IC50 was (1.7μM), while TP53-KO (7.5μM) demonstrated similar IC50 values to the variants (6.5-11.9μM). Two variants (Y220C and R248W), had significantly (<0.001 and <0.01 respectively) higher IC50 values (11.9 and 9.1 μM respectively). In Western blot analysis, no p53 downstream signaling via p21, GADD45, PUMA, and NOXA was observed for any variants. Conclusions: 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. Citation Format: Camilla Yu, Aaron Petty, Roberto Vargas. APR-246 cytotoxic effects are TP53 independent in endometrial cancer cell lines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4885.
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Ahire, Vidhula, D. Das, Kaushala Prasad Mishra, G. R. Kulkarni, and L. Ackland. "Inhibition of the p53 Y220C Mutant by 1-Hydroxy-2- Methylanthraquinone Derivatives: A Novel Strategy for Cancer Therapy." Journal of Environmental Pathology, Toxicology and Oncology 35, no. 4 (2016): 355–64. http://dx.doi.org/10.1615/jenvironpatholtoxicoloncol.2016012256.
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Bromley, Dennis, Matthias R. Bauer, Alan R. Fersht, and Valerie Daggett. "Anin silicoalgorithm for identifying stabilizing pockets in proteins: test case, the Y220C mutant of the p53 tumor suppressor protein." Protein Engineering Design and Selection 29, no. 9 (August 8, 2016): 377–90. http://dx.doi.org/10.1093/protein/gzw035.
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Luparello, Claudio, Ilenia Cruciata, Andreas C. Joerger, Cory A. Ocasio, Rhiannon Jones, Raysa Khan Tareque, Mark C. Bagley, et al. "Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells." International Journal of Molecular Sciences 22, no. 7 (March 26, 2021): 3410. http://dx.doi.org/10.3390/ijms22073410.
Abstract:
The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damage-inducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as “anticancer compounds” and “anticancer epi-compounds” and PK083 a “damage-corrective” compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes.
31
Bhuvaneshwari, C., and S. Ambiga. "Antioxidant and anticancer activities of Solanum nigrum Linn leaves." Journal of Current Opinion in Crop Science 3, no. 2 (June 28, 2022): 79–89. http://dx.doi.org/10.62773/jcocs.v3i2.171.
Abstract:
Solanum nigrum Linn, belonging to the family Solanaceae, is a flowering species native to Australia, South Africa, and Asia. In the present study, the dried S. nigrum leaves were extracted with benzene, diethyl ether, and ethanol by Soxhlet’s extraction and screened qualitatively and quantitatively to determine their total phytoconstituent content and their potential antioxidant evaluation, followed by the GCMS analysis to predict the hit compounds. The highest amounts of phenols (120.50 mg), alkaloids (90.50 mg), and flavonoids (108.75 mg) were present in the diethyl ether extract of the Solanum nigrum leaves. In contrast, saponins (42.50g) are abundant in ethanol extract. The GCMS analysis of diethyl ether extract reported the top compounds with area %, height %, and specific retention times. The major compounds in the GCMS analysis are isopropyl myristate, octadecanedioic acid, and hexadecanedioic acid. Antioxidant assays such as the DPPH assay and reducing power assay revealed that the diethyl ether extract has more antioxidant activity than the standard itself. The two compounds from the GCMS study were then docked against an oncogene BRAF V600E and a mutated tumour suppressor gene p53 Y220C mutant. The results showed that the interaction was good and had higher negative binding energies. We report that S. nigrum leaves have potent antioxidant and anticancer properties.
32
Arciello, Mario, Alessia Longo, Carmela Viscomi, Concetta Capo, Antonio Angeloni, Luisa Rossi, and Clara Balsano. "Core domain mutant Y220C of p53 protein has a key role in copper homeostasis in case of free fatty acids overload." BioMetals 28, no. 6 (October 5, 2015): 1017–29. http://dx.doi.org/10.1007/s10534-015-9886-0.
33
Tseng, Tsui-Hwa, Chau-Jong Wang, Yean-Jang Lee, Yi-Chia Shao, Chien-Heng Shen, Ko-Chao Lee, Shui-Yi Tung, and Hsing-Chun Kuo. "Suppression of the Proliferation of Huh7 Hepatoma Cells Involving the Downregulation of Mutant p53 Protein and Inactivation of the STAT 3 Pathway with Ailanthoidol." International Journal of Molecular Sciences 23, no. 9 (May 4, 2022): 5102. http://dx.doi.org/10.3390/ijms23095102.
Abstract:
Ailanthoidol (ATD) has been isolated from the barks of Zanthoxylum ailanthoides and displays anti-inflammatory, antioxidant, antiadipogenic, and antitumor promotion activities. Recently, we found that ATD suppressed TGF-β1-induced migration and invasion of HepG2 cells. In this report, we found that ATD exhibited more potent cytotoxicity in Huh7 hepatoma cells (mutant p53: Y220C) than in HepG2 cells (wild-type p53). A trypan blue dye exclusion assay and colony assay showed ATD inhibited the growth of Huh7 cells. ATD also induced G1 arrest and reduced the expression of cyclin D1 and CDK2. Flow cytometry analysis with Annexin-V/PI staining demonstrated that ATD induced significant apoptosis in Huh7 cells. Moreover, ATD increased the expression of cleaved PARP and Bax and decreased the expression of procaspase 3/8 and Bcl-xL/Bcl-2. In addition, ATD decreased the expression of mutant p53 protein (mutp53), which is associated with cell proliferation with the exploration of p53 siRNA transfection. Furthermore, ATD suppressed the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and the expression of mevalonate kinase (MVK). Consistent with ATD, the administration of S3I201 (STAT 3 inhibitor) reduced the expression of Bcl-2/Bcl-xL, cyclin D1, mutp53, and MVK. These results demonstrated ATD’s selectivity against mutp53 hepatoma cells involving the downregulation of mutp53 and inactivation of STAT3.
34
Tseng, Tsui-Hwa, Yi-Chia Shao, Yean-Jang Lee, and Huei-Jane Lee. "2-(4-Benzyloxy-3-methoxyphenyl)-5-(carbethoxyethylene)-7-methoxy-benzofuran, a Benzofuran Derivative, Suppresses Metastasis Effects in P53-Mutant Hepatocellular Carcinoma Cells." Biomedicines 11, no. 7 (July 19, 2023): 2027. http://dx.doi.org/10.3390/biomedicines11072027.
Abstract:
2-(4-Benzyloxy-3-methoxyphenyl)-5-(carbethoxyethylene)-7-methoxy-benzofuran (BMBF), a benzofuran derivative, is an intermediate found in the process of total synthesis of ailanthoidol. Benzofuran derivatives are a class of compounds that possess various biological and pharmacological activities. The present study explored the anti-metastasis effects of BMBF in hepatocellular carcinoma (HCC). Our preliminary findings indicate that BMBF suppresses the proliferation and changes the morphology of Huh7—an HCC cell line with a mutated p53 gene (Y220C). According to a scratching motility assay, non-cytotoxic concentrations of BMBF significantly inhibited the motility and migration in Huh7 cells. BMBF upregulated the expression of E-cadherin and downregulated the expression of vimentin, Slug, and MMP9, which are associated with epithelial–mesenchymal transition (EMT) and metastasis in Huh7 cells. BMBF decreased the expression of integrin α7, deactivated its downstream signal FAK/AKT, and inhibited p53 protein levels. Cell transfection with p53 siRNA resulted in the prevention of cell invasion because of the reduction in integrin α7, Slug, and MMP-9 in Huh7 cells. BMBF had anti-metastatic effects in PLC/PRF/5—an HCC cell line with R249S, a mutated p53 gene. Our findings indicate that BMBF has anti-metastatic effects in downregulating p53 and mediating the suppression of integrin α7, EMT, and MMP-9 in HCC cells with a mutated p53 gene.
35
Lv, Cuiting, Aihua Lan, Xiao Fan, Caiguo Huang, and Gong Yang. "Asperolide A induces apoptosis and cell cycle arrest of human hepatoma cells with p53-Y220C mutant through p38 mediating phosphorylation of p53 (S33)." Heliyon 9, no. 3 (March 2023): e13843. http://dx.doi.org/10.1016/j.heliyon.2023.e13843.
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Cheng, Ya-Yun, Denise Prosser, Liudmila Velikokhatnaya, and Anna Lokshin. "Abstract 5833: Functional characterization of TP53 mutations in human fallopian tube secretory epithelial cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5833. http://dx.doi.org/10.1158/1538-7445.am2022-5833.
Abstract:
Abstract Ovarian cancer is the fifth leading cause of cancer-related death in women and mainly develops in older women. High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer and recently has been shown to arise from the distal end of the fallopian tube. About 96% of HGSC cases were found to contain mutations in TP53 and missense mutation was the most frequent type. It is known that TP53 mutation is an early event occurred in HGSC and may drive tumorigenesis. Different TP53 mutations have been reported to promote cell survival, metastatic potential or tumorigenicity. However, the roles of TP53 mutations and the underlying molecular mechanisms have not been satisfactorily understood in HGSC. In order to functionally characterize TP53 mutations in a systematic approach, primary human fallopian tube secretory epithelial cells (FTSECs) from normal fallopian tube specimens were used. We isolated and transduced FTSECs with hTERT for extending cell lifespan. Afterwards, both overexpression and knock down experiments were performed. According to the IARC TP53 Database, we selected four TP53 hotspot mutations found in ovarian cancer patients for further investigation. The mutant TP53, including R175H, Y220C, R273C, and R273H, were expressed in FTSECs. Meanwhile, knock down was achieved by introducing shRNAs targeting TP53. The transduced cells were subjected to RNA sequencing experiments to identify the significantly influenced genes and signaling pathways. The candidate genes and pathways will be validated in FTSECs and a panel of ovarian cancer cell lines. Functional assays, such as cell viability assay, migration/invasion assay, and metabolism assay, will be performed to study the effects of TP53 mutations. The results can provide further understanding of TP53 mutations and the downstream signaling in HGSC tumorigenesis. Citation Format: Ya-Yun Cheng, Denise Prosser, Liudmila Velikokhatnaya, Anna Lokshin. Functional characterization of TP53 mutations in human fallopian tube secretory epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5833.
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Petty, Aaron, Arda Durmaz, Brian Yard, Jacob Scott, and Roberto Vargas. "Abstract 1090: Dominant-negative TP53 variants confer radiation resistance in endometrial cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1090. http://dx.doi.org/10.1158/1538-7445.am2023-1090.
Abstract:
Abstract Introduction: High-grade endometrial cancers (EC) belonging to the “serous-like” cluster are known to portend a worse clinical outcome. The direct contribution of commonly identified TP53 variants on radiotherapy (RT) response has not been demonstrated in EC. Methods: To assess the impact of TP53 variants, allelic frequency, and p53/p21 signaling on radio-resistance in vitro, we utilized a high-throughput radiation assay and intron targeting CRISPR-Cas9 knockout approach in two low copy-number/TP53 wild-type EC cell lines (JHUEM1/JHUEM2). This approach facilitated TP53 cDNA complementation in a TP53-null background without significant impact from copy-number burden. The effect on radiation response was determined using high-throughput methodology and area under the curve (AUC) calculation along 5 dose-points. All experiments were carried out using 2 monoclonal isolates for each guide RNA (4 total replicates) and 2 non-targeting controls. Results: Knockout (KO) of wild-type TP53 resulted in loss of downstream p21 signaling and increased radio-resistance, demonstrating the role of p53 signaling on RT response. Complementation with five common TP53 missense variants (Y220C, R273C, R273H, R248Q, R248W) into the KO cell lines led to increased p53 accumulation without an effect on p21 signaling or RT response. Complementation into the WT cell lines, mimicking tumors with low allelic frequency/heterozygous mutations, led to abrogation of p21 signaling and increased radio-resistance, establishing their gain-of-function/dominant-negative impact. Conclusions: Our findings directly implicate TP53 status on radiotherapy response in EC, providing biologic rationale for the clinical observation that these patients may benefit from chemotherapy. Additionally, our findings demonstrate that dominant-negative variant alleles similarly impact RT response by abrogating p21 signaling. Citation Format: Aaron Petty, Arda Durmaz, Brian Yard, Jacob Scott, Roberto Vargas. Dominant-negative TP53 variants confer radiation resistance in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1090.
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Yang, Yaxian, Heran Wang, Lucas Wang, WenTao Fan, Bin Lian, Ying Jin, Weiquan Luo, et al. "Frequency and patterns of TP53 mutations in lung cancer." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e21013-e21013. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e21013.
Abstract:
e21013 Background: Lung cancer (LC) is the second leading causes of cancer-related mortality and composed of diverse molecular types. Tumor suppressor gene TP53 is one of the most frequency mutation genes in cancer, however, whether there are the hot sports of TP53 mutations has always been a challenging issue. The aim of this study was to explore the spectrums and hot spots of TP53 mutation in LC. Methods: The total 1932 LC tissue samples (from same number of patients，all cases had patients' informed consent) in formalin fixed and paraffin embedded were collected from Guangzhou Huayin Health Medical Group Co.,Ltd. By targeting next generation sequencing (NGS) of 600 genes, the mutation information of TP53 and other genes was obtained. Results: Among 1932 samples, 1025(53%) were male, 1685(87.2%) were lung adenocarcinoma (LUAD), 232(12.0%) were lung squamous cell carcinoma (LSCC), 7(0.4%) were large-cell carcinoma and 8(0.4%) were small-cell carcinoma, median age was 62.82(range: 27-92). The mutated TP53 was detected in 890 (46%) samples. Other most frequently altered genes were EGFR (1114/1932, 57%), KRAS (213/1932, 11%), PIK3CA (116/1932, 6%), APC (107/1932, 6%) and ERBB2 (97/1932, 5%) . Additionally, 412 (21.3%) patients with TP53 and EGFR co-mutation, TP53 and KRAS co-mutation occurred in 81 (4.2%) patients, PIK3CA mutation co-occurred with TP53 in 53 (2.7%) patients. The total of 920 TP53 mutant sites were detected, and these sites scattered throughout the 11 exons, especially exon 5-8. 13 of these mutation sites which accounted as high frequency ( > 10), including R273C (18/920), R248W (16/920), Y220C (15/920), Y163C (14/920), R249S (13/920), R282W (13/920), H179R (12/920), R158L (12/920), R175H (11/920), G245D (11/920), R273H (10/920), Y234C (10/920), and R273L (10/902). In addition, missense mutations were the main type, and the proportion of SNP with C > T was the highest in mutation sites. Conclusions: This study characterized the mutational signatures that TP53 mutations are interspersed, and hot spots are just in small proportions in LC. This study may provide a basis for drug development for targeting TP53 mutations in the future.
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Babatunde, Olayode, Ryan Quin Notti, and William D. Tap. "Characterizing TP53 mutations in bone and soft tissue sarcoma." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): e23521-e23521. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e23521.
Abstract:
e23521 Background: Tumor protein P53 (TP53) is the most frequently mutated gene in cancer and most mutations inactivate wild type TP53 activity through heterogenous mechanisms. Whether different variants of mutant TP53 have different biologic potencies or clinical outcomes remain unclear. This ongoing study aims to characterize the spectrum of TP53 mutations in patients with bone and soft tissue sarcoma. Methods: We retrospectively identified and analyzed patients with bone and soft tissue sarcoma who underwent MSK-IMPACT (Memorial Sloan Kettering Cancer Center - Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing panel and had at least one mutation in the TP53 gene at Memorial Sloan Kettering Cancer Center. Mutations in the TP53 gene were categorized into the following sub-types: fusion, missense, splice site, or protein-truncating. Hotspots were defined as variants with frequency of 10 or greater. We queried the missense variants for the 800 most frequent variants recorded in the International Agency for Research on Cancer R20 (IARC), which were structurally characterized based on their impact on TP53 protein and rescue potencies with arsenic trioxide (ATO) in vitro (Song et al. Sci Transl Med. 2023). Results: We identified a total of 1257 patients with bone and soft tissue sarcoma who had at least one mutation in TP53. 92.5% of patients had only 1 mutation in TP53. In total, 1363 mutations were detected with 541 variants identified across all sarcoma subtypes. Most TP53 mutations were identified in soft tissue leiomyosarcoma (18.05%), uterine leiomyosarcoma (12.84%), sarcoma not otherwise specified (15.62%), undifferentiated pleomorphic sarcoma (12.11%), and osteosarcoma (7.78%). Of the 541 variants identified, the most frequent alterations were intragenic fusion (6.23%), R175H missense (2.93%), R248Q missense (2.27%), R273H missense (2.13%), and R213* protein-truncating (2.05%) mutations. Of the 800 most frequent missense variants in IARC R20 database, 233 missense variants were detected representing 52% of all mutations detected. Structural or likely structural mutations represented most of the identified missense mutations (77.46%). These mutations were clustered in the following hotspots: R175H, Y220C, R282W, H179Y, and C135Y. DNA-contact mutations were clustered in the following hotspots: R248Q, R273H, R273C, and R248W. Conclusions: This analysis highlights the heterogenous landscape of TP53 mutations in bone and soft tissue sarcomas. Structural variants are prevalent in sarcoma and occur at hotspots that may represent novel drug targets in the future.
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Moses, Renyta, Ryan Hausler, Gregory Kelly, Alexandra Indeglia, Sven Miller, John Karanicolas, Maureen Murphy, and Kara Maxwell. "Abstract 3025: Germline p53 R181 variants and DNA binding cooperativity in tumorigenesis." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3025. http://dx.doi.org/10.1158/1538-7445.am2024-3025.
Abstract:
Abstract TP53 is the most frequently mutated gene in cancer, and its encoded protein p53 has many tumor-suppressive functions. There are several different classes of mutant p53 acquired in human cancer and inherited in cancer-prone families with Li-Fraumeni Syndrome, where individuals have an 80-90% increased risk of cancer. These include structural mutations that are generally (e.g R175H) or locally (e.g Y220C) misfolded, DNA contact mutations (e.g R273H); and oligomerization mutations (A347D). Cooperativity mutations affect binding of the p53 tetramer to DNA via disruption of a salt bridge formed by the negatively charged glutamic acid (E) 180 residue of one p53 monomer and the positively charged arginine (R) 181 residue of another. p53 “cooperativity” mutations at the R181 residue (R181H and R181C) have been increasingly identified in cancer-prone families undergoing genetic testing; however, the mechanism by which these variants disrupt p53 tumor suppression in humans is not understood. We show that the purified DNA binding domains of p53 variants R181H and R181C bind less cooperatively to the p53 binding site in the CDKN1A (p21) promoter, despite retaining wild-type levels of structural stability. RNA-sequencing of CRISPR knock-in colorectal and breast cancer cell lines shows reduced ability of R181H and R181C to transactivate a curated set of ~300 known p53 target genes. Upon treatment with p53 activating molecule Nutlin-3a, the R181-mutant cells fail to cell cycle arrest in the G1 phase and maintain high proliferative rates. Interestingly, we observe some residual apoptotic activity in R181H and R181C mutant cells treated with DNA-damaging agent 5-fluorouracil, despite losing the transactivation of proapoptotic p53 targets; this suggests that these mutants retain the p53 transcription-independent mechanism of apoptosis which is observed in other p53 variants such as P47S and A347D. These studies will define the pathogenicity of R181 variants and guide therapeutic intervention for patients that harbor these p53 mutations. Citation Format: Renyta Moses, Ryan Hausler, Gregory Kelly, Alexandra Indeglia, Sven Miller, John Karanicolas, Maureen Murphy, Kara Maxwell. Germline p53 R181 variants and DNA binding cooperativity in tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3025.
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Nesline, Mary K., Paul DePietro, Maureen Cooper, Shengle Zhang, Sarah Howarth, Zachary D. Wallen, Michael D. Biorn, et al. "The impact of single gene testing (SGT) on subsequent comprehensive genomic profiling (CGP) success in community oncology practice for advanced non-small cell lung cancer (NSCLC): Results from a prospective observational reference laboratory testing program." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 6506. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.6506.
Abstract:
6506 Background: CGP concurrently tests tumor tissue for guideline-recommended predictive biomarkers for optimal therapy selection and identification of clinical trials in NSCLC patients. A common practice in the community oncology setting is to first order SGT, then consider CGP when SGT results are negative or after treatment failure. Given the limited tissue available and the scope of alterations not tested by SGT, we sought to characterize the effects of prior SGT on subsequent CGP testing success, and therapeutic opportunities identified by CGP beyond SGT for NSCLC patients in the community setting. Methods: Reference laboratory information systems were used to prospectively contact clinicians across 80 community practices who ordered at least 1 SGT for guideline-recommended genomic variants in NSCLC. CGP was offered for their patients prior to SGT or upon receipt of negative SGT results. SGT included individual assays for BRAF, EGFR, KRAS, MET exon 14 skipping mutations; ALK, RET, and ROS1 rearrangements; and PD-L1 IHC . CGP included DNA-seq for mutations, copy number variants in 523 genes including guideline-recommended genomic variants, MSI, and tumor mutational burden; RNA-seq for rearrangements/fusions/splice variants; and PD-L1 IHC. Results: Among a total of 580 NSCLC patients with CGP ordered (May 2021-December 2022), 168 (29%) had ≥1 SGT ordered prior to CGP (median=5). No patients had all SGT performed, with untested cases ranging from 10% for ALK to 90% for MET exon 14. The same FFPE tissue block was used for CGP in 150/168 (89%) of cases with prior negative SGT. Compared to CGP-only cases, CGP for cases with prior negative SGT was canceled twice as often at tissue review (16% vs 7%; p=.001), had higher DNA extraction failures (13% vs 8%; p=.09), and lower DNA sequencing success (70% vs 83%, p<.001). CGP detected guideline-recommended variants in 51% of all cases. Among prior negative SGT cases, frequencies were higher in genes where SGT was performed less often and is less sensitive than CGP RNA-seq ( RET fusions , MET exon 14 skipping). CGP also identified guideline-recommended variants in genes with no SGT offered during the study period ( ERBB2 mutations , NTRK2/3 fusions), as well as variants with emerging evidence for FDA expedited program-designated clinical trial therapies in 28% of patients, including NRG1 fusions and BRAF non-V600E , KEAP1, KRAS non-G12C, NFE2L2, STK11, and TP53 Y220C mutations. Conclusions: Prior negative SGT doubled subsequent CGP test cancellations for NSCLC due to tissue insufficiency and increased CGP DNA extraction failures. SGT practice in the community oncology setting does not meet practice guideline recommendations and negatively impacts the potential benefit of subsequent CGP for NSCLC patients.
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Battaglin, Francesca, Andrew Elliott, Joanne Xiu, Sandra Algaze, Jingyuan Wang, Priya Jayachandran, Shivani Soni, et al. "Identification and characterization of immunogenic neoantigens in biliary cancer (BC) and pancreatic cancer (PC)." Journal of Clinical Oncology 42, no. 3_suppl (January 20, 2024): 552. http://dx.doi.org/10.1200/jco.2024.42.3_suppl.552.
Abstract:
552 Background: Recognition of tumor neoantigens by autologous T cells activates immune surveillance and has been reported to promote sensitivity to immune checkpoint inhibitors (ICI) in mismatch repair deficient (MMRd)/microsatellite instability high (MSI-H) tumors. Neoantigen-targeted reactivity has also been reported in microsatellite stable (MSS) tumors. Neoantigens are emerging targets for novel immunotherapy strategies, including tumor vaccines, in BC and PC. We aimed to comprehensively assess the spectrum of immunogenic neoantigens in BC and PC. Methods: 3728 tumor specimens (1389 BC; 2339 PC) tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (720-gene panel) and RNA (whole transcriptome) were analyzed. MSI status was determined by immunohistochemistry of MMR protein and/or NGS. Immune epitope prediction was performed on translated peptide sequences harboring detected mutations using the NetMHCpan v4.0 method in the Immune Epitope Database, with HLA genotyping performed using arcasHLA. Immune/stromal cell abundance in the tumor microenvironment (TME) was quantified using the MCP Counter method. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy (T cell-inflamed signature, TIS). Results: MMRd/MSI-H rate was 1.8% in BC and 1.4% in PC. 117219 unique peptide:allele interactions with predicted binding-level affinity for patient-specific HLA alleles were identified (48781 in BC; 71182 in PC). MMRd/MSI-H tumors had higher neoantigen load at all affinity levels compared to MSS. Only 4 recurrent neoantigens with binding affinity (observed in >10 samples) were identified in BC and derived from mutations in KRAS (3/4) and IDH1 (1/4), while 78 were found in PC, mostly associated with mutations in KRAS (53/78) and TP53 (16/78). The frequency of individual neoantigens was particularly low in MSS BC (< 2%). Across both cancer types, TIS scores positively correlated with the abundance of immune cell populations in the TME, notably cytotoxic lymphocytes (r > 0.40). Recurrent neoantigens associated with highest average TIS scores resulted from mutation of KRAS (G12D/V, 1.8%/1.5% of samples, respectively) in BC yet mean TIS scores were low (~60th percentile overall). Similarly, TP53 (Y220C/R273C, 0.6%/0.7%, respectively) and CDKN2A (multiple variants, 0.5%) were associated with the highest yet relatively low mean TIS scores in MSS PC (~73th percentile) compared to mean TIS scores associated with MSH3 (K383fs, 12%) and KRAS (G12D, 12%) in MMRd/MSI-H PC (~90th percentile). Conclusions: This is the largest study to investigate the landscape of immunogenic neoantigens in BC and PC. The frequency of high-level binding affinity neoantigens was relatively low and associated with relatively lower TIS scores in MSS tumors, which may contribute to the immunogenic cold TME characterizing these tumor types.
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Steinbuck, Martin P., Xavier Cabana-Puig, Erica Palmer, Mimi M. Jung, Thomas Williams, Kristen Osaer, Jeff Zhang, Christopher M. Haqq, and Peter C. DeMuth. "Abstract 4099: AMP-peptide vaccination against multiple p53 mutant epitopes promotes lymph node delivery to generate potent, functional T cell immunity." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4099. http://dx.doi.org/10.1158/1538-7445.am2024-4099.
Abstract:
Abstract Background p53 is the most commonly mutated gene in human cancer, prevalent in nearly all tumor types. Despite its significant medical relevance and the knowledge that human T cells recognize these mutations[1,2], immunotherapies designed to promote responses against mutated p53 (mp53) have not had the hoped-for clinical impact[3]. The Amphiphile (AMP) platform improves the potency of vaccine immunotherapy by programming the delivery of vaccine components to the lymph nodes where efficient uptake by immune cells initiates tumor-targeted immune responses. AMP-modification of vaccine components (peptide antigens, molecular adjuvants) results in covalent conjugation to albumin-binding lipids. Upon injection, AMP-vaccines associate with tissue-resident albumin which efficiently distributes to draining lymph nodes. This approach was shown to promote activation of polyfunctional, cytotoxic T cells with promising safety and improved clinical outcomes in a Phase 1 trial of ELI-002, an mKRAS AMP therapeutic vaccine (AMPLIFY-201 NCT05726864). Application of this strategy to p53 mutations with ELI-008 offers the potential for improved immunotherapeutic activity in a setting of significant unmet need. Methods Following immunization of C57BL/6J mice with AMP-modified or soluble comparator vaccines consisting of mp53 peptides and CpG adjuvant, analyses were performed 7 days after the third bi-weekly dose. To assess antigen-specific T cell responses, ELISpot (IFNγ, GzmB), multiplexed proteomic, and flowcytometric analysis of effector cytokines (IFNγ, TNFα, IL-2) were performed following antigenic stimulation. Responses were determined in secondary lymphoid tissues and lung. Cytolytic capabilities of antigen-specific T cells were evaluated by monitoring specific killing of IV-transferred antigen-pulsed target cells. Results AMP-immunization generated robust immune responses yielding strong T cell activation against common p53 hot spot mutations (R248W, R248Q, R175H, G245S, R273H, Y220C, C135Y, R158H, H214R). Responses to AMP-vaccination were characterized by the generation of increased frequency of polyfunctional T cells (IFNγ, TNFα, IL2) specific to mp53 epitopes. Induced T cells demonstrated significant levels of cytolytic activity including GzmB production and elimination of target cells in vivo. Non-lymph targeted vaccines using soluble comparators were inactive. Conclusions AMP-conjugation permits efficient delivery directly to the lymph nodes and thus improves the immunogenicity of peptide vaccination. These substantially improved immune responses induced by ELI-008 represent a promising therapeutic opportunity for targeting cancer in a large fraction of human tumors. The AMP-platform technology is simple, rapid and scalable, promising broad clinical, off-the-shelf application for treating p53 mutated tumors. Citation Format: Martin P. Steinbuck, Xavier Cabana-Puig, Erica Palmer, Mimi M. Jung, Thomas Williams, Kristen Osaer, Jeff Zhang, Christopher M. Haqq, Peter C. DeMuth. AMP-peptide vaccination against multiple p53 mutant epitopes promotes lymph node delivery to generate potent, functional T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4099.
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Suehnholz, Sarah P., Moriah Nissan, Hongxin Zhang, Ritika Kundra, Calvin Lu, Amanda Dhaneshwar, Nicole Fernandez, et al. "Abstract 6585: OncoKB, MSK’s precision oncology knowledge base." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6585. http://dx.doi.org/10.1158/1538-7445.am2023-6585.
Abstract:
Abstract OncoKB, Memorial Sloan Kettering Cancer Center’s (MSK) precision oncology knowledge base (www.oncokb.org), is an FDA-recognized* somatic variant database that contains information about the oncogenic effect and clinical implications of genomic alterations in cancer. Since its 2016 public release, OncoKB has grown to include annotation for >5,770 alterations in ~700 cancer-associated genes. OncoKB data is integrated into the cBioPortal for Cancer Genomics and used to annotate >12,000 MSK patient sequencing reports annually, encompassing both solid tumor and hematological malignancies. Users in academic, commercial and hospital settings outside MSK can programmatically access OncoKB data via its web API with an OncoKB license, which is free for academic research. To date, users from ~ 1400 institutions across >70 countries have licensed access to OncoKB annotations. The OncoKB Therapeutic (Tx) Levels of Evidence assign tumor-type specific clinical actionability to individual mutational events based on data supporting whether an alteration is predictive of response to matched targeted therapies. To date, OncoKB includes 44 Level 1 genes (included in the FDA drug label), 23 Level 2 genes (included in professional guidelines), 33 Level 3A genes (predictive of drug response in well-powered clinical studies), 27 Level 4 genes (predictive of drug response based on compelling biological evidence), and 11 R1/R2 resistance genes. In 2022, several major content additions were made to OncoKB based on key shifts in the precision oncology landscape. For example, OncoKB included 2 new tumor-agnostic FDA drug approvals, dabrafenib + trametinib and selpercatinib for BRAF V600E and RET fusion-positive solid tumors respectively (Level 1), capturing 5 tumor-agnostic FDA drug approvals to date. OncoKB promoted ERBB2 oncogenic mutations and FGFR1 fusions to Level 1 following their inclusion as patient eligibility criteria in FDA drug labels for trastuzumab deruxtecan (NSCLC) and pemigatinib (myeloid/lymphoid neoplasms) respectively. NCCN guidelines for uterine sarcoma and pancreatic cancer listed PARP-inhibition for BRCA-mutant disease, making them Level 2 in these indications. Lastly, previously considered undruggable targets, TP53 Y220C and KRAS G12D, were included in OncoKB based on compelling evidence demonstrating response to allele-targeting drugs, PC14586 and RMC-6263, respectively. In sum, 7 novel clinically actionable biomarkers (Levels 1-4) and 11 follow-on precision oncology therapies for existing leveled biomarkers were added to OncoKB in 2022. Current OncoKB efforts are focused on prioritized high-volume cancer gene curation for annotation of whole exome/genome data, annotation of germline alterations and development of a clinical trials matching system. *FDA recognition of OncoKB is partial and limited to the information clearly marked on www.oncokb.org. Citation Format: Sarah P. Suehnholz, Moriah Nissan, Hongxin Zhang, Ritika Kundra, Calvin Lu, Amanda Dhaneshwar, Nicole Fernandez, Stephanie Carrero, Maria E. Arcila, Marc Ladanyi, Michael F. Berger, Aijazuddin Syed, Rose Brannon, Ross Levine, Ahmet Dogan, Ezra Rosen, Alexander Drilon, David B. Solit, Nikolaus Schultz, Debyani Chakravarty. OncoKB, MSK’s precision oncology knowledge base. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6585.
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Kim, Peter, Parisa Malekzadeh, Nolan Vale, Elizabeth Hedges, Nikolaos Zacharakis, and Steven Rosenberg. "152 Adoptive T cell therapy targeting somatic p53 mutations." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A165—A166. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0152.
Abstract:
BackgroundAdoptive cell therapies (ACT) directed against the products of somatic mutations in cancer cells can lead to long lasting clinical responses. We focused on ACT against shared p53 mutations to be used to potentially treat a broad range of patients with common cancers. We have built a library of anti-mutant p53 T cell receptors (TCRs) to be used for the treatment of patients with epithelial cancers in the autologous setting and as ‘off-the-shelf’ reagents for patients sharing the same p53 mutation and HLA.MethodsTumor infiltrating lymphocytes (TILs) were screened for recognition of p53 mutations and were expanded as previously described (1). For treatment of patient 4349 with metastatic breast cancer, the patient‘s peripheral blood T cells were retrovirally engineered to express the allogeneic anti-p53 R175H TCR.ResultsWe identified TILs recognizing ‘hotspot’ p53 mutations, such as R175H, Y220C, and R273C as well as less frequent but recurrent mutations, such as L111R, C135Y, and Q331H (table 1). First, we adoptively transferred TILs that included T cells reactive to a p53 mutation in an autologous manner for the treatment of patients with metastatic epithelial cancers (n=12). Except for the two patients who exhibited an objective response (RECIST), most of the patients did not respond to the therapy, possibly due to low frequencies of anti-mutant p53 cells in the infusion product, exhausted phenotype, and/or poor persistence (table 2). To overcome these barriers to TIL treatment, we retrovirally transduced autologous peripheral blood T cells to express an allogeneic anti-mutant p53 TCR. We engineered the HLA-A*02:01-restricted anti-p53 R175H TCR into patient 4349’s lymphocytes (transduction efficiency of 64%) and saw less expression of exhaustion markers relative to the TIL infusion products (table 2). This patient with metastatic breast cancer was refractory to the six prior chemotherapy regimens. After the transfer of 5.3e10 cells, the patient experienced an objective partial response, showing regression by 55% of skin and mediastinal lesions for 7 months. The persistence of the infused T cells was higher than the other patients who received the TIL treatment (table 2).Abstract 152 Table 1Anti-mutant p53 TCR library1 N=51,782 solid tumors (http://p53.fr/)2 Phenotype frequency (http://www.allelefrequencies.net/)3 Malekzadeh et al. J Clin Invest, 2019. 129(3): p. 1109–1114.4 Lo et al, Cancer Immunol Res, 2019. 7(4): p. 534–543Abstract 152 Table 2Patients who received mutant p53-reactive cell products1 TCRB sequencing (Adaptive Biotechnology)2 Flow cytometry against the murine TCR β constant region3 Lo et al, Cancer Immunol Res, 2019. 7(4): p. 534–543.NA not available, NR no response, PR partial response, PD progressive disease, SD stable disease, TX treatmentConclusionsThe library of anti-mutant p53 TCRs we have generated can potentially be used to treat ~6% of all cancer patients. We are pursuing the adoptive transfer of TILs against mutant p53 naturally occurring in the tumor or TCR-engineered cells using ‘off-the-shelf’ receptors against mutant p53.Ethics ApprovalThis study was approved by the Institutional Review Board (IRB) of the NCI, and the approval numbers are as follows:Protocol 10-C-0166 (TIL treatment); Protocol 18-C-0049 (allogeneic TCR engineered T cell therapy)ReferenceLo, W., et al., Immunologic Recognition of a Shared p53 Mutated Neoantigen in a Patient with Metastatic Colorectal Cancer. Cancer Immunol Res, 2019. 7(4): p. 534–543.
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Van Alsten, Sarah, Ebonee Butler, Benjamin Calhoun, Michael Love, Charles Perou, Katherine A. Hoadley, and Melissa Troester. "Abstract PO1-08-12: Genomic Characterization of the Carolina Breast Cancer Study." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO1–08–12—PO1–08–12. http://dx.doi.org/10.1158/1538-7445.sabcs23-po1-08-12.
Abstract:
Abstract Background: Breast cancer is a heterogeneous disease defined by distinct subtypes, mutational profiles, and genomic characteristics. Previous analyses in The Cancer Genome Atlas (TCGA) have been instrumental in understanding the genomic landscape of breast cancer, including identification of key driver mutations, mutational signatures, and distinguishing features of breast cancer subtypes. However, TCGA may not be representative of other population-based breast cancer cohorts, particularly those of earlier stage and including a more diverse set of patients. Our aim was to characterize the genomic landscape of breast cancer in the Carolina Breast Cancer Study (CBCS), a cohort which oversamples Black and young women. Methods: We used targeted sequencing to profile somatic alterations in 1,175 genes from 275 formalin fixed paraffin embedded primary breast tumors in CBCS, 52% of which came from Black women, 41% from women under age 50, and 29% of which were Basal-like based on bulk RNA profiling. We also evaluated TP53 mutation as a source of breast cancer heterogeneity, comparing the type and location of TP53 mutations in each cohort. We assessed chromosome arm-level gains and losses using GISTIC and defined genomic instability as the total number of aneuploid chromosome arms. Intratumoral heterogeneity was assessed with PyClone-VI and defined as the total number and Shannon’s Diversity Index of tumor-specific subclones. For genes mutated in more than 5% of samples and chromosomal aberrations significantly enriched in GISTIC, we estimated the prevalence of alterations and compared to previous distributions in 981 TCGA tumors. Results: Seven genes [TP53 (N=101, 37%), PIK3CA (N=76, 28%), GATA3 (N=32, 12%), CDH1 (N=31, 11%), MAP3K1 (N=22, 8%), KMT2C (N=20, 7%), and CBFB (N =19, 7%)] were mutated in more than 5% of CBCS tumors; all but CBFB which were also highly prevalent in TCGA. While most TP53 hotspot mutations observed in CBCS were previously reported in TCGA, CBCS had twice as many Y220C mutations, one-third fewer R175H mutations, and a non-significantly higher proportion of nonsense mutations than TCGA (20% vs 12%, p = 0.05). Hotspot mutation prevalence in other Luminal-associated driver genes (e.g. PIK3CA, GATA3, CDH1) did not differ by dataset. CBCS tumors showed a higher degree of genomic instability (8 arms vs. 5 arms, p < 0.001) and subclonal diversity than TCGA (48% vs 12% comprised of two or more subclones, p < 0.05). Both datasets showed significant amplifications of 1q and 8q, and deletions of 13q and 17p (where BRCA2 and TP53, respectively, are located), with CBCS having non-significantly higher prevalence of each of these changes. Conclusions: While comparisons should be interpreted in light of technical and population differences between TCGA and CBCS, the overall results show that the suite of commonly altered genes and chromosome arms were highly consistent between TCGA and the diverse CBCS cohort. CBCS tumors tended to display higher genomic instability, intratumoral heterogeneity, and number and diversity of TP53 mutations. This may reflect distinctions in tumor evolutionary state between CBCS and TCGA tumors, and/or could reflect differences in the study populations. Results underscore the importance of considering population characteristics – particularly stage and race – in large-scale genomic contexts, and highlight the importance of diverse cohorts in genomic research. Citation Format: Sarah Van Alsten, Ebonee Butler, Benjamin Calhoun, Michael Love, Charles Perou, Katherine A Hoadley, Melissa Troester. Genomic Characterization of the Carolina Breast Cancer Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-12.
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Deb, S., S. Bandyopadhyay, and S. Roy. "Spectroscopic study of Y210C lambda-repressor: implications for cooperative interaction." Protein Engineering Design and Selection 11, no. 6 (June 1, 1998): 481–87. http://dx.doi.org/10.1093/protein/11.6.481.
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Демидова, Т. Е., И. Н. Чижевская, and А. Е. Чижевский. "Formation of historical memory of students by means of network project activities." Management of Education 14, no. 1-1(74) (January 15, 2024): 165–74. http://dx.doi.org/10.25726/y2202-2949-1521-f.
Abstract:
Статья посвящена актуальной педагогической проблеме: формированию исторической памяти учащейся молодежи на территории Брянской области через вовлечение школьников и студентов в активную деятельность по созданию и развитию интернет-ресурсов, аккумулирующих фотографии, сохранившееся у жителей местного сообщества. Выявленные в ходе исследования тенденции свидетельствует о сложившемся противоречии между большими возможностями работы с семейными фотоархивами в формировании исторической памяти у учащейся молодежи и отсутствие системных решений в этой сфере на уровне региона и страны в целом. На устранение этого противоречия направлен сетевой проект «Родники нашей памяти», призванный через цифровизацию сохранить и сделать доступными для всех заинтересованных граждан России фотографии, которые сохранились в семьях на территории малой родины, отражающие жизнь людей родного края. The article is devoted to the actual pedagogical problem: of the formation of the historical memory of students in the Bryansk region through the involvement of schoolchildren and students in active activities for the creation and development of Internet resources accumulating photos preserved by residents of the local community. The trends revealed in the course of the study indicate the contradiction between the great opportunities of working with family photo archives in the formation of historical memory among students and the lack of systemic solutions in this area at the regional and country level as a whole. The network project «Springs of Our Memory» is aimed at eliminating this contradiction, designed through digitalization to preserve and make available to all interested citizens of Russia photos that have been preserved in families on the territory of the small homeland, reflecting the lives of people of their native land.
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Bauer, Matthias R., Andreas Krämer, Giovanni Settanni, Rhiannon N. Jones, Xiaomin Ni, Raysa Khan Tareque, Alan R. Fersht, John Spencer, and Andreas C. Joerger. "Targeting Cavity-Creating p53 Cancer Mutations with Small-Molecule Stabilizers: the Y220X Paradigm." ACS Chemical Biology 15, no. 3 (January 28, 2020): 657–68. http://dx.doi.org/10.1021/acschembio.9b00748.
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Carter, Bing Z., Po Yee Mak, Wenjing Tao, Lauren B. Ostermann, Steffen Boettcher, Yuki Nishida, Edward Ayoub, et al. "Combined Inhibition of Bcl-2 and Mcl-1 Circumvents Resistance of TP53 Deficient/Mutant AML to BH3 Mimetics." Blood 138, Supplement 1 (November 5, 2021): 2239. http://dx.doi.org/10.1182/blood-2021-148014.
Abstract:
Abstract AML patients with TP53 mutations have extremely poor clinical outcomes. This is due primarily to limited responses to available therapies including the highly promising FDA-approved combination of Bcl-2 inhibition by venetoclax (VEN) with hypomethylating agents (DiNardo CD et al., Blood 2020), which resulted in CR/CRi rates of 70-95% and good tolerability in elderly patients (DiNardo CD et al., Lancet Oncol 2018 and Blood 2019). Apoptosis is regulated by anti- and pro-apoptotic proteins. While p53 does not directly regulate anti-apoptotic Bcl-2 proteins that are resistance factors for VEN, p53 transcriptionally up-regulates pro-apoptotic Bcl-2 proteins. Reverse phase protein array analysis of samples from newly-diagnosed AML patients found that pro-apoptotic Bax was significantly decreased in patients with TP53 mutations (Carter BZ, ASH 2019), which, as expected, diminished the effectiveness of Bcl-2 inhibition. Thus, strategies to target additional anti-apoptotic proteins, or increase pro-apoptotic proteins, are needed to enhance the efficacy of Bcl-2 inhibition in these patients. We determined protein levels of Bcl-2 family members in isogeneic Molm13 cells with TP53-knockout (KO), or with various hotspot TP53 mutations including R175H, Y220C, M237I, R248Q, R273H, and R282W. We observed markedly decreased Bax expression, to a less degree Bak decrease, and variable alterations in other Bcl-2 proteins in these cells compared to TP53-wild-type (WT) controls. We treated the aforementioned cells with VEN or the Mcl-1 inhibitor AMG 176 and found that TP53-KO or mutant cells were more resistant to both VEN and AMG 176 compared to WT controls. However, the combination of two inhibitors was highly synergistic in both settings, controls (CI = 0.2) and TP53-KO and mutant cells (CI < 0.1). To demonstrate that the decreased sensitivity to BH3 mimetics was, at least in part, mediated through Bax reduction in the TP53-mutant cells, we treated Bax knockdown (KD) Molm13 cells with VEN, AMG 176, or both. The Bax KD cells were resistant to VEN and AMG 176, while the combination of the two agents synergistically induced cell death. To establish potential clinical relevance of co-targeting Bcl-2 and Mcl-1 in TP53-mutant AML, we co-cultured cells from various TP53-mutant AML patients (n = 8) with mesenchymal stromal cells and treated them with VEN, AMG 176, or both. The combination synergistically induced cell death in both CD45 + leukemia blasts (CI values between 0.04 ± 0.04 to 0.34 ± 0.10) and CD34 + AML stem/progenitor cells (CI values between 0.07 ± 0.08 to 0.28 ± 0.14). RNA-sequencing of mononuclear and MRD cells of clinical samples (Issa G, ASH 2019) collected after induction therapy revealed that Mcl-1 expression was significantly higher in the TP53-mutated mononuclear and MRD cells compared to their WT counterparts (Fig. 1), which suggests that Mcl-1 contributes to treatment resistance and disease relapse. This further suggests that Mcl-1 inhibition should be incorporated in AML treatment, including VEN-based therapies, for patients with TP53 mutations. Finally, we treated NSG mice inoculated with isogeneic TP53-WT luciferase/GFP-labeled Molm13 and BFP-labeled TP53 R248W/R213* Molm13 cells (10:1) with VEN, AMG 176, or their combination. Only the combination treatment markedly decreased the number of GFP- and BFP-labeled cells in circulation and significantly prolonged mouse survival (median 23 d, 25 d, 24.5 d for control, VEN, AMG 176, respectively; and 45 d for VEN + AMG 176: P = 0.0007, 0.0009, and 0.0011 of combination vs. control, VEN, and AMG 176, respectively) (Fig. 2). Collectively, we demonstrate that decreased Bax contributes to resistance of TP53-mutant AML to BH3 mimetics. Mcl-1 expression positively impacts therapy resistance and disease reoccurrence in TP53-mutant AML. Thus, targeting Bcl-2 or Mcl-1 individually is insufficient and inhibition of both proteins is needed to shift cell fate from survival to death and circumvents resistance of TP53 deficient/mutant AML and AML stem/progenitor cells to BH3 mimetics. The concept warrants further clinical evaluation. Figure 1 Figure 1. Disclosures Carter: Syndax: Research Funding; Ascentage: Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Andreeff: Medicxi: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Breast Cancer Research Foundation: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Amgen: Research Funding; ONO Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Syndax: Consultancy; Senti-Bio: Consultancy; Aptose: Consultancy; Glycomimetics: Consultancy; Oxford Biomedica UK: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company.