Exploring mutant p53 targeting strategies for cancer therapy

TP53 is an essential tumor suppressor gene. It is inactivated in 50% of tumors, most frequently by missense mutations that result in the expression of a mutant p53 protein (mutp53). Mutp53 loses the ability to activate tumor-suppressive target genes and acquires pro-tumorigenic gain-of-function properties. An emerging strategy for treatment of cancers with missense p53 mutations is pharmacological restoration of wild-type p53 activity. Initial evidence that p53 reactivation leads to tumor regression was obtained in mouse models where p53 loss was the initiating event. Many patient tumors, however, develop in the presence of wild-type p53 and inactivate it only at later stages of evolution. To bypass p53-dependent tumor suppression such tumors acquire alterations in the p53 pathway that, in principle, could render p53 reactivation inefficient. To test this, we have modeled late-stage p53 inactivation in mice. Surprisingly restoration of p53 in such late-inactivated tumors resulted in widespread apoptosis and superior survival of the animals. ARF gene alterations were identified as a cause of primary or acquired resistance that could be overcome by Mdm2 inhibitors. Together this study provided proof of concept that p53 reactivation is an effective therapy option for tumors with late-stage p53 inactivation and identified ARF as a predictive biomarker. Among the many different missense mutations, cooperativity mutations represent a mechanistically unique class that often results in a partial loss-of-function (pLOF). As pLOF is a characteristic of many non-hotspot p53 mutations, we have tested if residual functions of two distinct p53 cooperativity mutants (p53E177R “RR” and p53R178E “EE”) may be exploited to induce cell death. Using embryonic development as a model, we have shown that Mdm2-deficiency results in constitutive stabilization of p53 cooperativity mutants and triggers massive apoptosis and embryonic lethality. This indicated that the apoptosis deficiency, characteristic for p53 pLOF mutants, can be rescued by inhibition of Mdm2. Studies of p53 cooperativity mutant mice confirmed that stabilization of mutp53 by pharmacological or constitutive Mdm2 inhibition lowers the apoptotic threshold, sensitizes tumor cells to the pro-apoptotic activity of DNA damaging drugs, and generates a survival benefit under chemotherapy. This was even seen for the DNA binding-deficient cooperativity mutant EE, pointing at a critical role of non-transcriptional apoptotic functions in the context of chemotherapy. In parallel, p53EE was found to be incapable of suppressing tumor development, highlighting a differential role of p53’s non-transcriptional apoptotic functions in tumor suppression and cancer therapy. Collectively, our investigation of two cooperativity mutants suggests that non-hot-spot p53 variants retain residual wild-type activities, that can be harnessed for cancer therapy

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts.

Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated by the de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here, we use deep RNA sequencing from cancer cell lines treated with DNA methyltransferase inhibitor (DNMTi) and/or Histone deacetylase inhibitor (HDACi), to assemble a de novo transcriptome and identify several thousand ERV-derived, treatment-induced novel polyadenylated transcripts (TINPATs). Using immunopeptidomics, we demonstrate the human leukocyte antigen (HLA) presentation of 45 spectra-validated treatment-induced neopeptides (t-neopeptides) arising from TINPATs. We illustrate the potential of the identified t-neopeptides to elicit a T-cell response to effectively target cancer cells. We further verify the presence of t-neopeptides in AML patient samples after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight the potential of ERV-derived neoantigens in epigenetic and immune therapies

Partial p53 reactivation is sufficient to induce cancer regression

Impaired p53 function is one of the central molecular features of a tumor cell and even a partial reduction in p53 activity can increase the cancer risk in mice and men. From a therapeutic perspective it is noteworthy that tumor cells often become addicted to the absence of p53 providing a rationale for developing p53 reactivating compounds to treat cancer patients. Unfortunately, many of the compounds that are currently undergoing preclinical and clinical testing fail to fully reactivate mutant p53 proteins, raising the crucial question: how much p53 activity is needed to elicit a therapeutic effect

ИННОВАЦИОННЫЙ ПОДХОД К ОБУЧЕНИЮ ОДАРЕННЫХ ДЕТЕЙ В СОВРЕМЕННОЙ ОБЩЕОБРАЗОВАТЕЛЬНОЙ ШКОЛЕ

In article are analysed the main scientific approaches to a problem of technology of training of exceptional children in the context of application of pedagogical innovations in professional activity of the teacher of comprehensive school. The special attention is paid to such innovative approaches to implementation of teaching and educational process, within a system synergetic paradigm. The synergetrics, new interdisciplinary branch of scientific knowledge, a peculiar interdisciplinary reflection, collective experience, science, about open nonlinear systems which find conditions of dynamic chaos, of uncertainty, emerdzhentnost at the time of transition from an old state in new, built, and chaos in a rank of a scientific perspective. The main idea of article consists, that nonlinear training of exceptional children has to be more personal, functional and successful that will provide improvement of quality of training and efficiency of educational activity of exceptional children.В статье проанализированы основные научные подходы к проблеме технологии обучения одаренных детей в контексте применения педагогических инноваций в профессиональной деятельности преподавателя общеобразовательной школы. Особое внимание уделено таким инновационным подходам к осуществлению учебно-воспитательного процесса, в рамках системной синергетической парадигмы. Синергетика, новая междисциплинарная отрасль научного знания, своеобразная междисциплинарная рефлексия, коллективный опыт, наука, об открытых нелинейных системах, которые обнаруживают состояния динамического хаоса, неопределенности, эмерджентности в момент перехода из старого состояния в новое, возвела, а хаос в ранг научной проблематики. Основная идея статьи состоит, в том, что нелинейное обучение одаренных детей должно быть более личностным, функциональным и успешным, что обеспечит повышение качества обучения и продуктивность учебной деятельности одаренных детей

DNAM-1/CD226 is functionally expressed on acute myeloid leukemia (AML) cells and is associated with favorable prognosis

DNAM-1 is reportedly expressed on cytotoxic T and NK cells and, upon interaction with its ligands CD112 and CD155, plays an important role in tumor immunosurveillance. It has also been reported to be functionally expressed by myeloid cells, but expression and function on malignant cells of the myeloid lineage have not been studied so far. Here we analyzed expression of DNAM-1 in leukemic cells of acute myeloid leukemia (AML) patients. We found substantial levels of DNAM-1 to be expressed on leukemic blasts in 48 of 62 (> 75%) patients. Interaction of DNAM-1 with its ligands CD112 and CD155 induced release of the immunomodulatory cytokines IL-6, IL-8 IL-10 and TNF-α by AML cells and DNAM-1 expression correlated with a more differentiated phenotype. Multivariate analysis did not show any association of DNAM-1 positivity with established risk factors, but expression was significantly associated with clinical disease course: patients with high DNAM-1 surface levels had significantly longer progression-free and overall survival compared to DNAM-1(low) patients, independently whether patients had undergone allogenic stem cell transplantation or not. Together, our findings unravel a functional role of DNAM-1 in AML pathophysiology and identify DNAM-1 as a potential novel prognostic maker in AML

Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies

T cell-based immunotherapy, for example, with T cell-recruiting bispecific antibody (bsAb), has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions are still rare. Several tumor immune evasion mechanisms have been reported to counteract efficiency of T cell-engaging therapeutics. Platelets largely affect cancer pathophysiology by mediating tumor invasion, metastasis, and immune evasion. On treatment of patients in a clinical trial with a PSMA×CD3 bsAb (NCT04104607), we observed profound treatment-associated platelet activation, mirrored by a decrease of total platelet count. On modeling the treatment setting, we found that platelet activation significantly reduced bsAb-mediated CD4(+) and CD8(+) T-cell reactivity as revealed by impaired T-cell degranulation, secretion of perforin, and ultimately, inhibition of target cell lysis. This effect occurred in a transforming growth factor beta (TGF-β)-dependent manner and was not restricted to PSMA×CD3 bsAb, but rather observed with various CD3-directed bispecific constructs, including the approved CD19×CD3 bsAb blinatumomab. BsAb-mediated T-cell reactivity could be restored by platelet inhibition and specifically by blocking the TGF-β axis. Together, our findings demonstrate that platelets undermine the efficacy of T cell-recruiting bsAb and identify modulation of platelet function as a means to reinforce the effectiveness of bsAb treatment

p53 partial loss-of-function mutations sensitize to chemotherapy

The tumor suppressive transcription factor p53 is frequently inactivated in cancer cells by missense mutations that cluster in the DNA binding domain. 30% hit mutational hotspot residues, resulting in a complete loss of transcriptional activity and mutant p53-driven chemotherapy resistance. Of the remaining 70% of non-hotspot mutants, many are partial loss-of-function (partial-LOF) mutants with residual transcriptional activity. The therapeutic consequences of a partial-LOF have remained largely elusive. Using a p53 mutation engineered to reduce DNA binding, we demonstrate that partial-LOF is sufficient to enhance oncogene-driven tumorigenesis in mouse models of lung and pancreatic ductal adenocarcinoma and acute myeloid leukemia. Interestingly, mouse and human tumors with partial-LOF mutations showed mutant p53 protein accumulation similar as known for hotspot mutants. Different from the chemotherapy resistance caused by p53-loss, the partial-LOF mutant sensitized to an apoptotic chemotherapy response and led to a survival benefit. Mechanistically, the pro-apoptotic transcriptional activity of mouse and human partial-LOF mutants was rescued at high mutant protein levels, suggesting that accumulation of partial-LOF mutants enables the observed apoptotic chemotherapy response. p53 non-hotspot mutants with partial-LOF, therefore, represent tumorigenic p53 mutations that need to be distinguished from other mutations because of their beneficial impact on survival in a therapy context