Oncoscience最新文献

{"title":"A CRISPR-p53 interactome with potential implications for clinical CRISPR/Cas9 use","authors":"Long Jiang, F. Wermeling","doi":"10.18632/oncoscience.557","DOIUrl":"https://doi.org/10.18632/oncoscience.557","url":null,"abstract":"CRISPR/Cas9-based tools are anticipated to transform the gene therapy field by facilitating the correction of disease-causing mutations. However, CRISPR/Cas9 generates DNA damage, which triggers a DNA damage response centered around the tumor-suppressor p53. In this research perspective, we discuss implications of this and describe a CRISPR-p53 interactome with cancer-related genes that, if mutated, can give cells a selective advantage following exposure to CRISPR/Cas9. We propose that the genes in the CRISPR-p53 interactome should be monitored in the clinical setting and describe that transient p53 inhibition could be used to limit the enrichment of cells with such mutations.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"51 1","pages":"27 - 29"},"PeriodicalIF":0.0,"publicationDate":"2022-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84455461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HSP90 as an emerging barrier to immune checkpoint blockade therapy","authors":"D. Tang, Rui Kang","doi":"10.18632/oncoscience.554","DOIUrl":"https://doi.org/10.18632/oncoscience.554","url":null,"abstract":"Immunotherapy, especially the use of immune checkpoint inhibitors, has improved overall survival in cancer patients. However, a large proportion of patients initially do not respond to treatment or relapse after a period of response. Heat shock protein 90 (HSP90) is a conserved molecular chaperone that promotes the maturation and folding of substrate proteins involved in many different cellular pathways. Our recent drug screen and functional assay identified HSP90 as a universal control of the protein stability of nuclear transcription factor STAT1 in a variety of different cancer cells, thereby promoting subsequent gene expression of immune checkpoint molecules (IDO1 and PD-L1). In vivo, we used different mouse models of pancreatic cancer and demonstrated that targeting HSP90 enhanced the efficacy of PD-1 blockade therapy. These findings establish HSP90 as a targetable vulnerability in immune therapy.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1 1","pages":"20 - 22"},"PeriodicalIF":0.0,"publicationDate":"2022-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78037362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk between KIF15 and AR in castrate-resistant prostate cancers","authors":"Han Yang, Xuesen Dong","doi":"10.18632/oncoscience.556","DOIUrl":"https://doi.org/10.18632/oncoscience.556","url":null,"abstract":"","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"48 1","pages":"25 - 26"},"PeriodicalIF":0.0,"publicationDate":"2022-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89082102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetics and cancer disparities: when nature might be nurture","authors":"I. Jordan, K. K. Lee, J. McDonald, L. Mariño-Ramírez","doi":"10.18632/oncoscience.555","DOIUrl":"https://doi.org/10.18632/oncoscience.555","url":null,"abstract":"","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"28 1","pages":"23 - 24"},"PeriodicalIF":0.0,"publicationDate":"2022-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75145272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards the prevention of childhood leukemia","authors":"K. Nichols, I. Sánchez-García","doi":"10.18632/oncoscience.553","DOIUrl":"https://doi.org/10.18632/oncoscience.553","url":null,"abstract":"B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer and leading cause of pediatric cancer death. In childhood B-ALL, a mutation (hereditary or de novo) leads to appearance of preleukemic cells that are capable of normal lymphoid differentiation; however, upon acquisition of one or more second hit mutations, these preleukemic cells transform into full-blown leukemic blasts. While identification of the specific events that trigger the malignant evolution of preleukemic cells has remained elusive in humans, it has long been hypothesized that (delayed) exposure to infection promotes an immune response that then spurs the acquisition of additional genetic lesions [1]. Recently, independent studies using different genetically predisposed mice have demonstrated the occurrence of such an infection-triggered leukemogenic mechanism, collectively showing that several types of stress in the immune system can promote clonal evolution of preleukemic cells in a significant proportion of mice [2–4]. Interestingly, the immune stress does not act by selecting a preleukemic clone that already harbors the second hit; on the contrary, the infection acts by promoting acquisition of the second hit itself, therefore leading to full-blown B-ALL [1]. Together, these observations support the idea that by eliminating preleukemic cells, childhood B-ALL might be preventable [1–5]. Nevertheless, it has remained unclear how to target preleukemic cells as a means to prevent the development of B-ALL. To address this question, we took advantage of the Pax5+/− mice [2, 4]. Similar to children who harbor heterzygous germline PAX5 mutations, B-ALL develops in up to 25% of Pax5+/− mice, but only when these animals experience an immune stress, such as exposure to infection [2]. The leukemias that develop in this model acquire various types of second hit mutations which resemble those observed in human B-ALL, including activating mutations affecting the Janus Kinases (JAKs) [2]. We previously observed that pro-B cells in Pax5+/− mice are particularly dependent on the cytokine interleukin-7 (IL-7) for their survival, and that blocking IL-7-induced signaling using the JAK1/2 inhibitor ruxolitnib led to increased cell death in vitro [2]. Based on these findings, we used Pax5+/− mice to explore whether treatment with Editorial","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"2 1","pages":"17 - 19"},"PeriodicalIF":0.0,"publicationDate":"2022-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88776304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Galactosylceramidase in cancer: more than a psychosine scavenger","authors":"M. Belleri, M. Presta","doi":"10.18632/oncoscience.551","DOIUrl":"https://doi.org/10.18632/oncoscience.551","url":null,"abstract":"Sphingolipids, a class of compounds composed by a sphingoid base backbone, represent major components of biological membranes, and play a pivotal role in a variety of subcellular signaling processes. Abnormal sphingolipid metabolism sets the basis for the pathogenesis of variety of genetic diseases known collectively as sphingolipidosis, or sphingolipodystrophy. Among them, globoid cell leukodystrophy (also named Krabbe disease; OMIM #245200), is an autosomal recessive sphingolipidosis characterized by degeneration of oligodendroglia and progressive demyelination due to the genetic deficiency of β-galactosylceramidase (GALC; EC 3.2.1.46) [1], a lysosomal acid hydrolase that catalyzes the removal of β-galactose from β-galactosylceramide (GalCer) and other terminal β-galactose-containing sphingolipids. Based on a long-held and recently confirmed “psychosine hypothesis” [2], Krabbe disease may manifest as a consequence of the accumulation of the neurotoxic GALC substrate β-galactosylsphingosine (psychosine) in the central and peripheral nervous system [3]. Thus, most of the studies concerning the biological role of GALC have been performed on Krabbe patients and Galc-deficient twitcher mice (an authentic animal model of the disease [4]), leading to the envision that the major biological function of GALC may consist in its psychosine “scavenging” activity. However, experimental evidence indicates that GALC may act not only as a psychosine scavenger, but its modulation also exerting a series of psychosineindependent effects [5, 6]. For instance, GALC deficiency affects neovascularization in in vitro and in vivo in the presence of negligible, if any changes in psychosine levels [7, 8]. In addition, knock-down of the human GALC ortholog galcb in zebrafish embryos affects cell survival and neuronal differentiation in the absence of any significant accumulation of this metabolite [9]. In this frame, a recent study has shown that Galc knockdown in murine melanoma B16 cells causes a significant increase of the levels of the oncosuppressive sphingolipid ceramide mirrored by a decrease of sphingomyelins, phosphatidylethanolamines and cholesteryl esters, paralleled by an increased concentration of diacylglycerols [10]. These alterations of the lipidomic profile resulted in the inhibition of the tumorigenic activity of murine melanoma B16 cells. Increased levels of ceramide were observed also in GALC-silenced human melanoma A2058 cells and tumor xenografts, with a consequent decrease of their tumorigenic potential [10]. In keeping with these observations, a progressive increase of GALC expression occurs during tumor progression in human pathological skin specimens ranging from common nevi to stage IV melanoma. Again, the levels of GALC expression were inversely related to the levels of ceramide immunoreactivity in the same tumor samples [5, 10]. Together, these findings indicate that GALC might act as an oncogenic enzyme during melanoma progression by decreasin","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"4 1","pages":"11 - 12"},"PeriodicalIF":0.0,"publicationDate":"2022-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79502067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic lipid peroxidation profile from patients with breast cancer changes according to the lymph nodal metastasis status","authors":"Stefania Tagliari de Oliveira, Monica Pavaneli Bessani, T. B. Scandolara, Janaína Carla da Silva, Aedra Carla Bufalo Kawassaki, Pâmella Aparecida Ferreira Fagotti, Vitor Teixeira Maito, Janoário Athanázio de Souza, D. Rech, C. Panis","doi":"10.18632/oncoscience.550","DOIUrl":"https://doi.org/10.18632/oncoscience.550","url":null,"abstract":"Metastasis is the leading cause of cancer death. Considering that lymph nodes are the major pathway for cancer spreading and that the metastatic process is under oxidative stress effects, this study aims to evaluate the differential lipid peroxidation profile in the blood of breast cancer patients regarding their lymph nodal status (LN). A total of 105 women diagnosed with breast cancer were included before chemotherapy started. LN was determined by assessing the histopathological analysis of patients’ biopsies, and groups were categorized according to the presence (LN+, n = 48) or absence (LN−, n = 57) of metastases. Lipid peroxidation profiles (LPO) were determined in blood by high-sensitivity chemiluminescence. After patients’ categorization in groups according to their clinicopathological features, LN− patients aged over 50 years presented significantly lower LPO when compared to those under 50 years. Further, LN− patients carrying HER2 positive tumors presented augmented LPO when compared to patients bearing luminal B or triple-negative tumors. LN+ group also had reduced LPO when presented intratumoral clots. The significant contribution of this study was to show that LPO correlates with specific clinical features of patients with breast cancer according to their LN status and that such profile is significantly affected by the presence of metastases.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"7 1","pages":"1 - 10"},"PeriodicalIF":0.0,"publicationDate":"2022-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87523468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue-agnostic cancer drugs in the fight against molecular subsets of metastases of unknown origin","authors":"L. Roncati, B. Palmieri","doi":"10.18632/oncoscience.492","DOIUrl":"https://doi.org/10.18632/oncoscience.492","url":null,"abstract":"Metastasis of unknown origin (MUO) means that a cancer is detected when it is already in metastasis, but without any evidence of the primary tumor, even after a full clinico-radiological workup, histological examination, immunohistochemical investigations and tissue-of-origin testing. [1] The occult tumor cannot be identified because it has regressed, due to immune system, or because it is too small for imaging; however, it has been proposed that the undetectable size and the apparent dormant status do not preclude the spreading of cancer stem cells from the original tissue, giving rise to bulky mass at distant sites. [2] About 90% of MUOs are adenocarcinomas, the remaining squamous cell carcinomas, neuroendocrine tumors, composite malignancies and poorly differentiated or anaplastic neoplasms. [3] MUO occurs in about 3 to 5% of all oncological patients and it is burdened by a poor prognosis in 80-85% of the cases, due to its wide dissemination; the survival rates range from 6 to 16 months. These rates are lower in those patients with visceral involvement, ranging from 6 to 9 months. [3] Surely, to know the primary tumor is important because it dictates the best treatment plan and the expected outcome. However, thanks to next generation sequencing (NGS), it is nowadays possible to bypass this dogma and to search for driver mutations in hundreds of cancer-related genes with high sensibility and specificity in a 10-days turnaround time, by exploiting formalin-fixed paraffinembedded metastatic bioptic samples or circulating tumor DNA in the patient’s blood. [4] In addition to reveal the clinically actionable mutations for a personalized therapy, this modern technology provides information about the mutational burden and microsatellite instability (MSI). [4, 5] This last datum is particularly relevant because, on May 2017, the U.S. Food and Drug Administration (FDA) has approved the immunotherapy with pembrolizumab for all unresectable or metastatic, MSI-high (MSI-H) or mismatch repair deficient (dMMR), solid malignancies and, thus, pembrolizumab has become the first tissueagnostic cancer drug. [6] Similarly, on November 2018, the FDA has approved the use of larotrectinib for all adult and pediatric solid tumors characterized by neurotrophic tyrosine receptor kinase (NTRK) gene fusion. [7] The adjective ‘agnostic’ (‘without knowledge’ from Ancient Greek) indicates a new subset of anti-cancer drugs (e.g. Keytruda®, Vitrakvi®) targeted towards the tumor on the basis of specific mutations found inside it, without knowing its tissue/site of origin just as happens in MUO. Therefore, the tissue-agnostic cancer drugs represent current treatment options against NTRK fusion-positive or MSI-H/dMMR MUOs. Other pipelines under development include: entrectinib for the therapy of pediatric and adult patients with recurrent or refractory extracranial solid tumors harboring NTRK, c-Ros oncogene 1 (ROS1) or anaplastic lymphoma kinase (ALK) gene fusions; BLU667 and Lo","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"23 1","pages":"378 - 379"},"PeriodicalIF":0.0,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72970468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inside a mystery of oncoscience: The cancer-sniffing pets","authors":"L. Roncati","doi":"10.18632/oncoscience.490","DOIUrl":"https://doi.org/10.18632/oncoscience.490","url":null,"abstract":"Worldwide, sick people are daily enjoying the benefits of pet-therapy [1-6]. Next to this scientific evidence, the media report cases of patients who claim to have been saved by their cancer-sniffing pets through an early diagnosis of malignancy. By virtue of this, the concept of ‘canine cancer detection’ has been advanced, on the basis of the presumed olfactory ability of pets, in particular dogs, to smell very low concentrations of aromatic and/or alkanes compounds generated and released by malignant tumors in the patient’s breath, urine or watery stool and into adsorbent materials [7-15]. It is well known that the brain of a domestic dog (Canis lupus familiaris from the Latin) is dominated by a wide olfactory cortex unlike the humans, where a visual cortex predominates. More in detail, dogs are equipped up to 56 times more smellsensitive receptors than the human beings, reaching the number of 280 million in selected breeds, spread over an olfactory surface about the size of a pendrive (9.76 cm2), if compared to 5 million over an area about the size of a postage stamp (3.08 cm2) for the humans [16, 17]. This is thought to render its sense of smell up to 56 times more sensitive than human’s. The domestic cat (Felis silvestris catus from the Latin) also possesses an acute sense of smell, due to its well-developed olfactory bulb and, in addition, to a large surface of olfactory mucosa (about 5.8 cm2), which is almost twice that of the human beings [16]. In oncological medicine, among the diagnostic hallmarks of malignancy there are: lymphovascular and perineural invasion; infiltrative neoplastic growth; immune evasion; a high cytoproliferative index; an elevated mitotic cell count; and tumor necrosis [18, 19]. More in detail, tumor necrosis (νέκρωσις – death from the Greek) is a form of hypoxic death related to the high metabolic demand of cancer cells. It does not follow the apoptotic cascade, but the uncontrolled release of cell death products evokes in the surrounding space an inflammatory response Research Perspective","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"103 1","pages":"376 - 377"},"PeriodicalIF":0.0,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74377279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menin: Expanding and dichotomous roles in cancer","authors":"Bryson W. Katona, Rebecca A Glynn, Taylor Hojnacki, X. Hua","doi":"10.18632/oncoscience.485","DOIUrl":"https://doi.org/10.18632/oncoscience.485","url":null,"abstract":"Menin, the protein product of the MEN1 gene, is a ubiquitously expressed protein that lacks homology with other protein families, yet is highly conserved among various species [1]. Menin primarily resides in the nucleus, where it serves as a scaffold for epigenetic regulators [1, 2]. While much is known about menin and its diverse roles in numerous cellular processes, there remains much to be discovered, especially with regard to its role in cancer.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"44 1","pages":"368 - 370"},"PeriodicalIF":0.0,"publicationDate":"2019-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91522166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}