Cancer by Sfakianakis Alexandros: 03/20/18

Τρίτη 20 Μαρτίου 2018

Cancers, Vol. 10, Pages 86: New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma

Cancers, Vol. 10, Pages 86: New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma

Authors: Kathy Shair Akhil Reddy Vaughn Cooper

Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) oncogenic protein that has no intrinsic enzymatic activity or sequence homology to cellular or viral proteins. The oncogenic potential of LMP1 has been ascribed to pleiotropic signaling properties initiated through protein-protein interactions in cytosolic membrane compartments, but the effects of LMP1 extend to nuclear and extracellular processes. Although LMP1 is one of the latent genes required for EBV-immortalization of B cells, the biology of LMP1 in the pathogenesis of the epithelial cancer nasopharyngeal carcinoma (NPC) is more complex. NPC is prevalent in specific regions of the world with high incidence in southeast China. The epidemiology and time interval from seroconversion to NPC onset in adults would suggest the involvement of multiple risk factors that complement the establishment of a latent and persistent EBV infection. The contribution of LMP1 to EBV pathogenesis in polarized epithelia has only recently begun to be elucidated. Furthermore, the LMP1 gene has emerged as one of the most divergent sequences in the EBV genome. This review will discuss the significance of recent advances in NPC research from elucidating LMP1 function in epithelial cells and lessons that could be learned from mining LMP1 sequence diversity.

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Cancers, Vol. 10, Pages 86: New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma

Cancers, Vol. 10, Pages 86: New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma

Cancers doi: 10.3390/cancers10040086

Authors: Kathy Shair Akhil Reddy Vaughn Cooper

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STK24 expression is modulated by DNA copy number/methylation in lung adenocarcinoma and predicts poor survival

Future Oncology, Ahead of Print.

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Treatment-related features improve machine learning prediction of prognosis in soft tissue sarcoma patients

Abstract

Background and purpose

Current prognostic models for soft tissue sarcoma (STS) patients are solely based on staging information. Treatment-related data have not been included to date. Including such information, however, could help to improve these models.

Materials and methods

A single-center retrospective cohort of 136 STS patients treated with radiotherapy (RT) was analyzed for patients' characteristics, staging information, and treatment-related data. Therapeutic imaging studies and pathology reports of neoadjuvantly treated patients were analyzed for signs of response. Random forest machine learning-based models were used to predict patients' death and disease progression at 2 years. Pre-treatment and treatment models were compared.

Results

The prognostic models achieved high performances. Using treatment features improved the overall performance for all three classification types: prediction of death, and of local and systemic progression (area under the receiver operatoring characteristic curve (AUC) of 0.87, 0.88, and 0.84, respectively). Overall, RT-related features, such as the planning target volume and total dose, had preeminent importance for prognostic performance. Therapy response features were selected for prediction of disease progression.

Conclusions

A machine learning-based prognostic model combining known prognostic factors with treatment- and response-related information showed high accuracy for individualized risk assessment. This model could be used for adjustments of follow-up procedures.

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Eradicating Cancer Stem Cells: Concepts, Issues, and Challenges

Opinion statement:

The cells of malignant cancers result in the evolution of cells with stem-like characteristics, commonly known as cancer stem cells (CSCs). Progress of anticancer therapies is severely hampered because of disease relapse mostly in a more aggressive form due to CSCs. These CSCs are more or less like embryonic or tissue stem cells, known for their capacity of self-renewal, exactly recapitulate of the original tumor. Deregulation of key stem cell pathways like Wnt, Hedgehog (Hh), and Notch is attributed towards the rise of CSCs. Recent breakthroughs offer better insights into CSC signaling. Scientists have developed several combinatorial therapies like targeting one/multiple of these CSC pathways. The article summarized various markers used to identify CSCs and discuss major signaling pathways in them. The futuristic probabilities to use CSC therapeutics in clinical development have been discussed. Our views have been highlighted on the future directions for targeting advances in the clinical development.

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Human c-SRC kinase (CSK) overexpression makes T cells dummy

Abstract

Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide–MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on correct pMHC recognition on the outside and a restricted clustering on the inside of the cell. Since the majority of the adverse events are due to TCR recognition of the wrong target, we tested if blocking the signalling would affect the binding. By over-expressing the c-SRC kinase (CSK), a negative regulator of LCK, in redirected T cells, we showed that peripheral blood T cells inhibited anti-CD3/anti-CD28-induced phosphorylation of ERK, whereas TCR proximal signalling was not affected. Similarly, overexpression of CSK together with a therapeutic TCR prevented pMHC-induced ERK phosphorylation. Downstream effector functions were also almost completely blocked, including pMHC-induced IL-2 release, degranulation and, most importantly, target cell killing. The lack of effector functions contrasted with the unaffected TCR expression, pMHC recognition, and membrane exchange activity (trogocytosis). Therefore, co-expression of CSK with a therapeutic TCR did not compromise target recognition and binding, but rendered T cells incapable of executing their effector functions. Consequently, we named these redirected T cells "dummy T cells" and propose to use them for safety validation of new TCRs prior to therapy.

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Abscopal effects of radiotherapy and combined mRNA-based immunotherapy in a syngeneic, OVA-expressing thymoma mouse model

Abstract

Background

Tumor metastasis and immune evasion present major challenges of cancer treatment. Radiotherapy can overcome immunosuppressive tumor microenvironments. Anecdotal reports suggest abscopal anti-tumor immune responses. This study assesses abscopal effects of radiotherapy in combination with mRNA-based cancer vaccination (RNActive^®).

Methods

C57BL/6 mice were injected with ovalbumin-expressing thymoma cells into the right hind leg (primary tumor) and left flank (secondary tumor) with a delay of 4 days. Primary tumors were irradiated with 3 × 2 Gy, while secondary tumors were shielded. RNA and combined treatment groups received mRNA-based RNActive^® vaccination.

Results

Radiotherapy and combined radioimmunotherapy significantly delayed primary tumor growth with a tumor control in 15 and 53% of mice, respectively. In small secondary tumors, radioimmunotherapy significantly slowed growth rate compared to vaccination (p = 0.002) and control groups (p = 0.01). Cytokine microarray analysis of secondary tumors showed changes in the cytokine microenvironment, even in the non-irradiated contralateral tumors after combination treatment.

Conclusion

Combined irradiation and immunotherapy is able to induce abscopal responses, even with low, normofractionated radiation doses. Thus, the combination of mRNA-based vaccination with irradiation might be an effective regimen to induce systemic anti-tumor immunity.

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IL-6 and IL-10 are associated with good prognosis in early stage invasive breast cancer patients

Abstract

Macrophage-associated cytokines play an important role in cancer metastasis; however, the functions of interleukins (IL) 6 and 10 in breast cancer (BC) progression and metastasis are not clear. In this study the roles of IL-6/IL-10 in regulating vascular invasion and their prognostic significance in BC are investigated. MDA-MB-231 and MCF-7 migration (± IL-6 or IL-10) was assessed by scratch wound assay. Cancer cell adhesion to IL-6/IL-10 stimulated blood and lymphatic endothelial cells (EC) was investigated. Expression of IL-6 /IL-10 was assessed using immunohistochemistry in an annotated cohort of early stage BC (n = 1380) and associations with clinicopathological variables and clinical outcome evaluated. IL-6 did not alter BC cell migration however a dose-dependent inhibition in MDA-MB-231 migration with IL-10 treatment was observed (P = 0.03). BC cells were more adhesive to blood vs lymphatic EC, however, IL-6/IL-10 had no effect on adhesion patterns. High expression of IL-6/IL-10 was associated with clinicopathological criteria (e.g. hormone receptor status, all P < 0.05), improved disease-free survival (DFS; P < 0.05) and improved BC-specific survival (BCSS; only IL-6, P = 0.017). However, neither IL-6 nor IL-10 expression were independent prognostic factors from multivariate analysis. In BC subgroups, IL-6 and IL-10 were good prognosticators in terms of DFS in non-basal, non-triple-negative (non-TN), ER-positive, PgR-positive (only IL-10), and Her-2-negative (only IL-6) BC (all P < 0.05). IL-6 was associated with improved BCSS in non-basal, ER-positive and non-TN BC (all P < 0.05).

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The role of interleukin-2, all- trans retinoic acid, and natural killer cells: surveillance mechanisms in anti-GD2 antibody therapy in neuroblastoma

Abstract

Although anti-disialoganglioside (GD2) antibodies are successfully used for neuroblastoma therapy, a third of patients with neuroblastoma experience treatment failure or serious toxicity. Various strategies have been employed in the clinic to improve antibody-dependent cell-mediated cytotoxicity (ADCC), such as the addition of interleukin (IL)-2 to enhance natural killer (NK) cell function, adoptive transfer of allogeneic NK cells to exploit immune surveillance, and retinoid-induced differentiation therapy. Nevertheless, these mechanisms are not fully understood. We developed a quantitative assay to test ADCC induced by the anti-GD2 antibody Hu14.18K322A in nine neuroblastoma cell lines and dissociated cells from orthotopic patient-derived xenografts (O-PDXs) in culture. IL-2 improved ADCC against neuroblastoma cells, and differentiation with all-trans retinoic acid stabilized GD2 expression on tumor cells and enhanced ADCC as well. Degranulation was highest in licensed NK cells that expressed CD158b (P < 0.001) and harbored a killer-cell immunoglobulin-like receptor (KIR) mismatch against the tumor-specific human leukocyte antigen (HLA; P = 0.016). In conclusion, IL-2 is an important component of immunotherapy because it can improve the cytolytic function of NK cells against neuroblastoma cells and could lower the antibody dose required for efficacy, thereby reducing toxicity. The effect of IL-2 may vary among individuals and a biomarker would be useful to predict ADCC following IL-2 activation. Sub-populations of NK cells may have different levels of activity dependent on their licensing status, KIR expression, and HLA–KIR interaction. Better understanding of HLA–KIR interactions and the molecular changes following retinoid-induced differentiation is necessary to delineate their role in ADCC.

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Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells

Abstract

Ovarian cancer (OC) is the leading cause of gynecological cancer-related death in North America. Most ovarian cancer patients (OCPs) experience disease recurrence after first-line surgery and chemotherapy; thus, there is a need for novel second-line treatments to improve the prognosis of OC. Although peripheral blood-derived NK cells are known for their ability to spontaneously lyse tumour cells without prior sensitization, ascites-derived NK cells (ascites-NK cells) isolated from OCPs exhibit inhibitory phenotypes, impaired cytotoxicity and may play a pro-tumourigenic role in cancer progression. Therefore, it is of interest to improve the cytotoxic effector function of impaired OCP ascites-NK cells at the tumour environment. We investigated the efficacy of using an artificial APC-based ex vivo expansion technique to generate cytotoxic, expanded NK cells from previously impaired OCP ascites-NK cells, for use in an autologous model of NK cell immunotherapy. We are the first to obtain a log-scale expansion of OCP ascites-NK cells that upregulate the surface expression of activating receptors NKG2D, NKp30, NKp44, produce robust amounts of anti-tumour cytokines in the presence of OC cells and mediate direct tumour cytotoxicity against ascites-derived, primary OC cells obtained from autologous patients. Our findings demonstrate that it is possible to generate cytotoxic OCP ascites-NK cells from previously impaired OCP ascites-NK cells, which presents a promising immunotherapeutic target for the second-line treatment of OC. Future work should focus on evaluating the in vivo efficacy of autologous NK cell immunotherapy through the intraperitoneal delivery of NK cell expansion factors to a preclinical xenograft mouse model of human OC.

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Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

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Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+ TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy

Abstract

Rectal cancer, which comprises 30% of all colorectal cancer cases, is one of the most common forms of cancer in the world. Patients with locally advanced rectal cancer (LARC) are often treated with neoadjuvant chemoradiotherapy (neoCRT) followed by surgery. However, after neoCRT treatment, approximately one-third of the patients progress to local recurrence or distant metastasis. In these studies, we found that patients with tumors that exhibited cytosolic HMGB1(Cyto-HMGB1) translocation and/or the presence of PD-1+ tumor-infiltrating lymphocytes (TILs) before treatment had a better clinical outcome. The better outcome is likely due to the release of HMGB1, which triggers the maturation of dendritic cells (DCs) via TLR4 activation, and the subsequent recruitment of PD-1+ tumor-infiltrating lymphocytes to the tumor site, where they participate in immune-scavenging. In conclusion, our results provide evidence that cyto-HMGB1 and/or PD-1+TIL are not only predictive biomarkers before treatment, but they can also potentially designate patients for personalized oncological management including immunotherapy.

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A novel biologic platform elicits profound T cell costimulatory activity and antitumor immunity in mice

Abstract

Combination immunotherapies utilizing complementary modalities that target distinct tumor attributes or immunosuppressive mechanisms, or engage different arms of the antitumor immune response, can elicit greater therapeutic efficacy than the component monotherapies. Increasing the number of agents included in a therapeutic cocktail can further increase efficacy, however, this approach poses numerous challenges for clinical translation. Here, a novel platform to simplify combination immunotherapy by covalently linking immunotherapeutic agonists to the costimulatory receptors CD134 and CD137 into a single heterodimeric drug, "OrthomAb", is shown. This reagent not only retains costimulatory T cell activity, but also elicits unique T cell functions that are not programmed by either individual agonist, and preferentially expands effector T cells over Tregs. Finally, in an aggressive melanoma model OrthomAb elicits better therapeutic efficacy compared to the unlinked agonists. This demonstration that two drugs can be combined into one provides a framework for distilling complex combination drug cocktails into simpler delivery platforms.

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Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model

Abstract

Vaccination with DNA that encodes cancer antigens is a simple and convenient way to raise immunity against cancer and has already shown promise in the clinical setting. Conventional plasmid DNA is commonly used which together with the encoded antigen also includes bacterial immunostimulatory CpG motifs to target the DNA sensor Toll-like receptor 9. Recently DNA vaccines using doggybone DNA (dbDNA™), have been developed without the use of bacteria. The cell-free process relies on the use of Phi29 DNA polymerase to amplify the template followed by protelomerase TelN to complete individual closed linear DNA. The resulting DNA contains the required antigenic sequence, a promoter and a poly A tail but lacks bacterial sequences such as an antibiotic resistance gene, prompting the question of immunogenicity. Here we compared the ability of doggybone DNA vaccine with plasmid DNA vaccine to induce adaptive immunity using clinically relevant oncotargets E6 and E7 from HPV. We demonstrate that despite the inability to trigger TLR9, doggybone DNA was able to induce similar levels of cellular and humoral immunity as plasmid DNA, with suppression of established TC-1 tumours.

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Combined sublethal irradiation and agonist anti-CD40 enhance donor T cell accumulation and control of autochthonous murine pancreatic tumors

Abstract

Tumor-reactive T lymphocytes can promote the regression of established tumors. However, their efficacy is often limited by immunosuppressive mechanisms that block T cell accumulation or function. ACT provides the opportunity to ameliorate immune suppression prior to transfer of tumor-reactive T cells to improve the therapeutic benefit. We evaluated the combination of lymphodepleting whole body irradiation (WBI) and agonist anti-CD40 (αCD40) antibody on control of established autochthonous murine neuroendocrine pancreatic tumors following the transfer of naïve tumor-specific CD8 T cells. Sublethal WBI had little impact on disease outcome but did promote T cell persistence in the lymphoid organs. Host conditioning with αCD40, an approach known to enhance APC function and T cell expansion, transiently increased donor T cell accumulation in the lymphoid organs and pancreas, but failed to control tumor progression. In contrast, combined WBI and αCD40 prolonged T cell proliferation and dramatically enhanced accumulation of donor T cells in both the lymphoid organs and pancreas. This dual conditioning approach also promoted high levels of inflammation in the pancreas and tumor, induced histological regression of established tumors, and extended the lifespan of treated mice. Prolonged survival was entirely dependent upon adoptive transfer, but only partially dependent upon IFNγ production by donor T cells. Our results identify the novel combination of two clinically relevant host conditioning approaches that synergize to overcome immune suppression and drive strong tumor-specific T cell accumulation within well-established tumors.

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Engaging Anaphase Catastrophe Mechanisms to Eradicate Aneuploid Cancers

Cancer cells often have supernumerary centrosomes that promote genomic instability, a pathognomonic feature of cancer. During mitosis, cancer cells with supernumerary centrosomes undergo bipolar cell division by clustering centrosomes into two poles. When supernumerary centrosome clustering is antagonized, cancer cells are forced to undergo multipolar division leading to death of daughter cells. This proapoptotic pathway, called anaphase catastrophe, preferentially eliminates aneuploid cancer cells and malignant tumors in engineered mouse models. Anaphase catastrophe occurs through the loss or inhibition of the centrosomal protein CP110, a direct cyclin-dependent kinase 1 (CDK1) and CDK2 target. Intriguingly, CP110 is repressed by the KRAS oncoprotein. This sensitizes KRAS-driven lung cancers (an unmet medical need) to respond to CDK2 inhibitors. Anaphase catastrophe-inducing agents like CDK1 and CDK2 antagonists are lethal to cancer cells with supernumerary centrosomes, but can relatively spare normal cells with two centrosomes. This mechanism is proposed to provide a therapeutic window in the cancer clinic following treatment with a CDK1 or CDK2 inhibitor. Taken together, anaphase catastrophe is a clinically tractable mechanism that promotes death of neoplastic tumors with aneuploidy, a hallmark of cancer. Mol Cancer Ther; 17(4); 1–8. ©2018 AACR.

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Engaging Anaphase Catastrophe Mechanisms to Eradicate Aneuploid Cancers

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First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study, Published online: 21 March 2018; doi:10.1038/s41416-018-0057-2

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

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An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes, Published online: 21 March 2018; doi:10.1038/s41416-018-0030-0

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

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Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer, Published online: 21 March 2018; doi:10.1038/s41416-018-0053-6

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

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First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study, Published online: 21 March 2018; doi:10.1038/s41416-018-0057-2

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

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An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

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NF1 mutations in conjunctival melanoma

NF1 mutations in conjunctival melanoma

<i>NF1</i> mutations in conjunctival melanoma, Published online: 21 March 2018; doi:10.1038/s41416-018-0046-5

NF1 mutations in conjunctival melanoma

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Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer, Published online: 21 March 2018; doi:10.1038/s41416-018-0053-6

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

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Correction to: Health-Related Information-Seeking Behaviors and Preferences Among Mexican Patients with Cancer

Abstract

The original version of this article unfortunately contained a mistake. The name of "Viridiana Perez-Montessoro" is now corrected in the author group of this article. The original article has been corrected.

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Improved risk stratification by circulating tumor cell counts in pancreatic cancer

Purpose: Pancreatic cancer is one of the most devastating diseases with a 5-year survival rate of 3-5%. Here we investigated if circulating tumor cells (CTCs) may predict metastatic spread and survival in pancreatic cancer patients. Experimental Design: In a prospective study we enrolled 69 pancreatic cancer patients. In peripheral blood CTCs were identified by MACS enrichment (anti-cytokeratin/anti-EpCam) and subsequent automated analysis after combined anti-cytokeratin/anti-CD45/DAPI staining. CTC results were correlated to established clinicopathologic risk factors, detection of disseminated tumor cells (DTCs) in bone marrow and clinical outcome (follow up time: 48 months). Results: Median patient survival was 11 months (0-48 months). Thirty-eight patients were male and 31 female, and the majority received gemcitabine (58/69). CTCs were present in 23/69 patients (33.3%) ranging from 1-19 cells (17 with >1CTC). While clinicopathologic parameters and DTC status did not correlate with CTC incidence, progression-free survival (PFS) and overall survival (OS) were significantly reduced in CTC-positive patients in univariate (p=0.009, PFS; p=0.030, OS, both logrank) and multivariate analysis (HR: 4.543; CI: 1.549-13.329; p=0.006, PFS; HR: 2.093; CI: 1.081-4.050; p=0.028, OS, both Cox regression). Also within patients receiving chemotherapy, PFS was significantly reduced in CTC-positive patients in univariate (p=0.013) and multivariate (HR: 4.203; CI: 1.416-12.471; p=0.010) analysis. Conclusions: CTCs affect the outcome of patients with pancreatic cancer independent from other risk factors, including patients receiving (adjuvant) cytotoxic therapy. CTC stratification may allow a better upfront identification of patients with a longer life span who might profit from new adjuvant therapies.

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Adjuvant treatment for POLE proofreading domain-mutant cancers: sensitivity to radiotherapy, chemotherapy, and nucleoside analogs

Purpose: Pathogenic POLE proofreading domain mutations are found in many malignancies where they are associated with ultramutation and favorable prognosis. The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent POLE-mutant cancers. Experimental design: We examined the recurrence-free survival of women with POLE-mutant and POLE-wild-type endometrial cancers (ECs) in the observation arm of the randomized PORTEC-1 EC trial (N=245 patients with stage I EC for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between Pole-mutant mouse embryonic stem (mES) cells, generated using CRISPR-Cas9 (Pole mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines. Results: In the observation arm of the PORTEC-1 trial (N=245), women with POLE-mutant ECs (N=16) had an improved recurrence-free survival (10yr RFS 100% vs 80.1% for POLE-wild-type; HR=0.143, 95% CI=0.001-0.996, P=0.049). Pole mutations did not increase sensitivity to radiotherapy nor to chemotherapeutics in mES cells. In contrast, Pole-mutant cells displayed significantly increased sensitivity to cytarabine and fludarabine (IC50 Pole P286R-mutant vs wild-type: 0.05 vs 0.17 μM for cytarabine, 4.62 vs 11.1 μM for fludarabine; P <0.001 for both comparisons). Conclusions: The favorable prognosis of POLE-mutant cancers cannot be explained by increased sensitivity to currently used adjuvant treatments. These results support studies exploring minimization of adjuvant therapy for early-stage POLE-mutant cancers, including endometrial and colorectal cancers. Conversely, POLE mutations result in hypersensitivity to nucleoside analogs, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage POLE-mutant cancers.

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Safety and Antitumor Activity of Pembrolizumab in Patients with Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer

Purpose: We investigated the safety and antitumor activity of the anti-programmed death 1 monoclonal antibody pembrolizumab in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2^-) advanced breast cancer with programmed death ligand 1-positive (PD-L1-positive) tumors in the phase Ib open-label, multicohort KEYNOTE-028 (NCT02054806) study. Experimental Design: Patients with ER+/HER2^- advanced breast cancer with PD-L1-positive tumors (combined positive score ≥1) received pembrolizumab (10 mg/kg every 2 weeks) up to 2 years or until confirmed progression/intolerable toxicity. Primary endpoints were safety and overall response rate (ORR), based on Response Evaluation Criteria in Solid Tumors, version 1 (RECIST v1.1) as assessed by investigator review. Results: Between April 2014 and January 2015, 25 patients were enrolled. Median number of prior therapies for breast cancer, including endocrine agents, was 9 (range, 3-15). Median follow-up was 9.7 months (range, 0.7-31.8 months). Three patients experienced partial response (PR) and none experienced complete response (CR), resulting in an ORR of 12.0% (95% CI, 2.5-31.2%); 16% of patients had stable disease (SD), and clinical benefit rate (CR + PR + [SD for ≥24 weeks]) was 20% (95% CI, 7-41). Median duration of response was 12.0 months (range, 7.4-15.9 months). The incidence of treatment-related adverse events was 64%; nausea (20%) and fatigue (12%) were most common and were predominantly grade 1/2. No treatment-related discontinuations or deaths occurred. Conclusions: Pembrolizumab was well-tolerated with modest but durable objective response in certain patients with previously treated, advanced, PD-L1-positive, ER+/HER2^- breast cancer.

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Correction to: Health-Related Information-Seeking Behaviors and Preferences Among Mexican Patients with Cancer

Abstract

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Anaplastic lymphoma kinase mutation (ALK F1174C) in small cell carcinoma of the prostate and molecular response to alectinib

Purpose: Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise de novo or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (ALK) gene are involved in neuroblastoma, lung cancer, and other malignancies but its role in SCCP has not been documented. We describe a patient with refractory de novo SCCP with ALK F1174C activating mutation who obtained clinical benefit from treatment with ALK inhibitor. Experimental Design: Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in ALK gene, mRNA and its impact in clinical outcomes. In vitro prostate cell line/organoid models were generated by lentiviral-mediated expression of ALK and ALK F1174C and assessed for response to ALK inhibitors crizotinib and alectinib. Results: NGS analysis of the primary tumor and ctDNA of a 39-year old patient with refractory SSCP identified ALK F1174C mutation. Treatment with second-generation ALK inhibitor alectinib resulted in radiographic stable disease for over 6 months, symptomatic improvement, and significant molecular response as reflected by declining ctDNA allele fraction. Analysis of prostate cancer datasets showed that ALK amplification was associated with poor outcome. In prostate cancer cells and organoids, ALK F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron specific enolase. Alectinib was more effective than crizotinib in inhibiting ALK F1174C-expressing cell growth. Conclusions: These findings implicate ALK activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting ALK molecular alterations in some patients with SCCP.

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Improved risk stratification by circulating tumor cell counts in pancreatic cancer

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Adjuvant treatment for POLE proofreading domain-mutant cancers: sensitivity to radiotherapy, chemotherapy, and nucleoside analogs

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Safety and Antitumor Activity of Pembrolizumab in Patients with Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer

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Anaplastic lymphoma kinase mutation (ALK F1174C) in small cell carcinoma of the prostate and molecular response to alectinib

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Correction to: Health-Related Information-Seeking Behaviors and Preferences Among Mexican Patients with Cancer

Abstract

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Correction to: Health-Related Information-Seeking Behaviors and Preferences Among Mexican Patients with Cancer

Abstract

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Immunomodulatory Effects of Momordica charantia Extract in the Prevention of Oral Cancer

In recent times, bitter melon extract (BME) has gained significant attention for its anticancer efficacy against various malignancies. In this issue, Sur and colleagues show that BME prevents the development of 4-nitronitroquinoline 1-oxide–induced oral dysplasia and squamous cell carcinoma (SCC) in an immunocompetent mouse model. Importantly, gene ontology and pathway analyses revealed an elevated expression of s100a9, IL23a, IL1β, and PDCD1/PD1 of immune system during oral cancer development, which was significantly suppressed by BME. Overall, this study demonstrates the potential clinical benefits of BME in preventing and delaying the progression of oral dysplasia to SCC.Cancer Prev Res; 11(4); 1–2. ©2018 AACR.

See related article by Sur et al., p. 191

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The Conundrum of Omega-3 Fatty Acids in Cancer Prevention Studies: Which One? How Much? What Biomarkers?

Marine omega-3 fatty acids promote resolution of inflammation and have potential to reduce risk of obesity-related breast cancer. For prevention trials in obese women, inflammatory cytokines, aromatase, and measures of breast immune cell infiltration are logical, as are biomarkers of growth factor, adipokine, and estrogen signaling. Where best to look for marker change: in the circulation (easiest), in benign breast tissue (most relevant), or in visceral adipose (inflammation often most marked)? A null biomarker modulation trial may reflect limitations in design, source and dose of fatty acids, or biomarkers and should not lead to premature abandonment of marine omega-3 fatty acids for cancer prevention. Cancer Prev Res; 11(4); 1–4. ©2018 AACR.

See related article by Gucalp et al., p. 203

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Intrauterine growth restriction - impact on cardiovascular diseases later in life

Abstract

Intrauterine growth restriction (IUGR) is a fetal pathology which leads to increased risk for certain neonatal complications. Furthermore, clinical and experimental studies revealed that IUGR is associated with a significantly higher incidence of metabolic, renal and cardiovascular diseases (CVD) later in life. One hypothesis for the higher risk of CVD after IUGR postulates that IUGR induces metabolic alterations that then lead to CVD.

This minireview focuses on recent studies which demonstrate that IUGR is followed by early primary cardiovascular alterations which may directly progress to CVD later in life.

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Epithelioid Sarcoma Presenting as Recurrent Thumb Ulcer: a Lesson to Learn

Abstract

Epithelioid sarcoma first described by Enzinger (Cancer 26:1029–41, 1970) is a rare soft-tissue sarcoma typically presenting as a subcutaneous or deep dermal mass in distal portions of the extremities of adolescents and young adults. They are frequently mistaken for ulcers, abscesses, or infected warts that fail medical management. Patients often develop multiple local recurrences of long duration, with subsequent metastases in 30 to 50% of cases (Chase and Enzinger (Am J Surg Pathol 9:241–63, 1985)). We here report a case of left thumb epithelioid sarcoma that presented as an ulcer and subsequently metastasized to forearm, arm, axillary lymph nodes, and lungs.

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Intrauterine growth restriction - impact on cardiovascular diseases later in life

Abstract

This minireview focuses on recent studies which demonstrate that IUGR is followed by early primary cardiovascular alterations which may directly progress to CVD later in life.

http://ift.tt/2u4zsWR

Epithelioid Sarcoma Presenting as Recurrent Thumb Ulcer: a Lesson to Learn

Abstract

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Long-term outcomes of endoscopic submucosal dissection for high-grade dysplasia and early-stage carcinoma in the colorectum

Abstract

Background

Colorectal carcinomas (CRCs) arise from premalignant precursors in an adenoma-carcinoma sequence, in which adenoma with high-grade dysplasia (HGD) and early-stage carcinoma are defined as advanced neoplasia. A limited number of studies have evaluated the long-term outcomes of endoscopic submucosal dissection (ESD) for advanced colorectal neoplasia. This study aimed to assess the efficacy and safety of ESD for advanced colorectal neoplasia as well as the long-term outcomes, including local recurrence and metastasis.

Methods

We analyzed data collected from 610 consecutive patients with 616 advanced colorectal neoplasia lesions treated with ESD between January 2007 and December 2013. Clinical, endoscopic, and histological data were collected over a median follow-up period of 58 months to determine tumor stage and type, resection status, complications, tumor recurrence, and distant metastasis.

Results

The overall rates of en bloc resection, histological complete resection, and major complications were 94.3%, 89.4%, and 2.3%, respectively. Hybrid ESD was an independent factor of piecemeal resection. Tumor location in the colon was associated with increased risk of ESD-related complications. During the follow-up period, all patients remained free of metastasis. However, local recurrence occurred in 4 patients (0.8%); piecemeal resection was a risk factor.

Conclusions

ESD is effective and safe for resection of advanced colorectal neoplasia, with a high en bloc resection rate and favorable long-term outcomes. ESD is indicated for the treatment of HGD and early-stage CRC to obtain curative resection and reduce local recurrence rate.

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Long-term outcomes of endoscopic submucosal dissection for high-grade dysplasia and early-stage carcinoma in the colorectum

Abstract

Background

Methods

Results

Conclusions

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An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

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NF1 mutations in conjunctival melanoma

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First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

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Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

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NF1 mutations in conjunctival melanoma

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First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

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Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

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Assessment of dosimetric errors induced by deformable image registration methods in 4D pencil beam scanned proton treatment planning for liver tumours

Respiratory impacts in pencil beam scanned proton therapy (PBS-PT) are accounted by extensive 4D dose calculations, where deformable image registration (DIR) is necessary for estimating deformation vector fields (DVFs). We aim here to evaluate the dosimetric errors induced by different DIR algorithms in their resulting 4D dose calculations by using ground truth(GT)-DVFs from 4DMRI.

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Evaluation of 99mTc-Labeled Bevacizumab–N-HYNIC Conjugate in Human Ovarian Tumor Xenografts

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.

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ERAP1-dependent antigen cross-presentation determines efficacy of adoptive T cell therapy in mice

Cytotoxic T lymphocytes can reject established tumors if their target peptide is efficiently presented by major histocompatibility complex class I molecules (pMHC-I) on the surface of cancerous cells. Therapeutic success upon adoptive T cell transfer (ATT), however, requires additional cross-presentation of the same pMHC-I on non-cancerous cells. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that customizes the N-terminus of proteasome-generated peptides so they can be loaded onto MHC-I molecules in the endoplasmic reticulum (ER). We show here that ERAP1 is critically involved in the process of tumor rejection and assumes a dual role by independently operating on both sides. Direct presentation of two MHC-I restricted epitopes of a cancer-driving transplantation rejection antigen through ERAP1 moderately affected tumor rejection by adoptively transferred T-cell receptor (TCR) gene-modified T cells in each case. ERAP1 expression by antigen cross-presenting cells of the ATT recipients was critical for expansion of therapeutic monospecific T cells and correlated with tumor rejection. Specifically, lack of ERAP1 expression in the ATT recipient's non-cancerous cells enabled progression of pMHC-I-positive, IFNγ-responsive tumors, despite the presence of antigen-specific functional cytotoxic T lymphocytes. These data reveal a decisive role for ERAP1 in T cell mediated tumor rejection and will enhance the choice of MHC-I-restricted epitopes targeted by adoptive T cell transfer.

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Inhibition of Nr4a receptors enhances anti-tumor immunity by breaking Treg-mediated immune tolerance

Enhanced infiltration of regulatory T (Treg) cells into tumor tissue is detrimental to cancer patients and closely associated with poor prognosis as they create an immunosuppressive state that suppresses anti-tumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg cell genetic programs, contribute to Treg-mediated suppression of anti-tumor immunity in the tumor microenvironment. Mice lacking Nr4a1 and Nr4a2 genes specifically in Tregs showed resistance to tumor growth in transplantation models without exhibiting any severe systemic autoimmunity. The chemotherapeutic agent camptothecin (CPT) and a common cyclooxygenase-2 (COX-2) inhibitor were found to inhibit transcriptional activity and induction of Nr4a factors, and they synergistically exerted anti-tumor effects. Genetic inactivation or pharmacological inhibition of Nr4a factors unleashed effector activities of CD8+ cytotoxic T cells and evoked potent anti-tumor immune responses. These findings demonstrate that inactivation of Nr4a in Tregs breaks immune tolerance toward cancer, and pharmacological modulation of Nr4a activity may be a novel cancer treatment strategy targeting the immunosuppressive tumor microenvironment.

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Plk1-mediated phosphorylation of TSC1 enhances the efficacy of rapamycin

The AKT/TSC/mTOR axis is an important pathway controlling cell growth, survival and proliferation in response to extracellular cues. Recently, it was reported that AKT activity fluctuates across the cell cycle. However, it remains unclear whether downstream targets of AKT are also regulated by the cell cycle. Here we report that mTORC1 activity inversely correlates with AKT activity during the cell cycle. Mechanistically, Plk1 phosphorylation of TSC1 at S467 and S578 interfered with TSC1/TSC2 binding, destabilized TSC1, promoted dissociation of the TSC complex from the lysosome, and eventually led to mTORC1 activation. Tumors derived from cancer cells expressing the TSC1-S467E/S578E mutant exhibited greater sensitivity to rapamycin than those expressing WT TSC1. Collectively, our data support a model in which Plk1, instead of AKT, regulates the TSC/mTORC1 pathway during mitosis, eventually regulating the efficacy of rapamycin.

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Germline mutations in lysine specific demethylase 1 (LSD1/KDM1A) confer susceptibility to multiple myeloma

Given the frequent and largely incurable occurrence of multiple myeloma (MM), identification of germline genetic mutations that predispose cells to MM may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell. Here we identified familial and early-onset MM kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. Additionally, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in MM patients unselected for family history compared to controls. Both monoclonal gammopathy of unknown significance (MGUS) and MM cells have significantly lower KDM1A transcript levels compared with normal plasma cells. Transcriptome analysis of MM cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacological inhibition of KDM1A promoted plasma cell expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show KDM1A is the first autosomal dominant MM germline predisposition gene, providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B cell differentiation.

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Germline mutations in lysine specific demethylase 1 (LSD1/KDM1A) confer susceptibility to multiple myeloma

Inhibition of Nr4a receptors enhances anti-tumor immunity by breaking Treg-mediated immune tolerance

ERAP1-dependent antigen cross-presentation determines efficacy of adoptive T cell therapy in mice

Plk1-mediated phosphorylation of TSC1 enhances the efficacy of rapamycin

Co-targeting BCL-2 and PI3K induces BAX-dependent mitochondrial apoptosis in AML cells

Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients suggesting targeting BCL-2 alone is insufficient to yield durable responses. Here we assessed the efficacy of co-administration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 co-administration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38-/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment-associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK-/- cells and failed to induce apoptosis in BAX-/- and BAX-/-BAK-/- cells, whereas BIM-/- cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.

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Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible

Newly developed targeted anticancer drugs inhibit signaling pathways commonly altered in adult and pediatric cancers. However, as these pathways are also essential for normal brain development, concerns have emerged of neurologic sequelae resulting specifically from their application in pediatric cancers. The neural substrates and age dependency of these drug-induced effects in vivo are unknown, and their long-term behavioral consequences have not been characterized. This study defines the age-dependent cellular and behavioral effects of these drugs on normally developing brains and determines their reversibility with post-drug intervention. Mice at different postnatal ages received short courses of molecularly targeted drugs in regimens analagous to clinical treatment. Analysis of rapidly developing brain structures important for sensorimotor and cognitive function showed that, while adult administration was without effect, earlier neonatal administration of targeted therapies attenuated white matter oligodendroglia and hippocampal neuronal development more profoundly than later administration, leading to long-lasting behavioral deficits. This functional impairment was reversed by rehabilitation with physical and cognitive enrichment. Our findings demonstrate age-dependent, reversible effects of these drugs on brain development, which are important considerations as treatment options expand for pediatric cancers.Significance: Targeted therapeutics elicit age-dependent long-term consequences on the developing brain that can be ameliorated with environmental enrichment. Cancer Res; 1–15. ©2018 AACR.

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Co-targeting BCL-2 and PI3K induces BAX-dependent mitochondrial apoptosis in AML cells

Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible

Evaluation of 99mTc-Labeled Bevacizumab–N-HYNIC Conjugate in Human Ovarian Tumor Xenografts

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.

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Evaluation of 99mTc-Labeled Bevacizumab–N-HYNIC Conjugate in Human Ovarian Tumor Xenografts

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.

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[HIV and cancer : What's new in 2017?]

[HIV and cancer : What's new in 2017?]

Bull Cancer. 2018 Mar 13;:

Authors: Gobert A, Veyri M, Poizot-Martin I, Lavolé A, Solas C, Paliche R, Katlama C, Costagliola D, Spano JP

Abstract
Since the era of combined antiretroviral therapy, life expectancy of people living with HIV has been improved and is associated with a change in causes of death. Cancer, both AIDS-defining or non-AIDS-defining cancers, has become the leading cause of death in people living with HIV associated with an increase in the incidence of some cancers compared to the general population. Epidemiology and the identification of risk factors is a crucial issue, particularly to determine the most appropriate prevention and screening strategies in this population. In the absence of dedicated clinical trials, the cancer management in these patients is based on general recommendations, with specific attention to comorbidities and drug interactions. In addition, the development of new innovative therapies such as immunotherapy with inhibitory antibodies of immune checkpoints receptor represents a hope for the patient care, both infected or not with HIV. In this context, the establishment of the national network CancerVIH makes sense, allowing the establishment of multi-disciplinary consultation meetings involving all the practitioners involved in the care of these patients with cancer, as well as the constitution of a national cohort and the promotion of dedicated trials, to improve and optimize the management for these patients.

PMID: 29548534 [PubMed - as supplied by publisher]

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Abemaciclib Approval Expands Initial Treatment Options for Advanced Breast Cancer

FDA has approved the CDK4/6 inhibitor abemaciclib (Verzenio) as a first-line treatment in some women with advanced or metastatic breast cancer. Under the approval, the drug must be used in combination with an aromatase inhibitor.

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Abemaciclib Approval Expands Initial Treatment Options for Advanced Breast Cancer

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Recent developments and obstacles in the treatment of melanoma with BRAF and MEK inhibitors

Publication date: Available online 19 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Mohd Wahid, Arshad Jawed, Raju K. Mandal, Sajad A. Dar, Naseem Akhter, Pallavi Somvanshi, Farah Khan, Mohtashim Lohani, Mohammed Y. Areeshi, Shafiul Haque
Metastatic melanoma is a least common form of cancer as it accounts only for 1% of all cancer cases. But, it is most deadly in nature and is haunting mankind for long emotionally as well as economically. The sites for the onset of the disease are pigment-producing cells of the skin, mucosa, eye etc. It has the potential to spread other sites like subcutaneous tissue, lymph nodes, lungs, liver, bone and brain. The United States Food & Drug Administration has approved various drug molecules from time to time. The molecules (Dabrafenib-BRAF inhibitor and Trametinib-MEK inhibitor) have proved their credentials alone and in combination as well. These molecules have demonstrated good results for various end points like median progression free survival, overall survival, objective response etc. The median progression free survival for patients using dabrafenib and trametinib were 5.1 and 4.8 months, respectively (administered singly). It has increased to 11.4 months in the combination treatment "dabrafenib + trametinib", which is approximately 104% and 138% greater than dabrafenib and trametinib treated groups alone. Similarly, the overall survival rate and objective response rate for the patients administered with "dabrafenib + trametinib" have been increased by 72% 64%, respectively. All these increments in these parameters were for a short period of time as the molecules were unable to withstand the pressure of resistance developed in the patients. So, the current review suggests the use of BRAF and MEK inhibitors as intermittent therapy along with heat shock protein 90 (HSP90) molecules.

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Recent developments and obstacles in the treatment of melanoma with BRAF and MEK inhibitors

Cancers, Vol. 10, Pages 84: Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models

Cancers, Vol. 10, Pages 84: Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models

Cancers doi: 10.3390/cancers10030084

Authors: Celina Yang Kyle Bromma Devika Chithrani

Optimizing the interface between nanoparticles (NPs) and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG) functionalized gold nanoparticles (GNPs) was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES) in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid), to improve internalization at the cellular level. A 10–12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy.

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Cancers, Vol. 10, Pages 85: Role of Pattern Recognition Receptors in KSHV Infection

Cancers, Vol. 10, Pages 85: Role of Pattern Recognition Receptors in KSHV Infection

Cancers doi: 10.3390/cancers10030085

Authors: Timsy Uppal Roni Sarkar Ranjit Dhelaria Subhash Verma

Kaposi's sarcoma-associated herpesvirus or Human herpesvirus-8 (KSHV/HHV-8), an oncogenic human herpesvirus and the leading cause of cancer in HIV-infected individuals, is a major public health concern with recurring reports of epidemics on a global level. The early detection of KSHV virus and subsequent activation of the antiviral immune response by the host's immune system are crucial to prevent KSHV infection. The host's immune system is an evolutionary conserved system that provides the most important line of defense against invading microbial pathogens, including viruses. Viruses are initially detected by the cells of the host innate immune system, which evoke concerted antiviral responses via the secretion of interferons (IFNs) and inflammatory cytokines/chemokines for elimination of the invaders. Type I IFN and cytokine gene expression are regulated by multiple intracellular signaling pathways that are activated by germline-encoded host sensors, i.e., pattern recognition receptors (PRRs) that recognize a conserved set of ligands, known as 'pathogen-associated molecular patterns (PAMPs)'. On the contrary, persistent and dysregulated signaling of PRRs promotes numerous tumor-causing inflammatory events in various human cancers. Being an integral component of the mammalian innate immune response and due to their constitutive activation in tumor cells, targeting PRRs appears to be an effective strategy for tumor prevention and/or treatment. Cellular PRRs are known to respond to KSHV infection, and KSHV has been shown to be armed with an array of strategies to selectively inhibit cellular PRR-based immune sensing to its benefit. In particular, KSHV has acquired specific immunomodulatory genes to effectively subvert PRR responses during the early stages of primary infection, lytic reactivation and latency, for a successful establishment of a life-long persistent infection. The current review aims to comprehensively summarize the latest advances in our knowledge of role of PRRs in KSHV infections.

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Cancers, Vol. 10, Pages 84: Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models

Cancers, Vol. 10, Pages 84: Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models

Cancers doi: 10.3390/cancers10030084

Authors: Celina Yang Kyle Bromma Devika Chithrani

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Cancers, Vol. 10, Pages 85: Role of Pattern Recognition Receptors in KSHV Infection

Cancers, Vol. 10, Pages 85: Role of Pattern Recognition Receptors in KSHV Infection

Cancers doi: 10.3390/cancers10030085

Authors: Timsy Uppal Roni Sarkar Ranjit Dhelaria Subhash Verma

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Serum long noncoding RNA HOTAIR as a novel diagnostic and prognostic biomarker in glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive malignant adult primary brain tumor. Despite surgical resection followed by radiotherapy and chemotherapy, the median survival rate is approximately 14 months. Although experimental therapies are in clinical trials for GBM, there is an urgent need for a peripheral GBM biomarker for measuring treatment response. As we have previously demonstrated that the long noncoding RNA HOX Transcript Antisense Intergenic RNA, or HOTAIR, is dysregulated in GBM and required for GBM cell proliferation, we hypothesized that HOTAIR expression may be utilized as a peripheral biomarker for GBM. HOTAIR expression was measured in serum from 43 GBM and 40 controls using quantitative real-time PCR (qRT-PCR). The PCR products were subsequently subcloned into pCR™4-TOPO®TA vectors for DNA sequencing. A ROC curve was also generated to examine HOTAIR's prognostic value. The amount of HOTAIR in serum exosomes and exosome-depleted supernatant was calculated by qRT-PCR. The relative HOTAIR expression was also investigated in 15 pairs of GBM serum and tumors. We detected HOTAIR in serum from GBM patients. HOTAIR levels in serum samples from GBM patients was significantly higher than in the corresponding controls (P < 0.0001). The area under the ROC curve distinguishing GBM patients from controls was 0.913 (95% CI: 0.845–0.982, P < 0.0001), with 86.1% sensitivity and 87.5% specificity at the cut-off value of 10.8. HOTAIR expression was significantly correlated with high grade brain tumors. In addition, Pearson correlation analysis indicated a medium correlation of serum HOTAIR levels and the corresponding tumor HOTAIR levels (r = 0.734, P < 0.01). We confirmed via sequencing that the amplified HOTAIR from serum contained the HOTAIR sequence and maps to the known HOTAIR locus at 12q13. The serum-derived exosomes contain HOTAIR and the purified exosomes were validated by western blot and nanoparticle tracking analysis. Importantly, our results demonstrate that serum HOTAIR can be used as a novel prognostic and diagnostic biomarker for GBM.

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The decade of exosomal long RNA species: an emerging cancer antagonist

Abstract

Exosomes have emerged as a novel approach for the treatment and diagnosis of cancer after RNA content was discovered in exosomes in 2007. As important meditators of intercellular communication, exosomes have become a strong focus of investigation for researchers in the past decade, as witnessed through the exponential increase of research on exosomes. The capability of exosomes to transfer functionally active cargo highlights their importance as promising biomarkers and diagnostic molecules, as well as prospective drug delivery systems. The accessibility of exosomes in nearly all biofluids additionally alludes to its unprecedented ability in various types of cancers due to its extensive impact on tumor formation and progression. This review analyzes the role of exosomal long RNA species, which is comprised of mRNA, lncRNA, and circRNA, in tumor formation and progression, with an emphasis on their potential as future diagnostic biomarkers and treatment vectors in cancer biology. Their alignment with the development of exosomal databases is further examined in this review, in view of the accumulation of studies published on exosomes in the past decade.

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Serum long noncoding RNA HOTAIR as a novel diagnostic and prognostic biomarker in glioblastoma multiforme

Abstract

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The decade of exosomal long RNA species: an emerging cancer antagonist

Abstract

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The Value of Behavioral Counseling for Skin Cancer Prevention

Melanoma kills nearly 10 000 people in the United States each year. The more prevalent keratinocyte carcinomas, including basal and squamous cell carcinoma, cause less mortality but contribute to health care costs and can cause substantial morbidity. While treatment options for advanced melanoma have improved over the past decade, primary and secondary prevention, through protection from UV radiation (UVR) and early self-detection, have the potential to reduce the incidence of advanced skin cancer. Importantly, these interventions come with little cost or risk to patients. The updated US Preventive Services Task Force (USPSTF) recommendation statement and accompanying evidence report in the most recent issue of JAMA document the steady progress toward embracing strategies to reduce the burden of skin cancer and also reflect the important role that health-outcomes research plays in influencing policy.

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