Παρασκευή 20 Οκτωβρίου 2017

Cognition, quality-of-life and symptom clusters in breast cancer: using Bayesian networks to elucidate complex relationships

Abstract

Objective

Breast cancer patients frequently complain of cognitive dysfunction during chemotherapy. Patients also report experiencing a cluster of sleep problems, fatigue and depressive symptoms during chemotherapy. We aimed to understand the complex dynamic interrelationships of depression, fatigue, and sleep to ultimately elucidate their role in cognitive performance and quality of life among breast cancer survivors undergoing chemotherapy treatment.

Methods

Our study sample comprised 74 newly diagnosed stage I-III breast cancer patients scheduled to receive chemotherapy, and followed them for one year. An objective neuropsychological test battery and self-reported fatigue, mood, sleep quality, and quality of life were collected at three time points: before the start of chemotherapy (baseline: BL), at the end of cycle 4 chemotherapy (C4) and one year after the start of chemotherapy (Y1). We applied novel Bayesian network methods to investigate the role of sleep/fatigue/mood on cognition and quality of life prior to, during, and after chemotherapy.

Results

The fitted network exhibited strong direct and indirect links between symptoms, cognitive performance and quality of life. The only symptom directly linked to cognitive performance was C4 sleep quality; at C4, fatigue was directly linked to sleep, and thus indirectly influenced cognitive performance. Mood strongly influenced concurrent quality of life at C4 and Y1. Regression estimates indicated that worse sleep quality, fatigue and mood were negatively associated with cognitive performance or quality of life.

Conclusions

The Bayesian network identified local structure (e.g., fatigue-mood-QoL or sleep-cognition), and possible intervention targets (e.g., a sleep intervention to reduce cognitive complaints during chemotherapy).



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Cognition, quality-of-life and symptom clusters in breast cancer: using Bayesian networks to elucidate complex relationships

Abstract

Objective

Breast cancer patients frequently complain of cognitive dysfunction during chemotherapy. Patients also report experiencing a cluster of sleep problems, fatigue and depressive symptoms during chemotherapy. We aimed to understand the complex dynamic interrelationships of depression, fatigue, and sleep to ultimately elucidate their role in cognitive performance and quality of life among breast cancer survivors undergoing chemotherapy treatment.

Methods

Our study sample comprised 74 newly diagnosed stage I-III breast cancer patients scheduled to receive chemotherapy, and followed them for one year. An objective neuropsychological test battery and self-reported fatigue, mood, sleep quality, and quality of life were collected at three time points: before the start of chemotherapy (baseline: BL), at the end of cycle 4 chemotherapy (C4) and one year after the start of chemotherapy (Y1). We applied novel Bayesian network methods to investigate the role of sleep/fatigue/mood on cognition and quality of life prior to, during, and after chemotherapy.

Results

The fitted network exhibited strong direct and indirect links between symptoms, cognitive performance and quality of life. The only symptom directly linked to cognitive performance was C4 sleep quality; at C4, fatigue was directly linked to sleep, and thus indirectly influenced cognitive performance. Mood strongly influenced concurrent quality of life at C4 and Y1. Regression estimates indicated that worse sleep quality, fatigue and mood were negatively associated with cognitive performance or quality of life.

Conclusions

The Bayesian network identified local structure (e.g., fatigue-mood-QoL or sleep-cognition), and possible intervention targets (e.g., a sleep intervention to reduce cognitive complaints during chemotherapy).



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Everolimus in advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors: RADIANT-4 lung subgroup analysis

Summary

In the phase 3, RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), nonfunctional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, = 63 and placebo, = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in everolimus arm vs 3.6 (1.9-5.1) months in placebo arm (HR, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced any tumor shrinkage compared with placebo (13%). Most frequently reported (≥ 5% incidence) grade 3-4 drug-related adverse events (everolimus vs placebo) included stomatitis (11% vs 0%), hyperglycemia (10% vs 0%), and any infections (8% vs 0%). In patients with advanced, progressive, well-differentiated, nonfunctional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 population. These results support the use of everolimus in patients with advanced, nonfunctional lung NET.

This article is protected by copyright. All rights reserved.



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Everolimus in advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors: RADIANT-4 lung subgroup analysis

Summary

In the phase 3, RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), nonfunctional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, = 63 and placebo, = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in everolimus arm vs 3.6 (1.9-5.1) months in placebo arm (HR, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced any tumor shrinkage compared with placebo (13%). Most frequently reported (≥ 5% incidence) grade 3-4 drug-related adverse events (everolimus vs placebo) included stomatitis (11% vs 0%), hyperglycemia (10% vs 0%), and any infections (8% vs 0%). In patients with advanced, progressive, well-differentiated, nonfunctional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 population. These results support the use of everolimus in patients with advanced, nonfunctional lung NET.

This article is protected by copyright. All rights reserved.



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Clinical significance of Fusobacterium nucleatum, epithelial–mesenchymal transition, and cancer stem cell markers in stage III/IV colorectal cancer patients

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HIF-1α Promotes Breast Cancer Cell MCF-7 Proliferation and Invasion Through Regulating miR-210

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 297-301.


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PERK-Phosphorylated eIF2α Pathway Suppresses Tumor Metastasis Through Downregulating Expression of Programmed Death Ligand 1 and CXCL5 in Triple-Negative Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 282-287.


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Imaging of Integrin αvβ3 Expression in Lung Cancers and Brain Tumors Using Single-Photon Emission Computed Tomography with a Novel Radiotracer 99mTc-IDA-D-[c(RGDfK)]2

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 288-296.


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Denosumab for the treatment of bone disease in solid tumors and multiple myeloma

Future Oncology, Ahead of Print.


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HIF-1α Promotes Breast Cancer Cell MCF-7 Proliferation and Invasion Through Regulating miR-210

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 297-301.


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PERK-Phosphorylated eIF2α Pathway Suppresses Tumor Metastasis Through Downregulating Expression of Programmed Death Ligand 1 and CXCL5 in Triple-Negative Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 282-287.


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An Overview of Unfolded Protein Response Signaling and Its Role in Cancer

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 275-281.


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Imaging of Integrin αvβ3 Expression in Lung Cancers and Brain Tumors Using Single-Photon Emission Computed Tomography with a Novel Radiotracer 99mTc-IDA-D-[c(RGDfK)]2

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 288-296.


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Low Concentration of 5-Fluorouracil Increases the Effectiveness of Tumor RNA to Activate Murine Dendritic Cells

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 302-308.


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Absolute lymphocyte counts at end of induction correlate with distinct immune cell compartments in pediatric B cell precursor acute lymphoblastic leukemia

Abstract

Several retrospective studies in children with B cell precursor (BCP) acute lymphoblastic leukemia (ALL) provided clinical evidence that higher absolute lymphocyte counts (ALC) early into treatment significantly correlated with improved relapse-free and overall survival. It still remains unknown, however, whether the predictive role of higher ALCs reflects general bone marrow recovery or a more specific attribute of immune function. To investigate this question, we implemented a prospective observational cohort study in 20 children with BCP ALL on day 29 (D29) of induction chemotherapy and immunophenotyped their lymphoid (T, B and natural killer cells) and myeloid (neutrophils, monocytes, dendritic cells) compartments. In a first evaluation of a cohort treated with Children's Oncology Group-based induction chemotherapy, the immune cell compartments were differentially depleted at D29. Neither gender, risk status, minimal residual disease, nor bone marrow recovery markers correlated with D29 ALC. In contrast, both CD3+ T cell and dendritic cell compartments, which did not correlate with age, significantly correlated with D29 ALC (p < 0.0001). In addition, subset complexity of cellular immune compartments was preserved at D29. This study reveals that D29 ALC significantly correlates with distinct immune cell compartments but not with bone marrow recovery markers, suggesting that higher D29 ALCs may contribute to leukemia control by inducing specific host immune activity.



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NY-ESO-1- and survivin-specific T-cell responses in the peripheral blood from patients with glioma

Abstract

The prognosis for patients with glioblastoma is grim. Ex vivo expanded tumor-associated antigen (TAA)-reactive T-cells from patients with glioma may represent a viable source for anticancer-directed cellular therapies. Immunohistochemistry was used to test the survivin (n = 40 samples) and NY-ESO-1 (n = 38 samples) protein expression in tumor specimens. T-cells from peripheral blood were stimulated with TAAs (synthetic peptides) in IL-2 and IL-7, or using a combination of IL-2, IL-15 and IL-21. CD4+ and CD8+ T-cells were tested for antigen-specific proliferation by flow cytometry, and IFN-γ production was tested by ELISA. Twenty-eight out of 38 cancer specimens exhibited NY-ESO-1 protein expression, 2/38 showed a strong universal (4+) NY-ESO-1 staining, and 9/40 cancer lesions exhibited a strong (4+) staining for survivin. We could detect antigen-specific IFN-γ responses in 25% blood samples for NY-ESO-1 and 30% for survivin. NY-ESO-1-expanded T-cells recognized naturally processed and presented epitopes. NY-ESO-1 or survivin expression in glioma represents viable targets for anticancer-directed T-cells for the biological therapy of patients with glioma.



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Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells

Abstract

Malignant melanoma incidence has been increasing for over 30 years, and despite promising new therapies, metastatic disease remains difficult to treat. We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4+ and CD8+ T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4+ and CD8+ T cells. Parameters monitored on transduced T cells included activation (CD25, CD69), inhibitory (PD-1, TIM-3, CTLA-4), costimulatory (OX40), and memory (CCR7) markers. For the clinical trial, T cells were activated, transduced, selected for CD34t+ cells, then re-activated, and expanded in IL-2 and IL-15. After lymphodepleting chemotherapy, patients were given transduced T cells and IL-2, and were followed for clinical and biological responses. Transduced T cells were detected in the circulation of three treated patients for the duration of observation (42, 523, and 255 days). Patient 1 tolerated the infusion well but died from progressive disease after 6 weeks. Patient 2 had a partial response by RECIST criteria then progressed. After progressing, Patient 2 was given high-dose IL-2 and subsequently achieved complete remission, coinciding with the development of vitiligo. Patient 3 had a mixed response that did not meet RECIST criteria for a clinical response and developed vitiligo. In two of these three patients, adoptive transfer of tyrosinase-reactive TCR-transduced T cells into metastatic melanoma patients had clinical and/or biological activity without serious adverse events.



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Fourteenth Meeting of the Network Italiano per la Bioterapia dei Tumori (NIBIT) on Cancer Bio-Immunotherapy, Siena, Italy, October 13–15, 2016



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Immunotherapy for hepatocellular carcinoma patients: is it ready for prime time?

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second most common cause of cancer death worldwide. Current treatment options for patients with intermediate and advanced HCC are limited, and there is an unmet need for novel therapeutic approaches. HCC is an attractive target for immunomodulation therapy, since it arises in an inflammatory milieu due to hepatitis B and C infections and cirrhosis. However, a major barrier to the development and success of immunotherapy in patients with HCC is the liver's inherent immunosuppressive function. Recent advances in the field of cancer immunology allowed further characterization of immune cell subsets and function, and created new opportunities for therapeutic modulation of the immune system. In this review, we present the different immune cell subsets involved in potential immune modulation of HCC, discuss their function and clinical relevance, review the variety of immune therapeutic agents currently under investigation in clinical trials, and outline future research directions.



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Ki67 targeted strategies for cancer therapy

Abstract

Ki67 is a well-known proliferation marker for the evaluation of cell proliferation. Numerous studies have indicated that Ki67 index independently predicts cancer progression. Moreover, because Ki67 is highly expressed in malignant cells but almost could not be detected in normal cells, it has become a promising target for cancer therapy. In this review, we summarize recent advances in Ki67 targeted cancer therapy. In particular, we highlight recent development on the exploitation of Ki67 promoter to drive the expression of siRNAs or therapeutic genes in cancer cells specifically. The use of Ki67 as an attractive target opens a new avenue for cancer therapy.



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Correction to: High expression of HO-1 predicts poor prognosis of ovarian cancer patients and promotes proliferation and aggressiveness of ovarian cancer cells

Abstract

n the original version of the article, Table 2 was incorrect. The corrected Table 2 is shown here. Therefore, in Results (page 3 of original version, right column, line 13), the OR of non-optimal debulking should read OR = 3.036 with 95% CI 1.452–6.348.



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PrediCTC, liquid biopsy in precision oncology: a technology transfer experience in the Spanish health system

Abstract

Purpose

Management of metastatic disease in oncology includes monitoring of therapy response principally by imaging techniques like CT scan. In addition to some limitations, the irruption of liquid biopsy and its application in personalized medicine has encouraged the development of more efficient technologies for prognosis and follow-up of patients in advanced disease.

Methods

PrediCTC constitutes a panel of genes for the assessment of circulating tumor cells (CTC) in metastatic colorectal cancer patients, with demonstrated improved efficiency compared to CT scan for the evaluation of early therapy response in a multicenter prospective study. In this work, we designed and developed a technology transfer strategy to define the market opportunity for an eventual implementation of PrediCTC in the clinical practice.

Results

This included the definition of the regulatory framework, the analysis of the regulatory roadmap needed for CE mark, a benchmarking study, the design of a product development strategy, a revision of intellectual property, a cost-effectiveness study and an expert panel consultation.

Conclusion

The definition and analysis of an appropriate technology transfer strategy and the correct balance among regulatory, financial and technical determinants are critical for the transformation of a promising technology into a viable technology, and for the decision of implementing liquid biopsy in the monitoring of therapy response in advanced disease.



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SEOM clinical guidelines for anaplastic gliomas (2017)

Abstract

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors.



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Current trends in mouse models of glioblastoma

Abstract

Glioblastoma is the most deadly brain tumor type and is characterized by a severe and high rate of angiogenesis, remaining an incurable disease in the majority of cases. Mechanistic understanding of glioblastoma initiation and progression is complicated by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell or tissue of origin. To determine these mechanisms, mouse models that recapitulate the molecular and histological characteristics of glioblastoma are required. Unlike in other malignancies, viral-mediated mouse models of glioblastoma rather than chemically induced mouse models have been developed because of its sensitivity to viruses. Based on recent molecular analyses reported for human glioblastoma, this review critically evaluates genetically engineered, xenograft, allograft, viral-mediated, and chemically induced mouse models of glioblastoma. Further, we focus on the clinical value of these models by examining their contributions to studies of glioblastoma prevention, tumorigenesis, and chemoresistance.



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Using oncology real-world evidence for quality improvement and discovery: the case for ASCO's CancerLinQ

Future Oncology, Ahead of Print.


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Denosumab for the treatment of bone disease in solid tumors and multiple myeloma

Future Oncology, Ahead of Print.


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Using oncology real-world evidence for quality improvement and discovery: the case for ASCO's CancerLinQ

Future Oncology, Ahead of Print.


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Denosumab for the treatment of bone disease in solid tumors and multiple myeloma

Future Oncology, Ahead of Print.


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A noninterventional, multicenter, prospective phase IV study of trabectedin in patients with advanced soft tissue sarcoma

imageThis prospective, noninterventional study is the first phase IV trial designed to evaluate trabectedin in patients with advanced soft tissue sarcoma in real-life clinical practice across Europe. To be included in the study, patients must have received more than or equal to one cycle of trabectedin and be currently on treatment. The primary endpoint was progression-free survival as defined by investigators. The secondary endpoints included objective response rate, disease control rate, time to progression and the growth modulation index (GMI), overall survival, and an assessment of the cancer-related symptoms and safety. A total of 218 patients from 41 European centers were evaluated. Patients received a median of six cycles per patient, mostly on an outpatient basis (n=132; 60.6%). The median progression-free survival was 5.9 months, with 70 and 49% of patients free from progression at 3 and 6 months after treatment, respectively. Three (1.4%) patients achieved a complete response and 55 (25.2%) patients achieved a partial response for an objective response rate of 26.6%. A total of 85 (39.0%) patients had disease stabilization for a disease control rate of 65.6%. The median GMI was 0.8, with 5.1 and 38.8% of patients with a GMI of greater than 1.1 to less than 1.33 and greater than or equal to 1.33, respectively. The median overall survival was 21.3 months. Febrile neutropenia (2.3% of patients), neutropenia, nausea, and pneumonia (1.4% each) were the most common trabectedin-related grade 3/4 serious adverse drug reactions. Trabectedin confers clinically meaningful long-term benefits to patients with multiple soft tissue sarcoma histotypes, being either comparable or better than those observed previously in clinical trials, and with a manageable safety profile.

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Two faces of Hippo: activate or suppress the Hippo pathway in cancer

imageThe Hippo pathway has generated considerable interest in recent years because of its involvement in several key hallmarks of cancer progression and metastasis. Research on the Hippo signaling pathway in cancer has been used to determine the activity of yes-associated protein (YAP) in tumorigenesis and disease progression. Previous studies have shown that the Hippo pathway can be used as a target to inhibit YAP activity and is a viable treatment for cancer. However, more studies are required to further advance our understanding of the Hippo signaling pathway in cancer. It has been shown that knockout of serine/threonine-kinases LATS1/2 in the Hippo pathway suppresses cancer immunity in mice. In addition, suppression of the oncogene YAP could contribute toward cancer immune therapy. Therefore, regulation of Hippo signaling can be an attractive alternative strategy for cancer treatment. This review will provide a summary of currently known compounds that activate or suppress the Hippo pathway.

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Bcl-2 and Bcl-xL mediate resistance to receptor tyrosine kinase-targeted therapy in lung and gastric cancer

imagePromising clinical efficacy has been observed with receptor tyrosine kinase inhibitors (TKIs) particularly in lung and gastric cancers with mutations or amplifications in the targeted receptor tyrosine kinases (RTKs). However, the efficacy and the duration of the response to these inhibitors are limited by the emergence of drug resistance. Here, we report treatment of RTK-dependent lung and gastric cancer cell lines with TKIs increased protein levels of Bcl-2 and Bcl-xL. The combination of the Bcl-2 and Bcl-xL inhibitor ABT-263 and TKIs was superior to TKIs alone in reducing cell viability and capacity of resistant colony formation. Furthermore, resistant cells established with exposure of RTK-dependent cells to increasing concentrations of TKIs also express higher levels of Bcl-2 or Bcl-xL compared with their parental cells. The combination of inhibitors of PI3K/AKT, MEK/ERK, and Bcl-2/Bcl-xL effectively reduced the viability of resistant cells and inhibited tumor size in a xenograft model derived from resistant cells by inducing apoptosis. Our results define a generalizable resistance mechanism to TKIs and rationalize inhibition of Bcl-2 and Bcl-xL as a strategy to augment responses and blunt acquired resistance to TKIs in lung and gastric cancer.

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Extended topoisomerase 1 inhibition through liposomal irinotecan results in improved efficacy over topotecan and irinotecan in models of small-cell lung cancer

imageLiposomal irinotecan (irinotecan liposome injection, nal-IRI), a liposomal formulation of irinotecan, is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior antitumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan. We evaluated the antitumor activity of nal-IRI compared with irinotecan and topotecan in preclinical models of small-cell lung cancer (SCLC) including in a model pretreated with carboplatin and etoposide, a first-line regimen used in SCLC. Nal-IRI demonstrated antitumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, and NCI-H1048 cell line-derived models as well as in three patient-derived xenograft models. The antitumor activity of nal-IRI was superior to that of topotecan in all models tested, which generally exhibited limited control of tumor growth and was superior to irinotecan in four out of five models. Further, nal-IRI demonstrated antitumor activity in tumors that progressed following treatment with topotecan or irinotecan, and demonstrated significantly greater antitumor activity than both topotecan and irinotecan in NCI-H1048 tumors that had progressed on previous carboplatin plus etoposide treatment. These results support the clinical development of nal-IRI in patients with SCLC.

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A novel hydroxyphenyl hydrazone derivate YCL0426 inhibits cancer cell proliferation through sequestering iron

imageCancer cells have an increased requirement for iron than normal cells, and iron chelators are under active consideration for cancer treatment. The metal-sequestering potential and antiproliferative mechanisms of a novel hydroxyphenyl hydrazone derivate YCL0426 were investigated here. Antiproliferative activity of YCL0426 was detected by MTT assay. The iron-sequestering potential was evaluated by ferrozine–Fe(II) sequestering assay and Fe(II) titration assay. Cell-cycle-arresting profile was checked by flow cytometry and the DNA synthesis status was evaluated by BrdU incorporation assay. SW480 cells stably expressing Rad51-EGFP fusion protein were used to evaluate the DNA damaging potential of the compound. The impact of extra Fe(II) supplement on compound activities was also examined. YCL0426 shows significant antiproliferative activity on 15 cancer cell lines with mean IC50 values of 5.25 μmol/l. YCL0426 displayed concentration-dependent Fe(II) sequestering ability in ferrozine–Fe(II) sequestering assay, and induced upregulation of transferrin receptor 1 and divalent metal transporter 1 expression in HepG2 cells, which are genes responsible for Fe(II) uptake. YCL0426 blocked DNA synthesis in BrdU incorporation assay, and arrested cell cycle at S or G1 phase. Besides, YCL0426 induced Rad51 foci formation and histone H2AX phosphorylation with EC50 values of 1.35 and 2.29 μmol/l, respectively, indicating the emergence of DNA damage. All these cellular responses, and even the growth-inhibiting activity of YCL0426, can be readily reversed by Fe(II) repletion, indicating that iron sequestering is responsible, at least in part, for the antiproliferative activity of YCL0426. YCL0426 is a potent iron chelator that exerts significant antiproliferative activities by inducing G1/S arrest and DNA damage.

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Rhabdomyosarcoma cells are susceptible to cell death by LDK378 alone or in combination with sorafenib independently of anaplastic lymphoma kinase status

imageAnaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is often overexpressed in rhabdomyosarcoma (RMS). However, its oncogenic and functional role in RMS remains unclear. Therefore, we investigated the antitumor activity of LDK378 (ceritinib), a new second-generation ALK inhibitor approved for patients with ALK-positive non-small-cell lung cancers. Here, we report that LDK378 reduces cell viability and induces cell death in RMS cell lines at low micromolar IC50 concentrations irrespective of ALK expression levels or phosphorylation status. Compared with Karpas 299 non-Hodgkin's lymphoma cells carrying the NPM–ALK fusion gene, RMS cell lines proved to be far less sensitive to LDK378. The broad-range caspase inhibitor zVAD.fmk significantly protects RMS cells from LDK378-mediated cell death, indicating that LDK378 induces caspase-dependent apoptotic cell death. Before the onset of apoptosis, LDK378 reduces phosphorylation of AKT, S6 ribosomal protein, STAT3 and – to a lesser extent – phosphorylation of ERK, showing that it suppresses key survival pathways. Importantly, we identify a synergistic induction of cell death by combining subtoxic concentrations of LDK378 with the multitargeting kinase inhibitor sorafenib. Calculation of the combination index confirmed that this interaction is synergistic. Also, LDK378 cooperates with sorafenib to significantly reduce colony formation of RMS cells, showing that this combination affects long-term clonogenic growth. In conclusion, LDK378 induces caspase-dependent apoptotic cell death in RMS cells independent of their ALK status and synergizes at subtoxic concentrations with sorafenib to induce cell death. These findings have important implications for the use of LDK378 in RMS.

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Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer

imageA close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R2=0.429), whereas EETS and DPR were less correlated with OS (R2=0.0682, 0.186). EETS was well correlated with DPR (R2=0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy.

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Ability of polymer-bound P-glycoprotein inhibitor ritonavir to overcome multidrug resistance in various resistant neuroblastoma cell lines

imagePolymer prodrugs can considerably improve the treatment of tumors with multidrug resistance, often caused by overexpression of P-glycoprotein (P-gp). Here, we present the effect of the N-(2-hydroxypropyl) methacrylamide-based polymer conjugate with P-gp inhibitor ritonavir (RIT) on the increase of free doxorubicin (DOX) and polymer-bound DOX cytotoxicity in the human neuroblastoma 4 cell line and its resistant clones to different cytostatics. The increase in cytotoxicity after polymer–RIT conjugate pretreatment was higher for the lines overexpressing P-gp and less pronounced for those with decreased P-gp levels. Moreover, the effect of polymer conjugate containing inhibitor and DOX on the same polymer chain was lower than that of two individual polymer conjugates used sequentially. In conclusion, the polymer–RIT conjugate can significantly increase the cytotoxicity of free DOX and polymer–DOX conjugates in cells with various multidrug resistance origins and can thus be considered a suitable therapeutic enhancer of polymer prodrugs.

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A noninterventional, multicenter, prospective phase IV study of trabectedin in patients with advanced soft tissue sarcoma

imageThis prospective, noninterventional study is the first phase IV trial designed to evaluate trabectedin in patients with advanced soft tissue sarcoma in real-life clinical practice across Europe. To be included in the study, patients must have received more than or equal to one cycle of trabectedin and be currently on treatment. The primary endpoint was progression-free survival as defined by investigators. The secondary endpoints included objective response rate, disease control rate, time to progression and the growth modulation index (GMI), overall survival, and an assessment of the cancer-related symptoms and safety. A total of 218 patients from 41 European centers were evaluated. Patients received a median of six cycles per patient, mostly on an outpatient basis (n=132; 60.6%). The median progression-free survival was 5.9 months, with 70 and 49% of patients free from progression at 3 and 6 months after treatment, respectively. Three (1.4%) patients achieved a complete response and 55 (25.2%) patients achieved a partial response for an objective response rate of 26.6%. A total of 85 (39.0%) patients had disease stabilization for a disease control rate of 65.6%. The median GMI was 0.8, with 5.1 and 38.8% of patients with a GMI of greater than 1.1 to less than 1.33 and greater than or equal to 1.33, respectively. The median overall survival was 21.3 months. Febrile neutropenia (2.3% of patients), neutropenia, nausea, and pneumonia (1.4% each) were the most common trabectedin-related grade 3/4 serious adverse drug reactions. Trabectedin confers clinically meaningful long-term benefits to patients with multiple soft tissue sarcoma histotypes, being either comparable or better than those observed previously in clinical trials, and with a manageable safety profile.

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Two faces of Hippo: activate or suppress the Hippo pathway in cancer

imageThe Hippo pathway has generated considerable interest in recent years because of its involvement in several key hallmarks of cancer progression and metastasis. Research on the Hippo signaling pathway in cancer has been used to determine the activity of yes-associated protein (YAP) in tumorigenesis and disease progression. Previous studies have shown that the Hippo pathway can be used as a target to inhibit YAP activity and is a viable treatment for cancer. However, more studies are required to further advance our understanding of the Hippo signaling pathway in cancer. It has been shown that knockout of serine/threonine-kinases LATS1/2 in the Hippo pathway suppresses cancer immunity in mice. In addition, suppression of the oncogene YAP could contribute toward cancer immune therapy. Therefore, regulation of Hippo signaling can be an attractive alternative strategy for cancer treatment. This review will provide a summary of currently known compounds that activate or suppress the Hippo pathway.

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Bcl-2 and Bcl-xL mediate resistance to receptor tyrosine kinase-targeted therapy in lung and gastric cancer

imagePromising clinical efficacy has been observed with receptor tyrosine kinase inhibitors (TKIs) particularly in lung and gastric cancers with mutations or amplifications in the targeted receptor tyrosine kinases (RTKs). However, the efficacy and the duration of the response to these inhibitors are limited by the emergence of drug resistance. Here, we report treatment of RTK-dependent lung and gastric cancer cell lines with TKIs increased protein levels of Bcl-2 and Bcl-xL. The combination of the Bcl-2 and Bcl-xL inhibitor ABT-263 and TKIs was superior to TKIs alone in reducing cell viability and capacity of resistant colony formation. Furthermore, resistant cells established with exposure of RTK-dependent cells to increasing concentrations of TKIs also express higher levels of Bcl-2 or Bcl-xL compared with their parental cells. The combination of inhibitors of PI3K/AKT, MEK/ERK, and Bcl-2/Bcl-xL effectively reduced the viability of resistant cells and inhibited tumor size in a xenograft model derived from resistant cells by inducing apoptosis. Our results define a generalizable resistance mechanism to TKIs and rationalize inhibition of Bcl-2 and Bcl-xL as a strategy to augment responses and blunt acquired resistance to TKIs in lung and gastric cancer.

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Extended topoisomerase 1 inhibition through liposomal irinotecan results in improved efficacy over topotecan and irinotecan in models of small-cell lung cancer

imageLiposomal irinotecan (irinotecan liposome injection, nal-IRI), a liposomal formulation of irinotecan, is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior antitumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan. We evaluated the antitumor activity of nal-IRI compared with irinotecan and topotecan in preclinical models of small-cell lung cancer (SCLC) including in a model pretreated with carboplatin and etoposide, a first-line regimen used in SCLC. Nal-IRI demonstrated antitumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, and NCI-H1048 cell line-derived models as well as in three patient-derived xenograft models. The antitumor activity of nal-IRI was superior to that of topotecan in all models tested, which generally exhibited limited control of tumor growth and was superior to irinotecan in four out of five models. Further, nal-IRI demonstrated antitumor activity in tumors that progressed following treatment with topotecan or irinotecan, and demonstrated significantly greater antitumor activity than both topotecan and irinotecan in NCI-H1048 tumors that had progressed on previous carboplatin plus etoposide treatment. These results support the clinical development of nal-IRI in patients with SCLC.

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miR-449a: a potential therapeutic agent for cancer

imageMicroRNAs (miRNAs) have been reported to be associated with cancer progression and carcinogenesis. They are small, highly conserved, noncoding RNA molecules consisting of 19–25 nucleotides. By binding to complementary binding sites within the 3′-untranslated region of target mRNAs, miRNAs inhibit the translation of mRNAs or promote their degradation. miRNAs play critical roles in cancer initiation and development by functioning either as oncogenes or as tumor suppressors. Similarly, several studies have shown that miRNAs are involved in regulating various biological processes, including apoptosis, proliferation, cellular differentiation, signal transduction, and carcinogenesis. Among miRNAs, one that may be of particular interest in cancer biology is miR-449a, which has been reported to inhibit tumor growth, invasion, and metastasis, and to promote apoptosis and differentiation through the transforming growth factor-β activated kinase 1, NOTCH, nuclear factor-κB/P65/vascular endothelial growth factor, retinoblastoma-E2F, mitogen-activated protein kinase signaling pathways, WNT–β-catenin signaling, tumor protein P53, and androgen receptor signaling pathways. The miR-449 cluster is located in the second intron of CDC20B on chromosome 5q11.2, a region that has been identified as a susceptibility locus in cancer, and the abnormal expression of miR-449a may be related to the occurrence and development of tumors. As one example, miR-449a has been reported to be involved in the development of carcinoma and may be a potential prognostic indicator. On the basis of the putative pathogenetic relationships between cancer and miR-449a, we consider that miR-449a has the potential to serve as a therapeutic agent for the treatment of some types of cancer. In this review, the role of miR-449a in tumorigenesis and its mechanism of action are explored. Furthermore, its potential as a therapeutic agent in cancer treatment is considered.

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N1-guanyl-1,7-diaminoheptane enhances the chemosensitivity of acute lymphoblastic leukemia cells to vincristine through inhibition of eif5a-2 activation

imageN1-guanyl-1,7-diaminoheptane (GC7), a deoxyhypusine synthase inhibitor, has been shown to exert antiproliferation effects in many solid tumors by regulating eukaryotic translation initiation factor 5a2 (eif5a-2). However, little is known about the role of GC7 and eif5a-2 in drug resistance in acute lymphoblastic leukemia (ALL). In the present study, we investigated the effect of GC7 on drug-resistant ALL and its potential mechanism. We found that using the CCK-8 assay that combined treatment with GC7 and vincristine (VCR) significantly inhibited the cell viability of two ALL cell lines. Using EdU incorporation assays and flow cytometry, we also showed that GC7 could markedly enhance the VCR sensitivity of ALL cells by suppressing cell proliferation and promoting apoptosis. Furthermore, we showed that GC7 could downregulate eif5a-2 and myeloid cell leukemia-1 (Mcl-1) expression. Knockdown of eif5a-2 inhibited the expression of Mcl-1 and significantly enhanced the VCR sensitivity. Moreover, eif5a-2 knockdown decreased the regulatory role of GC7 in increasing VCR sensitivity. Thus, our findings indicate that combined treatment with GC7 could enhance VCR sensitivity of ALL cells by regulating the eif5a-2/Mcl-1 axis. Together, our results highlight the potential clinical application of GC7 in VCR-based chemotherapy for the treatment of ALL.

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A novel hydroxyphenyl hydrazone derivate YCL0426 inhibits cancer cell proliferation through sequestering iron

imageCancer cells have an increased requirement for iron than normal cells, and iron chelators are under active consideration for cancer treatment. The metal-sequestering potential and antiproliferative mechanisms of a novel hydroxyphenyl hydrazone derivate YCL0426 were investigated here. Antiproliferative activity of YCL0426 was detected by MTT assay. The iron-sequestering potential was evaluated by ferrozine–Fe(II) sequestering assay and Fe(II) titration assay. Cell-cycle-arresting profile was checked by flow cytometry and the DNA synthesis status was evaluated by BrdU incorporation assay. SW480 cells stably expressing Rad51-EGFP fusion protein were used to evaluate the DNA damaging potential of the compound. The impact of extra Fe(II) supplement on compound activities was also examined. YCL0426 shows significant antiproliferative activity on 15 cancer cell lines with mean IC50 values of 5.25 μmol/l. YCL0426 displayed concentration-dependent Fe(II) sequestering ability in ferrozine–Fe(II) sequestering assay, and induced upregulation of transferrin receptor 1 and divalent metal transporter 1 expression in HepG2 cells, which are genes responsible for Fe(II) uptake. YCL0426 blocked DNA synthesis in BrdU incorporation assay, and arrested cell cycle at S or G1 phase. Besides, YCL0426 induced Rad51 foci formation and histone H2AX phosphorylation with EC50 values of 1.35 and 2.29 μmol/l, respectively, indicating the emergence of DNA damage. All these cellular responses, and even the growth-inhibiting activity of YCL0426, can be readily reversed by Fe(II) repletion, indicating that iron sequestering is responsible, at least in part, for the antiproliferative activity of YCL0426. YCL0426 is a potent iron chelator that exerts significant antiproliferative activities by inducing G1/S arrest and DNA damage.

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Gallic acid induces G1 phase arrest and apoptosis of triple-negative breast cancer cell MDA-MB-231 via p38 mitogen-activated protein kinase/p21/p27 axis

imageGallic acid (GA) possesses potential antitumoral activity on different types of malignancies. In this study, we aimed to explore the antitumoral effects of GA on triple-negative breast cancer (TNBC) cells, the breast cancer cells showing resistance to hormonal therapy or HER2 receptor targeting therapy. We observed that GA treatment significantly decreased the cell viability of human TNBC cell line MDA-MB-231 and HS578T in a dose-dependent manner. In addition, GA exerted a relative lower cytotoxicity on noncancer breast fibroblast MCF-10F. Next, we analyzed the changes of cell-cycle distribution in response to GA treatment and found that GA led to an increase of G0/G1 and sub-G1 phase ratio in MDA-MB-231 cells. We further explored the crucial mediators controlling cell cycle and inducing apoptotic signaling, and the findings showed that GA downregulated cyclin D1/CDK4 and cyclin E/CDK2, upregulated p21Cip1and p27Kip1, and induced activation of caspase-9 and caspase-3. In addition, we demonstrated that p38 mitogen-activated protein kinase was involved in the GA-mediated cell-cycle arrest and apoptosis. Collectively, our findings indicate that GA inhibits the cell viability of TNBC cells, which may attribute to the G1 phase arrest and cellular apoptosis via p38 mitogen-activated protein kinase/p21/p27 axis. Thus, we suggest that GA could be beneficial to TNBC treatment.

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AKT1low quiescent cancer cells promote solid tumor growth

Human tumor growth depends on rapidly dividing cancer cells undergoing population expansion. Even advanced tumors, however, contain slowly proliferating cancer cells for reasons that remain unclear. Here, we selectively disrupt the ability of rapidly proliferating cancer cells to spawn AKT1low daughter cells that are rare, slowly proliferating, tumor-initiating, and chemotherapy-resistant using β1-integrin activation and the AKT1-E17K mutant oncoprotein as experimental tools in vivo. We find that selective depletion of AKT1low slow proliferators actually reduces the growth of a molecularly diverse panel of human cancer cell xenograft models without altering global cell proliferation or survival in vivo. Moreover, we find that unusual cancer patients with AKT1-E17K-mutant solid tumors also fail to produce AKT1low quiescent cancer cells and that this correlates with significantly prolonged survival after initial treatment compared to other patients. These findings support a model whereby human solid tumor growth depends on not only rapidly proliferating cancer cells but also on the continuous production of AKT1low slow proliferators.



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Phase 1 study of enavatuzumab, a first-in-class humanized monoclonal antibody targeting the TWEAK receptor, in patients with advanced solid tumors

This phase I study evaluates the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose limiting toxicities (DLT) included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23-33 mL/h with an elimination half-life of 7-18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The maximum tolerated dose of enavatuzumab is 1.0 mg/kg IV every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities are needed before embarking on further single agent or combination strategies.



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Overcoming resistance to cetuximab with honokiol, a small-molecule polyphenol

Overexpression and activation of the Epidermal Growth Factor Receptor (EGFR) have been linked to poor prognosis in several human cancers. Cetuximab is a monoclonal antibody against EGFR, that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anti-cancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non-small cell lung cancer cell line. Treatment of cetuximab resistant clones with honokiol and cetuximab resulted in a robust anti-proliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. Additionally, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab resistant clones which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab resistant HNSCC patient derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo. There was significant growth delay in PDX tumors after combination treatment with a subsequent down-regulation of active MAPK, AKT, and DRP1 signaling as seen in vitro. Collectively these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab.



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Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Co-administration

NAMPT, an enzyme essential for NAD+ biosynthesis, has been extensively studied as an anti-cancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective, and has a potent and broad spectrum of anti-cancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD+. LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when co-administered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic.



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Theranostic radiolabeled anti-CD20 sdAb for targeted radionuclide therapy of Non-Hodgkin Lymphoma

Anti-CD20 radioimmunotherapy is an effective approach for therapy of relapsed or refractory CD20pos lymphomas, but faces limitations due to poor tumor penetration and undesirable pharmacokinetics of full antibodies. Camelid single-domain Ab fragments (sdAbs) might circumvent some of the limitations of radiolabeled full antibodies. In this study, a set of hCD20-targeting sdAbs was generated and their capacity to bind hCD20 was evaluated in vitro and in vivo. A lead sdAb, sdAb 9079, was selected based on its specific tumor targeting and significant lower kidney accumulation compared to other sdAbs. SdAb 9079 was then radiolabeled with 68Ga and 177Lu for PET imaging and targeted therapy. The therapeutic potential of 177Lu-DTPA-sdAb was compared to that of 177Lu-DTPA-Rituximab and unlabeled Rituximab in mice bearing hCD20pos tumors. Radiolabeled with 68Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in non-target organs, except kidneys. The tumor uptake of 177Lu-DTPA-sdAb 9079 after 1.5h was 3.4 ± 1.3% ID/g, with T/B and T/M ratios of 13.3 ± 4.6 and 32.9 ± 15.6. Peak tumor accumulation of 177Lu-DTPA-Rituximab was about 9 times higher, but concomitantly with high accumulation in non-target organs and very low T/B and T/M ratios (0.8 ± 0.1 and 7.1 ± 2.4). Treatment of mice with 177Lu-DTPA-sdAb 9079 significantly prolonged median survival compared to control groups and was as effective as treatment with Rituximab or its 177Lu-labeled variant. Taken together, sdAb 9079 displays promising features as a theranostic drug to treat CD20pos lymphomas.



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ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms

Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALKATI) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 out of 45 (24.4%) melanomas. Ten melanomas express wild type (wt) ALK and/or ALKATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo, the melanomas expressing wt ALK or ALKATI were not sensitive to ALK inhibitors. Additionally, a patient with mucosal melanoma expressing ALKATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy whereas melanomas expressing ALKATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALKATI.



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Phase 1 study of enavatuzumab, a first-in-class humanized monoclonal antibody targeting the TWEAK receptor, in patients with advanced solid tumors

This phase I study evaluates the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose limiting toxicities (DLT) included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23-33 mL/h with an elimination half-life of 7-18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The maximum tolerated dose of enavatuzumab is 1.0 mg/kg IV every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities are needed before embarking on further single agent or combination strategies.



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Caveolae-mediated endocytosis as a novel mechanism of resistance to trastuzumab emtansine (T-DM1)

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2+ metastatic breast cancer, however its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2+ tumors, are not well understood. We used HER2+ cell lines to develop models of T-DM1 resistance utilizing a cyclical dosing schema in which cells received T-DM1 in an "on-off" routine until a T-DM1 resistant population was generated. T-DM1 resistant N87 cells (N87-TM) were cross-resistant to a panel of trastuzumab-ADCs (T-ADCs) with non-cleavable-linked auristatins. N87-TM cells do not have a decrease in HER2 protein levels or an increase in drug transporter protein (e.g. MDR1) expression compared to parental N87 cells. Intriguingly, T-ADCs utilizing auristatin payloads attached via an enzymatically cleavable linker overcome T-DM1 resistance in N87-TM cells. Importantly, N87-TM cells implanted into athymic mice formed T-DM1 refractory tumors which remain sensitive to T-ADCs with cleavable-linked auristatin payloads. Comparative proteomic profiling suggested enrichment in proteins that mediate caveolae formation and endocytosis in the N87-TM cells. Indeed, N87-TM cells internalize T-ADCs into intracellular caveolin-1 (CAV1) positive puncta and alter their trafficking to the lysosome compared to N87 cells. T-DM1 colocalization into intracellular CAV1 positive puncta correlated with reduced response to T-DM1 in a panel of HER2+ cell lines. Together, these data suggest caveolae-mediated endocytosis of T-DM1 may serve as a novel predictive biomarker for patient response to T-DM1.



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Theranostic radiolabeled anti-CD20 sdAb for targeted radionuclide therapy of Non-Hodgkin Lymphoma

Anti-CD20 radioimmunotherapy is an effective approach for therapy of relapsed or refractory CD20pos lymphomas, but faces limitations due to poor tumor penetration and undesirable pharmacokinetics of full antibodies. Camelid single-domain Ab fragments (sdAbs) might circumvent some of the limitations of radiolabeled full antibodies. In this study, a set of hCD20-targeting sdAbs was generated and their capacity to bind hCD20 was evaluated in vitro and in vivo. A lead sdAb, sdAb 9079, was selected based on its specific tumor targeting and significant lower kidney accumulation compared to other sdAbs. SdAb 9079 was then radiolabeled with 68Ga and 177Lu for PET imaging and targeted therapy. The therapeutic potential of 177Lu-DTPA-sdAb was compared to that of 177Lu-DTPA-Rituximab and unlabeled Rituximab in mice bearing hCD20pos tumors. Radiolabeled with 68Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in non-target organs, except kidneys. The tumor uptake of 177Lu-DTPA-sdAb 9079 after 1.5h was 3.4 ± 1.3% ID/g, with T/B and T/M ratios of 13.3 ± 4.6 and 32.9 ± 15.6. Peak tumor accumulation of 177Lu-DTPA-Rituximab was about 9 times higher, but concomitantly with high accumulation in non-target organs and very low T/B and T/M ratios (0.8 ± 0.1 and 7.1 ± 2.4). Treatment of mice with 177Lu-DTPA-sdAb 9079 significantly prolonged median survival compared to control groups and was as effective as treatment with Rituximab or its 177Lu-labeled variant. Taken together, sdAb 9079 displays promising features as a theranostic drug to treat CD20pos lymphomas.



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ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms

Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALKATI) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 out of 45 (24.4%) melanomas. Ten melanomas express wild type (wt) ALK and/or ALKATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo, the melanomas expressing wt ALK or ALKATI were not sensitive to ALK inhibitors. Additionally, a patient with mucosal melanoma expressing ALKATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy whereas melanomas expressing ALKATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALKATI.



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[18F]fluorothymidine positron emission tomography informs the synergistic efficacy of capecitabine and trifluridine/tipiracil in colon cancer

In cancer therapy, enhanced thymidine uptake by the salvage pathway can bypass dTMP depletion, thereby conferring resistance to thymidylate synthase inhibition. We investigated whether sequential combination therapy of capecitabine and trifluridine/tipiracil (TAS-102) could synergistically enhance antitumor efficacy in colon cancer xenograft models. We also examined 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil. [3H]FLT uptake after 5-fluorouracil treatment in vitro and [18F]FLT uptake after capecitabine (360 mg/kg/day) in athymic nude mice (Balb/c-nu) with xenografts (n = 10-12 per group) were measured using eight human colon cancer cell lines. We determined the synergistic effects of sequential combinations of 5-fluorouracil and trifluridine in vitro as well as the sequential combination of oral capecitabine (30-360 mg/kg) and trifluridine/tipiracil (trifluridine 75 or 150 mg/kg with tipiracil) in six xenograft models (n = 6-10 per group). We observed significant increases in [3H]FLT uptake in all cell lines and [18F]FLT uptake in five xenograft models after 5-fluorouracil and capecitabine treatment, respectively. Increased [18F]FLT uptake after capecitabine followed by extinction of uptake correlated strongly with tumor growth inhibition (ρ = −0.81, P = 0.02). The effects of these combinations were synergistic in vitro. A synergy for sequential capecitabine and trifluridine/tipiracil was found only in mouse xenograft models showing increased [18F]FLT uptake after capecitabine. Our results suggest that the sequential combination of capecitabine and trifluridine/tipiracil is synergistic in tumors with an activated salvage pathway after capecitabine treatment in mice, and [18F]FLT PET imaging may predict the response to capecitabine and the synergistic antitumor efficacy of a sequential combination of capecitabine and trifluridine/tipiracil.

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Subtype-specific cancer-associated fibroblasts contribute to the pathogenesis of uterine leiomyoma.

Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here we report the elucidation of the biological characteristics of the two most prevalent LM subtypes, MED12 mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) LM. Since each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-LM were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of ECM in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both LM subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these LM subtypes emphasize the importance of subtypes and genotypes in designing non-surgical therapeutic strategies for LM.

http://ift.tt/2xcCMME

RUNX1 upregulation by cytotoxic drugs promotes apoptosis

Mutations in the RUNX1 gene have been associated with chemotherapy resistance and poor prognosis in patients with acute myeloid leukemia (AML), T cell acute lymphoblastic leukemia (T-ALL) and myelodysplastic syndromes (MDS). However, the underlying mechanisms connecting RUNX1 to the success of therapy remain elusive. Here we explore the hypothesis that RUNX1 is directly involved in the response of hematopoietic cells to cytotoxic agents. RUNX1 was upregulated post-transcriptionally by cytotoxic agents in C57BL/6 mice in vivo and hematopoietic cell lines. Upregulation was also seen in primary human AML cells after treatment with cytarabine in vitro. Upon overexpression, RUNX1 restricted proliferation, promoted apoptosis, and augmented the DNA damage response. This unknown activity of RUNX1 required an intact runt homology domain (RHD), a domain where most leukemia-associated point mutations cluster. Consistent with this, two RHD-defective RUNX1 proteins lacked any anti-proliferative or apoptotic activity, and RHD-defective (K83N, N109D) mutant RUNX1 conferred resistance to ionizing radiation when overexpressed in Ba/F3 cells under certain conditions. Our experiments reveal a novel function of RUNX1 and offer an explanation for the link between RUNX1 mutations and chemotherapy and radiation resistance. Moreover, these data suggest that pharmacological modulation of RUNX1 might be an attractive new approach to treat hematological malignancies.

http://ift.tt/2xcYhg0

New generation nanomedicines constructed from self-assembling small molecule prodrugs alleviate cancer drug toxicity

The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel (CTX) as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these CTX derivatives, docosahexaenoic acid-derived compound 1 retained high anti-proliferative activity. SNM assembled with compound 1 displayed an unexpected enhancement of tolerability in animals along with effective therapeutic efficacy in a mouse xenograft model of human cancer, compared to free drug administered in its clinical formulation. Overall, our studies showed how attaching flexible lipid chains to a hydrophobic and highly toxic anticancer drug can convert it to a systemic self-deliverable nanotherapy, preserving its pharmacological efficacy while improving its safety profile.

http://ift.tt/2zErVN8

SGK1 is a critical component of an AKT-independent pathway essential for PI3K-mediated tumor development and maintenance

Activation of the PI3K-AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, while necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, co-targeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade.

http://ift.tt/2xcCAwU

A synthetic CD8{alpha}:MyD88 co-receptor enhances CD8+ T cell responses to weakly immunogenic and lowly expressed tumor antigens

T cell-based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T cell efficacy, including suboptimal T cell receptor (TCR) activation and an immunosuppressive tumor environment. Here we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8+ T cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α:MyD88-engineered T cells exhibited increased proliferation and expression of effector and co-stimulatory molecules in a tumor antigen-dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor (TLR) signaling-related proteins. CD8α:MyD88-expressing T cells improved anti-tumor responses in mice. Enhanced anti-tumor activity was associated with a unique tumor cytokine/chemokine signature, improved T cell infiltration, reduced markers of T cell exhaustion, elevated levels of proteins associated with antigen presentation, and fewer macrophages with an immunosuppressive phenotype in tumors. Given these observations, CD8α:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T cell responses to tumor antigens.

http://ift.tt/2zESj9x

Protein acyltransferase DHHC3 regulates breast tumor growth, oxidative stress and senescence

DHHC-type protein acyltransferases may regulate the localization, stability and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. ZDHHC3-ablated tumors also showed enhanced recruitment of innate immune cells (anti-tumor macrophages, natural killer cells) associated with clearance of senescent tumors. These anti-tumor effects were reversed upon reconstitution with wildtype, but not enzyme-active site-deficient DHHC3. Concomitant ablation of the upregulated oxidative stress protein TXNIP substantially negated the effects of ZDHHC3 depletion on oxidative stress and senescence. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely played a key role in TXNIP upregulation. In conclusion, DHHC3-mediated protein palmitoylation supports breast tumor growth by modulating cellular oxidative stress and senescence.

http://ift.tt/2xbm1RK

Small molecule inhibition of PD-1 transcription is an effective alternative to antibody blockade in cancer therapy

The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase GSK-3α/β, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small molecule inhibitors of GSK-3α/β (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PDL-1 blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Further, the conditional genetic deletion of GSK-3α/β reduced PD-1 expression on CD8+ T cells, and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor infiltrating lymphocytes (TILs), while increasing Tbx21 (T-bet) transcription, and the expression of CD107a+ (LAMP1) and granzyme B (GZMB) on CD8+ T-cells. Lastly, the adoptive transfer of T-cells treated ex vivo with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti-PD-1 pre-treatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies.

http://ift.tt/2zFtL0j

[18F]fluorothymidine positron emission tomography informs the synergistic efficacy of capecitabine and trifluridine/tipiracil in colon cancer

In cancer therapy, enhanced thymidine uptake by the salvage pathway can bypass dTMP depletion, thereby conferring resistance to thymidylate synthase inhibition. We investigated whether sequential combination therapy of capecitabine and trifluridine/tipiracil (TAS-102) could synergistically enhance antitumor efficacy in colon cancer xenograft models. We also examined 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil. [3H]FLT uptake after 5-fluorouracil treatment in vitro and [18F]FLT uptake after capecitabine (360 mg/kg/day) in athymic nude mice (Balb/c-nu) with xenografts (n = 10-12 per group) were measured using eight human colon cancer cell lines. We determined the synergistic effects of sequential combinations of 5-fluorouracil and trifluridine in vitro as well as the sequential combination of oral capecitabine (30-360 mg/kg) and trifluridine/tipiracil (trifluridine 75 or 150 mg/kg with tipiracil) in six xenograft models (n = 6-10 per group). We observed significant increases in [3H]FLT uptake in all cell lines and [18F]FLT uptake in five xenograft models after 5-fluorouracil and capecitabine treatment, respectively. Increased [18F]FLT uptake after capecitabine followed by extinction of uptake correlated strongly with tumor growth inhibition (ρ = −0.81, P = 0.02). The effects of these combinations were synergistic in vitro. A synergy for sequential capecitabine and trifluridine/tipiracil was found only in mouse xenograft models showing increased [18F]FLT uptake after capecitabine. Our results suggest that the sequential combination of capecitabine and trifluridine/tipiracil is synergistic in tumors with an activated salvage pathway after capecitabine treatment in mice, and [18F]FLT PET imaging may predict the response to capecitabine and the synergistic antitumor efficacy of a sequential combination of capecitabine and trifluridine/tipiracil.

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Subtype-specific cancer-associated fibroblasts contribute to the pathogenesis of uterine leiomyoma.

Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here we report the elucidation of the biological characteristics of the two most prevalent LM subtypes, MED12 mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) LM. Since each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-LM were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of ECM in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both LM subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these LM subtypes emphasize the importance of subtypes and genotypes in designing non-surgical therapeutic strategies for LM.

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RUNX1 upregulation by cytotoxic drugs promotes apoptosis

Mutations in the RUNX1 gene have been associated with chemotherapy resistance and poor prognosis in patients with acute myeloid leukemia (AML), T cell acute lymphoblastic leukemia (T-ALL) and myelodysplastic syndromes (MDS). However, the underlying mechanisms connecting RUNX1 to the success of therapy remain elusive. Here we explore the hypothesis that RUNX1 is directly involved in the response of hematopoietic cells to cytotoxic agents. RUNX1 was upregulated post-transcriptionally by cytotoxic agents in C57BL/6 mice in vivo and hematopoietic cell lines. Upregulation was also seen in primary human AML cells after treatment with cytarabine in vitro. Upon overexpression, RUNX1 restricted proliferation, promoted apoptosis, and augmented the DNA damage response. This unknown activity of RUNX1 required an intact runt homology domain (RHD), a domain where most leukemia-associated point mutations cluster. Consistent with this, two RHD-defective RUNX1 proteins lacked any anti-proliferative or apoptotic activity, and RHD-defective (K83N, N109D) mutant RUNX1 conferred resistance to ionizing radiation when overexpressed in Ba/F3 cells under certain conditions. Our experiments reveal a novel function of RUNX1 and offer an explanation for the link between RUNX1 mutations and chemotherapy and radiation resistance. Moreover, these data suggest that pharmacological modulation of RUNX1 might be an attractive new approach to treat hematological malignancies.

from Cancer via ola Kala on Inoreader http://ift.tt/2xcYhg0
via IFTTT

New generation nanomedicines constructed from self-assembling small molecule prodrugs alleviate cancer drug toxicity

The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel (CTX) as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these CTX derivatives, docosahexaenoic acid-derived compound 1 retained high anti-proliferative activity. SNM assembled with compound 1 displayed an unexpected enhancement of tolerability in animals along with effective therapeutic efficacy in a mouse xenograft model of human cancer, compared to free drug administered in its clinical formulation. Overall, our studies showed how attaching flexible lipid chains to a hydrophobic and highly toxic anticancer drug can convert it to a systemic self-deliverable nanotherapy, preserving its pharmacological efficacy while improving its safety profile.

from Cancer via ola Kala on Inoreader http://ift.tt/2zErVN8
via IFTTT

SGK1 is a critical component of an AKT-independent pathway essential for PI3K-mediated tumor development and maintenance

Activation of the PI3K-AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, while necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, co-targeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade.

from Cancer via ola Kala on Inoreader http://ift.tt/2xcCAwU
via IFTTT

A synthetic CD8{alpha}:MyD88 co-receptor enhances CD8+ T cell responses to weakly immunogenic and lowly expressed tumor antigens

T cell-based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T cell efficacy, including suboptimal T cell receptor (TCR) activation and an immunosuppressive tumor environment. Here we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8+ T cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α:MyD88-engineered T cells exhibited increased proliferation and expression of effector and co-stimulatory molecules in a tumor antigen-dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor (TLR) signaling-related proteins. CD8α:MyD88-expressing T cells improved anti-tumor responses in mice. Enhanced anti-tumor activity was associated with a unique tumor cytokine/chemokine signature, improved T cell infiltration, reduced markers of T cell exhaustion, elevated levels of proteins associated with antigen presentation, and fewer macrophages with an immunosuppressive phenotype in tumors. Given these observations, CD8α:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T cell responses to tumor antigens.

from Cancer via ola Kala on Inoreader http://ift.tt/2zESj9x
via IFTTT

Protein acyltransferase DHHC3 regulates breast tumor growth, oxidative stress and senescence

DHHC-type protein acyltransferases may regulate the localization, stability and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. ZDHHC3-ablated tumors also showed enhanced recruitment of innate immune cells (anti-tumor macrophages, natural killer cells) associated with clearance of senescent tumors. These anti-tumor effects were reversed upon reconstitution with wildtype, but not enzyme-active site-deficient DHHC3. Concomitant ablation of the upregulated oxidative stress protein TXNIP substantially negated the effects of ZDHHC3 depletion on oxidative stress and senescence. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely played a key role in TXNIP upregulation. In conclusion, DHHC3-mediated protein palmitoylation supports breast tumor growth by modulating cellular oxidative stress and senescence.

from Cancer via ola Kala on Inoreader http://ift.tt/2xbm1RK
via IFTTT

Small molecule inhibition of PD-1 transcription is an effective alternative to antibody blockade in cancer therapy

The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase GSK-3α/β, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small molecule inhibitors of GSK-3α/β (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PDL-1 blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Further, the conditional genetic deletion of GSK-3α/β reduced PD-1 expression on CD8+ T cells, and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor infiltrating lymphocytes (TILs), while increasing Tbx21 (T-bet) transcription, and the expression of CD107a+ (LAMP1) and granzyme B (GZMB) on CD8+ T-cells. Lastly, the adoptive transfer of T-cells treated ex vivo with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti-PD-1 pre-treatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies.

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BTSA1 Activates BAX to Promote Apoptosis in Acute Myeloid Leukemia [Research Watch]

The small-molecule BAX activator BTSA1 promotes apoptosis of AML cells in vitro and in vivo.



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Study Identifies Subtypes of Pediatric High-Grade Gliomas [News in Brief]

Molecular analysis finds that patient groups differ by driver mutation, age, tumor location, and other criteria.



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Nivolumab Induces Tumor Evolution in Patients with Melanoma [Research Watch]

Nivolumab treatment results in immunoediting and loss of tumor cells expressing neoantigens.



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SEMA3C Depletion Promotes Neuroblastoma Metastatic Dissemination [Research Watch]

A neuroblastoma chick embryo xenograft model recapitulates tumor initiation and dissemination.



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Breast Cancer Cells Recycle Ammonia to Generate Amino Acids [Research Watch]

Ammonia generated from glutamate metabolism enhances the proliferation of breast cancer cells.



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Suppression of adaptive responses to targeted cancer therapy by transcriptional repression [Research Briefs]

Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, remodeling of enhancers and key signalling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.



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HIF-1α Promotes Breast Cancer Cell MCF-7 Proliferation and Invasion Through Regulating miR-210

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 297-301.


http://ift.tt/2l65MEc

PERK-Phosphorylated eIF2α Pathway Suppresses Tumor Metastasis Through Downregulating Expression of Programmed Death Ligand 1 and CXCL5 in Triple-Negative Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 282-287.


http://ift.tt/2xWBeur

An Overview of Unfolded Protein Response Signaling and Its Role in Cancer

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 275-281.


http://ift.tt/2l4lIGT

Imaging of Integrin αvβ3 Expression in Lung Cancers and Brain Tumors Using Single-Photon Emission Computed Tomography with a Novel Radiotracer 99mTc-IDA-D-[c(RGDfK)]2

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 288-296.


http://ift.tt/2xVIGGa

Low Concentration of 5-Fluorouracil Increases the Effectiveness of Tumor RNA to Activate Murine Dendritic Cells

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 302-308.


http://ift.tt/2gVdiNF

Surveying the Literature: Synopsis of Recent Key Publications

No abstract available

http://ift.tt/2gyd4yQ

Effect of Stellate Ganglion Block on the Regional Hemodynamics of the Upper Extremity: A Randomized Controlled Trial

BACKGROUND: BACKGROUND:The success of stellate ganglion block (SGB) is traditionally determined on the basis of findings such as Horner's syndrome, temperature rise in the face, hyperemia of the tympanic membrane, and nasal congestion. However, decreases in vascular resistance and increases in blood flow in the arm may be more meaningful findings. To date, the effect of SGB on the regional hemodynamics of the arm has not been evaluated using pulsed-wave Doppler ultrasound. METHODS: METHODS:A total of 52 patients who were to undergo orthopedic surgery of the forearm were randomly assigned to either the mepivacaine group (SGB with 5 mL of 0.5% mepivacaine) or the saline group (SGB with 5 mL of normal saline). Before surgery, a single anesthesiologist performed a SGB under ultrasound guidance. The temperature of the upper extremity and the resistance index and blood flow in the brachial artery were measured before SGB, 15 and 30 minutes after SGB, and 1 hour after surgery. The severity of pain, requirement for rescue analgesics, and side effects of the local anesthetic agent were all documented. RESULTS: RESULTS:After SGB, the resistance index decreased significantly and the blood flow increased significantly in the brachial artery of members of the mepivacaine group (15 minutes: P = .004 and P

http://ift.tt/2ywupPZ

Postoperative Outcomes in Obstructive Sleep Apnea Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis of Comparative Studies

BACKGROUND: BACKGROUND:Obstructive sleep apnea (OSA) is a common comorbidity in patients undergoing cardiac surgery and may predispose patients to postoperative complications. The purpose of this meta-analysis is to determine the evidence of postoperative complications associated with OSA patients undergoing cardiac surgery. METHODS: METHODS:A literature search of Cochrane Database of Systematic Reviews, Medline, Medline In-process, Web of Science, Scopus, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL until October 2016 was performed. The search was constrained to studies in adult cardiac surgical patients with diagnosed or suspected OSA. All included studies must report at least 1 postoperative complication. The primary outcome is major adverse cardiac or cerebrovascular events (MACCEs) up to 30 days after surgery, which includes death from all-cause mortality, myocardial infarction, myocardial injury, nonfatal cardiac arrest, revascularization process, pulmonary embolism, deep venous thrombosis, newly documented postoperative atrial fibrillation (POAF), stroke, and congestive heart failure. Secondary outcome is newly documented POAF. The other exploratory outcomes include the following: (1) postoperative tracheal intubation and mechanical ventilation; (2) infection and/or sepsis; (3) unplanned intensive care unit (ICU) admission; and (4) duration of stay in hospital and ICU. Meta-analysis and meta-regression were conducted using Cochrane Review Manager 5.3 (Cochrane, London, UK) and OpenBUGS v3.0, respectively. RESULTS: RESULTS:Eleven comparative studies were included (n = 1801 patients; OSA versus non-OSA: 688 vs 1113, respectively). MACCEs were 33.3% higher odds in OSA versus non-OSA patients (OSA versus non-OSA: 31% vs 10.6%; odds ratio [OR], 2.4; 95% confidence interval [CI], 1.38–4.2; P = .002). The odds of newly documented POAF (OSA versus non-OSA: 31% vs 21%; OR, 1.94; 95% CI, 1.13–3.33; P = .02) was higher in OSA compared to non-OSA. Even though the postoperative tracheal intubation and mechanical ventilation (OSA versus non-OSA: 13% vs 5.4%; OR, 2.67; 95% CI, 1.03–6.89; P = .04) were significantly higher in OSA patients, the length of ICU stay and hospital stay were not significantly prolonged in patients with OSA compared to non-OSA. The majority of OSA patients were not treated with continuous positive airway pressure therapy. Meta-regression and sensitivity analysis of the subgroups did not impact the OR of postoperative complications for OSA versus non-OSA groups. CONCLUSIONS: CONCLUSIONS:Our meta-analysis demonstrates that after cardiac surgery, MACCEs and newly documented POAF were 33.3% and 18.1% higher odds in OSA versus non-OSA patients, respectively. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Accepted for publication August 16, 2017. Funding: The STOP-Bang tool is proprietary to University Health Network. This study is supported by University Health Network Foundation, and Department of Anesthesiology, University Health Network, University of Toronto. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Frances Chung, MD, FRCPC, Department of Anesthesiology and Pain Medicine, Toronto Western Hospital, University Health Network, 399 Bathurst St, Toronto, Ontario, M5T 2S8, Canada. Address e-mail to frances.chung@uhn.ca. © 2017 International Anesthesia Research Society

http://ift.tt/2yxYcrs

Physiology and Role of Intraocular Pressure in Contemporary Anesthesia

More than 26 million Americans suffer with cataracts, and with 3.6 million cataract extractions performed annually in the United States, it is the most common surgical procedure. The integrity of the delicate structures of the eye that mediate vision is dependent on the intraocular pressure (IOP). Yet, IOP acts to compress the vessels within the globe—akin to a Starling resistor—and is a key component that determines the ocular perfusion pressure, defined as the difference between arterial pressure and IOP. The retina is one of the most metabolically active tissues in the body, and its functional integrity is dependent on an adequate blood supply, with retinal function linearly related to the ocular perfusion pressure. Retinal cell death has been demonstrated at low perfusion pressures (below 50 mm Hg). Modern ophthalmic surgery involves globe irrigation, manipulation, and instrumentation, resulting in dynamic pressure fluxes within the eye. Marked elevations of IOP (up to 4–5 times the normal value) with consequent borderline retinal and optic disk perfusion pressures occur for prolonged periods during many ophthalmic procedures. General surgeries, including laparoscopic, spinal, and cardiac procedures, especially, with their demand for steep Trendelenburg or prolonged prone positioning and/or hypotensive anesthesia, can induce IOP changes and ocular perfusion imbalance. These rapid fluctuations in IOP, and so in perfusion, play a role in the pathogenesis of the visual field defects and associated ocular morbidity that frequently complicate otherwise uneventful surgeries. The exact etiology of such outcomes is multifactorial, but ocular hypoperfusion plays a significant and frequently avoidable role. Those with preexisting compromised ocular blood flow are especially vulnerable to intraoperative ischemia, including those with hypertension, diabetes, atherosclerosis, or glaucoma. However, overly aggressive management of arterial pressure and IOP may not be possible given a patient's comorbidity status, and it potentially exposes the patient to risk of catastrophic choroidal hemorrhage. Anesthetic management significantly influences the pressure changes in the eye throughout the perioperative period. Strategies to safeguard retinal perfusion, reduce the ischemic risk, and minimize the potential for expulsive bleeding must be central to the anesthetic techniques selected. This review outlines: important physiological principles; ophthalmic and general procedures most likely to develop damaging IOP levels and their causative factors; the effect of anesthetic agents and techniques on IOP; recent scientific evidence highlighting the significance of perfusion changes during surgery; and key aspects of postoperative visual loss and management approaches for high-risk patients presenting for surgery. Accepted for publication September 6, 2017. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Dermot J. Kelly, MRCPI, FFARCSI, DABA, Department of Anesthesia, Royal Victoria Eye and Ear Hospital, Adelaide Rd, Dublin 2, Ireland. Address e-mail to drdermotkelly@gmail.com. © 2017 International Anesthesia Research Society

http://ift.tt/2gwa85W

Insight Into Our Technology: Anesthesia Information Management Systems

Anesthesia information management systems (AIMS) have evolved from simple, automated intraoperative record keepers in a select few institutions to widely adopted, sophisticated hardware and software solutions that are integrated into a hospital's electronic health record system and used to manage and document a patient's entire perioperative experience. AIMS implementations have resulted in numerous billing, research, and clinical benefits, yet there remain challenges and areas of potential improvement to AIMS utilization. This article provides an overview of the history of AIMS, the components and features of AIMS, and the benefits and challenges associated with implementing and using AIMS. As AIMS continue to proliferate and data are increasingly shared across multi-institutional collaborations, visual analytics and advanced analytics techniques such as machine learning may be applied to AIMS data to reap even more benefits. Accepted for publication September 8, 2017. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Allan F. Simpao, MD, MBI, Department of Anesthesiology and Critical Care, Division of General Anesthesia, Perelman School of Medicine at the University of Pennsylvania and The Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104. Address e-mail to simpaoa@email.chop.edu. © 2017 International Anesthesia Research Society

http://ift.tt/2yxkCZY