Accelerating Therapeutic Development through Innovative Trial Design in Colorectal Cancer

Opinion statement

Current trial design is challenged by the advancement of technologies that have enabled deeper understanding of the molecular drivers of colorectal cancer (CRC). The speed of trial testing and the ability to test larger volumes of promising novel agents in the face of smaller populations identified by molecular profiling are challenges posed to clinical studies. Master protocols that utilize umbrella designs are equipped to deal with potential biomarker and matched treatments simultaneously. Although complex in nature, they increase trial efficiency by utilizing shared screening platforms, test multiple treatments together, and simplify regulatory submission and reporting under a common protocol. Emerging technologies such as circulating tumor DNA (ctDNA) may help speed up adjuvant trials. These studies have been traditionally slow to complete due to low event rates and the high numbers needed to recruit. ctDNA used as a surrogate for minimal residual disease (MRD) and as an early marker of relapse may help counter some of these factors that deter innovation in this setting. Finally, in the era of precision medicine, surgery should not be forgotten as the only potentially curative option to date in metastatic disease. Five-year overall survival following resection of liver metastasis exceeds what can be achieved with chemotherapy alone in selected cases. Surgical advances have lowered morbidity and allow for greater resection volumes and repeated interventions. Although historically challenging, a well-designed randomized surgical intervention trial would greatly facilitate moving single-institution guidelines reported by case series into wider clinical practice.

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Accelerating Therapeutic Development through Innovative Trial Design in Colorectal Cancer

Opinion statement

Current trial design is challenged by the advancement of technologies that have enabled deeper understanding of the molecular drivers of colorectal cancer (CRC). The speed of trial testing and the ability to test larger volumes of promising novel agents in the face of smaller populations identified by molecular profiling are challenges posed to clinical studies. Master protocols that utilize umbrella designs are equipped to deal with potential biomarker and matched treatments simultaneously. Although complex in nature, they increase trial efficiency by utilizing shared screening platforms, test multiple treatments together, and simplify regulatory submission and reporting under a common protocol. Emerging technologies such as circulating tumor DNA (ctDNA) may help speed up adjuvant trials. These studies have been traditionally slow to complete due to low event rates and the high numbers needed to recruit. ctDNA used as a surrogate for minimal residual disease (MRD) and as an early marker of relapse may help counter some of these factors that deter innovation in this setting. Finally, in the era of precision medicine, surgery should not be forgotten as the only potentially curative option to date in metastatic disease. Five-year overall survival following resection of liver metastasis exceeds what can be achieved with chemotherapy alone in selected cases. Surgical advances have lowered morbidity and allow for greater resection volumes and repeated interventions. Although historically challenging, a well-designed randomized surgical intervention trial would greatly facilitate moving single-institution guidelines reported by case series into wider clinical practice.

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Value-Based Care in Hematopoietic Cell Transplantation and Cellular Therapy: Challenges and Opportunities

Abstract

Purpose of Review

Improved tolerability and outcomes after hematopoietic cell transplantation (HCT), along with the availability of alternative donors, have expanded its use. With this growth, and the development of additional cellular therapies, we also aim to increase effectiveness, efficiency, and the quality of the care provided. Fundamentally, the goal of value-based care is to have better health outcomes with streamlined processes, improved patient experience, and lower costs for both the patients and the health care system. HCT and cellular therapy treatments are multiphase treatments which allow for interventions at each juncture.

Recent Findings

We present a summary of the current literature with focus on program structure and overall system capacity, coordination of therapy across providers, standardization across institutions, diversity and disparities in care, patient quality of life, and cost implications.

Summary

Each of these topics provides challenges and opportunities to improve value-based care for HCT and cellular therapy patients.

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via IFTTT

Value-Based Care in Hematopoietic Cell Transplantation and Cellular Therapy: Challenges and Opportunities

Abstract

Purpose of Review

Improved tolerability and outcomes after hematopoietic cell transplantation (HCT), along with the availability of alternative donors, have expanded its use. With this growth, and the development of additional cellular therapies, we also aim to increase effectiveness, efficiency, and the quality of the care provided. Fundamentally, the goal of value-based care is to have better health outcomes with streamlined processes, improved patient experience, and lower costs for both the patients and the health care system. HCT and cellular therapy treatments are multiphase treatments which allow for interventions at each juncture.

Recent Findings

We present a summary of the current literature with focus on program structure and overall system capacity, coordination of therapy across providers, standardization across institutions, diversity and disparities in care, patient quality of life, and cost implications.

Summary

Each of these topics provides challenges and opportunities to improve value-based care for HCT and cellular therapy patients.

http://ift.tt/2EXP8fo

Ablation approach for primary liver tumors: Peri-operative outcomes

Background and Objectives

Ablation is a common treatment modality for malignant primary liver tumors(PLTs), outcomes following laparoscopic (LA) versus open ablation (OA) are ill-defined. This project compares peri-procedural outcomes of LA versus OA for PLTs.

Materials and Methods

Patients with PLTs undergoing radiofrequency ablation were queried from ACS NSQIP Database (2005-2013) using CPT codes. Patients undergoing percutaneous ablation or hepatic resection were excluded. Multivariable logistic regression analyses determined the association of ablation approach with 30-day morbidity and mortality.

Results

Of 5747 with PLTs, 655 (11.4%) ablations were identified: 177 (27.0%) underwent OA, 478 (73.0%) underwent LA. Patients undergoing LA had lower mortality (1.9% vs 5.1%, P = 0.026), lower minor morbidity (2.3% vs 5.7%, P = 0.031), and lower major morbidity (4.2% vs 17.0%, P < 0.001). Adjusting for demographics, disease-specific variables (preoperative ascites, total bilirubin, platelet count, albumin, and INR), 30-day mortality (OR 3.85, 95%CI: 1.38-10.80, P = 0.010), minor morbidity (OR 2.98, 95%CI: 1.16-7.67, P = 0.024), and major morbidity (OR 4.59 95%CI: 2.41-8.76, P < 0.001) were statistically lower in LA. OA demonstrated increased length of stay(LOS) (5 vs 2 days, P < 0.001), and longer operative time (152 vs 112 min, P < 0.001).

Conclusion

LA offers decreased peri-procedural morbidity, mortality, and reduced LOS. LA should be the preferred method for hepatic ablation.

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Number of nodes in sentinel lymph node biopsy for breast cancer: Are surgeons still biased?

Background and Objectives

The purpose of this study was to assess the number of lymph nodes removed at SLNB, and what factors might bias a surgeon's decision to remove additional nodes.

Methods

A prospectively maintained database was reviewed. All patients that had SLNB for primary treatment of breast cancer between January 2012 and March 2016 were identified. Clinicopathologic factors were used to compare the number of LNs and rates of node positivity.

Results

One thousand six hundred and three patients were included. The average number of SLNs, non-SLNs, and total LNs was 2.53, 0.54, 3.08, respectively. Significantly more LNs were removed in age <40 versus age >40 (3.73, 3.04 P < 0.01), invasive versus DCIS (3.13, 2.73 P < 0.001), Grade III versus Grade II (3.42, 2.99 P < 0.01), T2 versus T1 (3.40, 2.96 P < 0.01), and ER- versus ER+ (3.45, 3.05 P < 0.05). SLN positivity was significantly higher (P < 0.05) in invasive versus DCIS (27%, 4%), T2 versus T1 (30%. 17%), Grade II versus Grade I (42%, 18%), and ILC versus IDC (38%, 26%).

Conclusions

There was a significant difference in the number of lymph nodes removed at SLNB in certain groups however; node positivity was not necessarily higher in these groups. Surgeons must be cognizant of potential bias when performing SLNB.

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In transit sentinel node drainage as a prognostic factor for patients with cutaneous melanoma

Background

Minor basin or in transit node drainage can be found in patients with cutaneous melanoma who undergo sentinel node biopsy. Its clinical impact is still unclear. Our objective is to evaluate clinical outcomes in patients who presented with in transit sentinel node (ITN) drainage.

Material and Methods

Retrospective analysis of patients who underwent sentinel node biopsy (SNB) in a single Brazilian institution between 2000 and 2015.

Results

Our cohort comprised 1223 SNB. There were 64 patients (5.2%) with ITN. Melanoma of the limbs (OR 10.61, P < 0.0001) and acral subtype (OR 3.49, P < 0.0001) were associated with ITN drainage. Among these 64 patients, 14 (21.9%) had a positive SNB. The ITN was positive for metastases in five patients, four in a popliteal basin and one on the trunk. Regarding completion node dissection (CND), two patients had positive non-sentinel nodes (NSN), both in major basins. In patients who developed recurrence, time to recurrence was shorter (mean time 18 vs 31.4 months, P = 0.001) and time to death was shorter (mean time 31.6 vs 40 months, P = 0.039) in those who had ITN drainage.

Conclusion

ITN drainage was associated with earlier recurrences and deaths from melanoma.

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Melanoma patterns of care in Ontario: A call for a strategic alignment of multidisciplinary care—Response to letter

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Development and prospective validation of a model estimating risk of readmission in cancer patients

Introduction

Hospital readmissions among cancer patients are common. While several models estimating readmission risk exist, models specific for cancer patients are lacking.

Methods

A logistic regression model estimating risk of unplanned 30-day readmission was developed using inpatient admission data from a 2-year period (n = 18 782) at a tertiary cancer hospital. Readmission risk estimates derived from the model were then calculated prospectively over a 10-month period (n = 8616 admissions) and compared with actual incidence of readmission.

Results

There were 2478 (13.2%) unplanned readmissions. Model factors associated with readmission included: emergency department visit within 30 days, >1 admission within 60 days, non-surgical admission, solid malignancy, gastrointestinal cancer, emergency admission, length of stay >5 days, abnormal sodium, hemoglobin, or white blood cell count. The c-statistic for the model was 0.70. During the 10-month prospective evaluation, estimates of readmission from the model were associated with higher actual readmission incidence from 20.7% for the highest risk category to 9.6% for the lowest.

Conclusions

An unplanned readmission risk model developed specifically for cancer patients performs well when validated prospectively. The specificity of the model for cancer patients, EMR incorporation, and prospective validation justify use of the model in future studies designed to reduce and prevent readmissions.

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Obesity and vitamin D status may help explain the racial and ethnic disparities in ampullary cancer survival rates

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Reply to Grant, William: Obesity and vitamin D status may help explain the racial and ethnic disparities in ampullary cancer survival rates

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Targeting Polo-like Kinase 1 by a Novel Pyrrole-imidazole Polyamide-Hoechst Conjugate Suppresses Tumor Growth in vivo

The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst conjugate, PIP3, targeted to specific DNA sequence in the Plk1 promoter. PIP3 could specifically inhibit the cell cycle regulated Plk1 expression and consequently retard tumor cell growth. Cancer cells treated with PIP3 exhibited severe mitotic defects and increased apoptosis, while normal cells were not affected by PIP3 treatment. Furthermore, subcutaneous injection of PIP3 into mice bearing human cancer xenografts induced significant tumor growth suppression with low host toxicity. Therefore, PIP3 exhibits the potential as an effective agent for targeted cancer therapy.

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p110{alpha} inhibition overcomes stromal cell-mediated ibrutinib resistance in mantle cell lymphoma

Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here we demonstrate that stromal cells protect MCL cells from ibrutinib-induced apoptosis and support MCL cell regrowth after drug removal by impairing ibrutinib-mediated down-regulation of phosphoinositide-3-kinase (PI3K)/AKT signaling. Importantly, the stromal cell-mediated ibrutinib resistance was overcome in vitro by inhibiting AKT activity using the PI3K catalytic p110α subunit specific inhibitor BYL719. This was seen both for MCL cell lines and primary MCL cells. Furthermore, inhibition of p110α activity by BYL719 potentiated the ability of ibrutinib to inhibit MCL tumor growth in vivo in a mouse xenograft model. The stromal cell-mediated ibrutinib resistance was found to be due to a direct interaction with MCL cells and involves the integrin VLA-4, since disrupting stromal cell-MCL cell interaction using a VLA-4 blocking antibody abrogated the ibrutinib resistance. This suggests that combined treatment with ibrutinib and a p110α inhibitor, alternatively by disrupting stromal cell-MCL cell interaction, may be a promising therapeutic strategy to overcome stromal cell-mediated ibrutinib resistance in MCL.

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Inhibition of the histone H3K27 demethylase UTX enhances tumor cell radiosensitivity

The processes mediating the repair of DNA double strand breaks (DSBs) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines. Irradiation of tumor cells resulted in a rapid loss of H3K27me3, which was prevented by the siRNA-mediated knockdown of the H3K27 demethylase UTX. Knockdown of UTX also enhanced the radiosensitivity of each tumor cell line. Treatment of tumor cells with the H3K27 demethylase inhibitor GSKJ4 immediately before irradiation prevented the radiation-induced decrease in H3K27me3 and enhanced radiosensitivity. As determined by neutral comet analysis and H2AX expression, this GSKJ4 treatment protocol inhibited the repair of radiation-induced DSBs. Consistent with in vitro results, treatment of mice bearing leg tumor xenografts with GSKJ4 significantly enhance radiation-induce tumor growth delay. In contrast to results generated from tumor cell lines, radiation had no effect on H3K27me3 levels in normal fibroblast cell lines and GSKJ4 did not enhance their radiosensitivity. These data suggest that H3K27me3 demethylation contributes to DSB repair in tumor cells and that UTX, the demethylase responsible, provides a target for selective tumor cell radiosensitization.

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Anti-HER2 scFv-directed extracellular vesicle-mediated mRNA-based gene delivery inhibits growth of HER2-positive human breast tumor xenografts by prodrug activation

This paper deals with specific targeting of the prodrug/enzyme regimen, CNOB/HChrR6, to treat a serious disease namely HER2+ve human breast cancer with minimal off-target toxicity. HChrR6 is an improved bacterial enzyme that converts CNOB into the cytotoxic drug MCHB. Extracellular vesicles (EVs) were used for mRNA-based HchrR6 gene delivery: EVs may cause minimal immune rejection, and mRNA may be superior to DNA for gene delivery. To confine HChrR6 generation and CNOB activation to the cancer, the EVHB chimeric protein was constructed. It contains high affinity anti-HER2 scFv antibody (ML39) and is capable of latching on to EV surface. Cells transfected with EVHB-encoding plasmid generated EVs displaying this protein ("directed EVs"). Transfection of a separate batch of cells with the new plasmid, XPort/HChrR6, generated EVs containing HChrR6 mRNA; incubation with pure EVHB enabled these to target the HER2 receptor, generating "EXO-DEPT" EVs. EXO-DEPT treatment specifically enabled HER2-overexpressing BT474 cells to convert CNOB into MCHB in actinomycin D independent manner, showing successful and specific delivery of HCHrR6 mRNA. EXO-DEPTs --but not undirected EVs-- plus CNOB caused near-complete growth-arrest of orthotopic BT474 xenografts in vivo, demonstrating for the first time EV-mediated delivery of functional exogenous mRNA to tumors. EXO-DEPTs may be generated from patient's own dendritic cells to evade immune rejection, and without plasmids and their potentially harmful genetic material, raising the prospect of clinical use of this regimen. This approach can be employed to treat any disease overexpressing a specific marker.

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Nigericin exerts anticancer effects on human colorectal cancer cells by inhibiting Wnt/{beta}-catenin signaling pathway

Nigericin, an antibiotic derived from Streptomyces hygroscopicus that works by acting as an H+, K+ and Pb2+ ionophore, has exhibited promising anticancer activity. The main purpose of this study is to investigate its inhibitory effects on Wnt/β-catenin signaling pathway in colorectal cancer (CRC) cells and clarify the underlying mechanism. We exposed two CRC lines (SW620 and KM12) to increasing concentrations of nigericin for different time periods and the 50% inhibiting concentration (IC50) values were evaluated. Our data showed that nigericin treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in CRC cells. The subsequent experiments in vitro and in vivo implied that nigericin could significantly suppress the tumor growth, migration and invasion, and induce the apoptosis of CRC cells. Our results of western blot and immunofluorescence assay showed that nigericin could suppress the Wnt/β-catenin signaling pathway in CRC cells with dose-dependent increased expressions of downstream effectors and target proteins. To further elucidate the inhibitory effects of nigericin via a β-catenin-dependent signaling mechanism, we established the stably β-catenin over-expression CRC cells. Western blot, SuperTOPflash luciferase reporter and immunoprecipitation assays all confirmed β-catenin as a critical intermediary and player in Wnt/β-catenin pathway, and nigericin exerted anti-cancer effects on CRC cells by directly targeting the β-catenin destruction complex. These results suggested that Wnt/β-catenin signaling might have an essential role in CRC progression. Nigericin targeting Wnt/β-catenin signaling might provide new insight into the molecular mechanism of nigericin towards cancer cells, and suggest possible clinical application in CRC.

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Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions

EGFR exon 20 insertions (Ex20Ins) account for 4-10% of EGFR activating mutations in non-small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to 1st and 2nd generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterised osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signalling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo. The anti-tumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC.

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The unfolded protein response: a novel therapeutic target for poor prognostic BRAF mutant colorectal cancer

BRAFV600E mutations occur in 10% of colorectal cancer (CRC) cases, are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n=31; validation set: n=26) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT CRC subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT CRC cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT CRC.

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Targeting PRPK Function Blocks Colon Cancer Metastasis

The biological functions of the p53 related protein kinase (PRPK) remain unclear. We have previously demonstrated that PRPK is phosphorylated by the T-LAK cell-originated protein kinase (TOPK) and that phosphorylated PRPK (p-PRPK) promotes colon cancer metastasis. Here, we analyzed colon adenocarcinomas from 87 patients, and found that higher expression levels of p-PRPK were associated with later stages of metastatic dissemination (stages III or IV), as compared to earlier stages (stages I and II). Indeed, levels of p-PRPK were higher in metastatic versus malignant human colon adenocarcinomas. Knocking down PRPK expression attenuated colorectal liver and lung metastasis of colon cancer cells in vivo. An in vitro kinase assay indicated that active PRPK does not phosphorylate p53 directly. We found that PRPK phosphorylates survivin, a regulator of colon cancer metastasis. PRPK phosphorylates survivin at Thr34, which is important for survivin stability. Taken together, our data strongly suggest that the PRPK signaling pathway promotes colon cancer metastasis by modulating survivin stability, and that PRPK could be a new prognostic marker for the survival of colon cancer patients. In addition, we identified an FDA approved bacteriostatic antibiotic, fusidic acid sodium salt (fusidic acid or FA) as an inhibitor of PRPK, and show that FA combined with 5-fluorouracil (5-FU) inhibited PRPK activity and colon cancer metastasis to the lung in mice. We contend that the combination of FA with 5-FU could be an alternative therapeutic strategy to traditional chemotherapy for colon cancer patients with poor prognosis.

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"A tricin derivative from Deschampsia antarctica Desv. inhibits colorectal carcinoma growth and liver metastasis through the induction of a specific immune response"

In colorectal carcinoma (CRC) patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic CRC have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina™ is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina™ in CRC models. We used human and murine CRC cell lines for investigating proliferation, apoptosis and cell cycle effects of Antartina™ therapy in vitro. Avatar and immunocompetent CRC animal models were applied for evaluating the effects of Antartina™ in vivo. Immune response against CRC model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T cell sub-population, and by tumor rechallenge experiments. Antartina™ inhibits in vitro human CRC cell proliferation; however, in vivo experiments in Avatar CRC model Antartina™ display a limited antitumor effect. In an immunocompetent CRC mice model Antartina™ potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in >30% of mice and increased animal survival. In addition, Antartina™ induced a potent specific cytotoxic T cell response against CRC, and a long-lasting antitumor immunity. Interestingly, Antartina™ increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina™ has the ability to induce antitumor immunity against CRC and can be used to develop new tools for the treatment of CRC.

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EGF Receptor and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors

Germ cell tumors (GCTs) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and non-seminoma forms of GCT exhibit distinct differentiation states, clinical behavior and response to treatment, however the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mammalian target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase (MAPK) pathways were differentially active in the two classes of GCT. Here we show that non-seminomatous germ cell tumors (NSGCTs, including embryonal carcinoma, yolk sac tumor and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Lastly, proliferation of NSGCT cells in vitro and in vivo is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways.

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MCT4 Expression is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis

Monocarboxylate transporters (MCTs) are transmembrane proteins which control the lactate metabolism and associated with poor prognosis in solid tumors including colorectal cancer (CRC). Here we aimed to investigate the biological and clinical role of MCTs in CRC and to assess the potential of therapeutic application. A total of 16 human CRC cell lines, 11 patient-derived cells from malignant ascites (PDC), and 39 matched pairs of primary CRC and normal colorectal tissues were used to assess the role of MCT in vitro and in vivo. siRNA methodology was used to determine the effect of MCT inhibition and molecular mechanism of hypoxia- and angiogenesis-related factors in addition to MCT4. The effect of MCT inhibition was confirmed in mouse xenograft models. MCT4 expression in surgical tissue was evaluated by immunohistochemistry (IHC) and used for survival analysis. Expression of MCTs was demonstrated in CRC cell lines. siRNA-mediated MCT silencing caused significant decline of cell proliferation both in vitro and in vivo. An additive effect of MCT inhibition was induced by combined treatment with chemotherapy or radiotherapy. In particular, the expression of MTC4 was markedly increased in PDCs and MCT4 inhibition significantly decreased PDC proliferation. Hypoxia inducible factor 1-α (HIF1α) was also highly expressed in PDCs, whereas HIF1α knockdown reduced MCT4 expression and of other angiogenesis-related mediators. The patients with high MCT4 expression by IHC showed shorter relapse-free survival compared with low expression. These findings suggest that MCT4 may represent a new therapeutic target for CRC with peritoneal carcinomatosis and serve as a prognostic indicator.

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Preclinical activity of abemaciclib alone or in combination with anti-mitotic and targeted therapies in breast cancer

The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+/HER2- and ER+/HER2+ subtypes. However, a subset of triple negative breast cancer (TNBC) cell lines with intact Rb-signaling were also found to be responsive. Equivalent levels of tumor growth inhibition were observed in ER+/HER2-, ER+/HER2+ as well as biomarker selected TNBC xenografts in response to abemaciclib. In addition, abemaciclib combined with hormonal blockade and/or HER2-targeted therapy induced significantly improved anti-tumor activity. CDK4/6 inhibition with abemaciclib combined with anti-mitotic agents, both in vitro and in vivo, did not antagonize the effect of either agent. Finally, we identified a set of Rb/E2F-regulated genes that consistently track with growth inhibitory response and constitute potential pharmacodynamic-biomarkers of response to abemaciclib. Taken together, these data represent a comprehensive analysis of the preclinical activity of abemaciclib, used alone or in combination, in human breast cancer models. The subtypes most likely to respond to abemaciclib-based therapies can be identified by measurement of a specific set of biomarkers associated with increased dependency on cyclinD:CDK4/6:Rb signaling. These data support the clinical development of abemaciclib as mono-therapy or as a combination partner in selected ER+/HER2-, HER2+/ER+ and TNBCs.

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Characterization of ABBV-221, a Tumor-Selective EGFR Targeting Antibody Drug Conjugate

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR highlighting the need for therapies with activity against tumors with non-amplified EGFR overexpression. Additionally, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR targeting ADC comprised of an affinity matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and anti-tumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR amplified GBM PDX model and is highly effective alone and in combination with standard of care (SOC) temozolomide in an EGFRvIII positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase 1 clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR.

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Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long term growth inhibition in estrogen receptor positive breast cancer

The cyclin dependent kinase (CDK) -retinoblastoma (RB) -E2F pathway plays a critical role in the control of cell cycle in estrogen receptor positive (ER+) breast cancer. Small molecule inhibitors of CDK4/6 have shown promise in this tumour type in combination with hormonal therapies, reflecting the particular dependence of this subtype of cancer on cyclin D1 and E2F transcription factors. mTOR inhibitors have also shown potential in clinical trials in this disease setting. Recent data has suggested cooperation between the phosphatidylinositol 3-kinase (PI3K)/mTOR pathway and CDK4/6 inhibition in preventing early adaptation and eliciting growth arrest, but the mechanisms of the interplay between these pathways have not been fully elucidated. Here we show that profound and durable inhibition of ER+ breast cancer growth is likely to require multiple hits on E2F mediated transcription. We demonstrate that inhibition of mTORC1/2 does not affect ER function directly, but does cause a decrease in cyclin D1 protein, RB phosphorylation and E2F mediated transcription. Combination of an mTORC1/2 inhibitor with a CDK4/6 inhibitor results in more profound effects on E2F dependent transcription, which translates into more durable growth arrest and a delay to the onset of resistance. Combined inhibition of mTORC1/2, CDK4/6 and ER delivers even more profound and durable regressions in breast cancer cell lines and xenografts. Furthermore, we show that CDK4/6 inhibitor resistant cell lines re-activate the CDK-RB-E2F pathway, but remain sensitive to mTORC1/2 inhibition, suggesting that mTORC1/2 inhibitors may represent an option for patients that have relapsed on CDK4/6 therapy.

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Analysis of Tissue and Circulating Tumor DNA by Next Generation Sequencing of Hepatocellular Carcinoma: Implications for Targeted Therapeutics

Hepatocellular carcinoma (HCC) has limited treatment options. Molecular analysis of its mutational landscape may enable the identification of novel therapies. However, biopsy is not routinely performed in HCC. The utility of analyzing cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is not established. We performed 32 ctDNA NGS analyses on 26 patients; 10 of these patients had tissue NGS (236 to 626 genes). ctDNA was evaluated using an assay that detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion alterations in 54 to 70 genes. The ctDNA demonstrated that 23 of 26 patients (88.5%) had ≥ 1 characterized alteration, and all these individuals had ≥ 1 potentially actionable alteration. The most frequently mutated gene was TP53 (16 of 26 patients, 61.5%). There were 47 unique characterized molecular alterations amongst 18 total gene alterations (variants of unknown significance (VUSs) excluded). ctDNA and tissue NGS frequently showed different profiles, perhaps due to length of time between tissue and blood samples (median = 370 days (range, 29 to 876 days)). Serial ctDNA evaluation in an illustrative patient treated with capecitabine demonstrated emergence of a new TP53 alteration after progression. In conclusion, ctDNA profiling is feasible in advanced HCC, and serial assessment using ctDNA NGS can reveal genomic changes with time. NGS of ctDNA provides a minimally invasive alternative for identifying potentially actionable gene alterations and potential molecular targeted therapies. Dynamic changes in molecular portfolio associated with therapeutic pressure in difficult-to-biopsy patients can be observed.

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Impact of chemical-induced mutational load increase on immune checkpoint therapy in poorly responsive murine tumors

A recurring historical finding in cancer drug development is encouraging anti-tumor effects observed in tumor-bearing mice which fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26 and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade. Exome sequencing confirmed an increase in somatic mutations by mutagen treatment, an effect mimicked in EMT-6 variants chronically exposed in vivo to cisplatin or cyclophosphamide. Certain mutagenized variants of B16F1, EMT-6/P, CT26 and MC38 (but not RENCA) were more immunogenic than their parents, yet anti-PD-L1 sensitization developed only in some EMT-6/P and B16F1 variants. Treatment response patterns corresponded with changes in immune cell infiltration and especially increases in CD8+ T cells. Chronically cisplatin-exposed EMT-6 variants were also more responsive to anti-PD-L1 therapy. Though tumor PD-L1 expression was upregulated in in vivo chemotherapy exposed variants, PD-L1 expression levels were not consistently associated with anti-PD-L1 treatment activity across mutagenized or chemotherapy-exposed variants. In summary, mutagenized and more immunogenic mouse tumors were not universally sensitized to PD-L1 blockade. Chemically mutagenized variants may be useful to evaluate the impact of immunologically 'hot' or 'cold' tumors with a high mutational load - to which certain chemotherapy agents may contribute - on immunotherapy outcomes.

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Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions

EGFR exon 20 insertions (Ex20Ins) account for 4-10% of EGFR activating mutations in non-small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to 1st and 2nd generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterised osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signalling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo. The anti-tumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC.

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Targeting Polo-like Kinase 1 by a Novel Pyrrole-imidazole Polyamide-Hoechst Conjugate Suppresses Tumor Growth in vivo

The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst conjugate, PIP3, targeted to specific DNA sequence in the Plk1 promoter. PIP3 could specifically inhibit the cell cycle regulated Plk1 expression and consequently retard tumor cell growth. Cancer cells treated with PIP3 exhibited severe mitotic defects and increased apoptosis, while normal cells were not affected by PIP3 treatment. Furthermore, subcutaneous injection of PIP3 into mice bearing human cancer xenografts induced significant tumor growth suppression with low host toxicity. Therefore, PIP3 exhibits the potential as an effective agent for targeted cancer therapy.

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p110{alpha} inhibition overcomes stromal cell-mediated ibrutinib resistance in mantle cell lymphoma

Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here we demonstrate that stromal cells protect MCL cells from ibrutinib-induced apoptosis and support MCL cell regrowth after drug removal by impairing ibrutinib-mediated down-regulation of phosphoinositide-3-kinase (PI3K)/AKT signaling. Importantly, the stromal cell-mediated ibrutinib resistance was overcome in vitro by inhibiting AKT activity using the PI3K catalytic p110α subunit specific inhibitor BYL719. This was seen both for MCL cell lines and primary MCL cells. Furthermore, inhibition of p110α activity by BYL719 potentiated the ability of ibrutinib to inhibit MCL tumor growth in vivo in a mouse xenograft model. The stromal cell-mediated ibrutinib resistance was found to be due to a direct interaction with MCL cells and involves the integrin VLA-4, since disrupting stromal cell-MCL cell interaction using a VLA-4 blocking antibody abrogated the ibrutinib resistance. This suggests that combined treatment with ibrutinib and a p110α inhibitor, alternatively by disrupting stromal cell-MCL cell interaction, may be a promising therapeutic strategy to overcome stromal cell-mediated ibrutinib resistance in MCL.

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Inhibition of the histone H3K27 demethylase UTX enhances tumor cell radiosensitivity

The processes mediating the repair of DNA double strand breaks (DSBs) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines. Irradiation of tumor cells resulted in a rapid loss of H3K27me3, which was prevented by the siRNA-mediated knockdown of the H3K27 demethylase UTX. Knockdown of UTX also enhanced the radiosensitivity of each tumor cell line. Treatment of tumor cells with the H3K27 demethylase inhibitor GSKJ4 immediately before irradiation prevented the radiation-induced decrease in H3K27me3 and enhanced radiosensitivity. As determined by neutral comet analysis and H2AX expression, this GSKJ4 treatment protocol inhibited the repair of radiation-induced DSBs. Consistent with in vitro results, treatment of mice bearing leg tumor xenografts with GSKJ4 significantly enhance radiation-induce tumor growth delay. In contrast to results generated from tumor cell lines, radiation had no effect on H3K27me3 levels in normal fibroblast cell lines and GSKJ4 did not enhance their radiosensitivity. These data suggest that H3K27me3 demethylation contributes to DSB repair in tumor cells and that UTX, the demethylase responsible, provides a target for selective tumor cell radiosensitization.

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Anti-HER2 scFv-directed extracellular vesicle-mediated mRNA-based gene delivery inhibits growth of HER2-positive human breast tumor xenografts by prodrug activation

This paper deals with specific targeting of the prodrug/enzyme regimen, CNOB/HChrR6, to treat a serious disease namely HER2+ve human breast cancer with minimal off-target toxicity. HChrR6 is an improved bacterial enzyme that converts CNOB into the cytotoxic drug MCHB. Extracellular vesicles (EVs) were used for mRNA-based HchrR6 gene delivery: EVs may cause minimal immune rejection, and mRNA may be superior to DNA for gene delivery. To confine HChrR6 generation and CNOB activation to the cancer, the EVHB chimeric protein was constructed. It contains high affinity anti-HER2 scFv antibody (ML39) and is capable of latching on to EV surface. Cells transfected with EVHB-encoding plasmid generated EVs displaying this protein ("directed EVs"). Transfection of a separate batch of cells with the new plasmid, XPort/HChrR6, generated EVs containing HChrR6 mRNA; incubation with pure EVHB enabled these to target the HER2 receptor, generating "EXO-DEPT" EVs. EXO-DEPT treatment specifically enabled HER2-overexpressing BT474 cells to convert CNOB into MCHB in actinomycin D independent manner, showing successful and specific delivery of HCHrR6 mRNA. EXO-DEPTs --but not undirected EVs-- plus CNOB caused near-complete growth-arrest of orthotopic BT474 xenografts in vivo, demonstrating for the first time EV-mediated delivery of functional exogenous mRNA to tumors. EXO-DEPTs may be generated from patient's own dendritic cells to evade immune rejection, and without plasmids and their potentially harmful genetic material, raising the prospect of clinical use of this regimen. This approach can be employed to treat any disease overexpressing a specific marker.

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Nigericin exerts anticancer effects on human colorectal cancer cells by inhibiting Wnt/{beta}-catenin signaling pathway

Nigericin, an antibiotic derived from Streptomyces hygroscopicus that works by acting as an H+, K+ and Pb2+ ionophore, has exhibited promising anticancer activity. The main purpose of this study is to investigate its inhibitory effects on Wnt/β-catenin signaling pathway in colorectal cancer (CRC) cells and clarify the underlying mechanism. We exposed two CRC lines (SW620 and KM12) to increasing concentrations of nigericin for different time periods and the 50% inhibiting concentration (IC50) values were evaluated. Our data showed that nigericin treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in CRC cells. The subsequent experiments in vitro and in vivo implied that nigericin could significantly suppress the tumor growth, migration and invasion, and induce the apoptosis of CRC cells. Our results of western blot and immunofluorescence assay showed that nigericin could suppress the Wnt/β-catenin signaling pathway in CRC cells with dose-dependent increased expressions of downstream effectors and target proteins. To further elucidate the inhibitory effects of nigericin via a β-catenin-dependent signaling mechanism, we established the stably β-catenin over-expression CRC cells. Western blot, SuperTOPflash luciferase reporter and immunoprecipitation assays all confirmed β-catenin as a critical intermediary and player in Wnt/β-catenin pathway, and nigericin exerted anti-cancer effects on CRC cells by directly targeting the β-catenin destruction complex. These results suggested that Wnt/β-catenin signaling might have an essential role in CRC progression. Nigericin targeting Wnt/β-catenin signaling might provide new insight into the molecular mechanism of nigericin towards cancer cells, and suggest possible clinical application in CRC.

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The unfolded protein response: a novel therapeutic target for poor prognostic BRAF mutant colorectal cancer

BRAFV600E mutations occur in 10% of colorectal cancer (CRC) cases, are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n=31; validation set: n=26) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT CRC subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT CRC cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT CRC.

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Targeting PRPK Function Blocks Colon Cancer Metastasis

The biological functions of the p53 related protein kinase (PRPK) remain unclear. We have previously demonstrated that PRPK is phosphorylated by the T-LAK cell-originated protein kinase (TOPK) and that phosphorylated PRPK (p-PRPK) promotes colon cancer metastasis. Here, we analyzed colon adenocarcinomas from 87 patients, and found that higher expression levels of p-PRPK were associated with later stages of metastatic dissemination (stages III or IV), as compared to earlier stages (stages I and II). Indeed, levels of p-PRPK were higher in metastatic versus malignant human colon adenocarcinomas. Knocking down PRPK expression attenuated colorectal liver and lung metastasis of colon cancer cells in vivo. An in vitro kinase assay indicated that active PRPK does not phosphorylate p53 directly. We found that PRPK phosphorylates survivin, a regulator of colon cancer metastasis. PRPK phosphorylates survivin at Thr34, which is important for survivin stability. Taken together, our data strongly suggest that the PRPK signaling pathway promotes colon cancer metastasis by modulating survivin stability, and that PRPK could be a new prognostic marker for the survival of colon cancer patients. In addition, we identified an FDA approved bacteriostatic antibiotic, fusidic acid sodium salt (fusidic acid or FA) as an inhibitor of PRPK, and show that FA combined with 5-fluorouracil (5-FU) inhibited PRPK activity and colon cancer metastasis to the lung in mice. We contend that the combination of FA with 5-FU could be an alternative therapeutic strategy to traditional chemotherapy for colon cancer patients with poor prognosis.

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"A tricin derivative from Deschampsia antarctica Desv. inhibits colorectal carcinoma growth and liver metastasis through the induction of a specific immune response"

In colorectal carcinoma (CRC) patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic CRC have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina™ is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina™ in CRC models. We used human and murine CRC cell lines for investigating proliferation, apoptosis and cell cycle effects of Antartina™ therapy in vitro. Avatar and immunocompetent CRC animal models were applied for evaluating the effects of Antartina™ in vivo. Immune response against CRC model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T cell sub-population, and by tumor rechallenge experiments. Antartina™ inhibits in vitro human CRC cell proliferation; however, in vivo experiments in Avatar CRC model Antartina™ display a limited antitumor effect. In an immunocompetent CRC mice model Antartina™ potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in >30% of mice and increased animal survival. In addition, Antartina™ induced a potent specific cytotoxic T cell response against CRC, and a long-lasting antitumor immunity. Interestingly, Antartina™ increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina™ has the ability to induce antitumor immunity against CRC and can be used to develop new tools for the treatment of CRC.

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EGF Receptor and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors

Germ cell tumors (GCTs) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and non-seminoma forms of GCT exhibit distinct differentiation states, clinical behavior and response to treatment, however the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mammalian target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase (MAPK) pathways were differentially active in the two classes of GCT. Here we show that non-seminomatous germ cell tumors (NSGCTs, including embryonal carcinoma, yolk sac tumor and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Lastly, proliferation of NSGCT cells in vitro and in vivo is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways.

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MCT4 Expression is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis

Monocarboxylate transporters (MCTs) are transmembrane proteins which control the lactate metabolism and associated with poor prognosis in solid tumors including colorectal cancer (CRC). Here we aimed to investigate the biological and clinical role of MCTs in CRC and to assess the potential of therapeutic application. A total of 16 human CRC cell lines, 11 patient-derived cells from malignant ascites (PDC), and 39 matched pairs of primary CRC and normal colorectal tissues were used to assess the role of MCT in vitro and in vivo. siRNA methodology was used to determine the effect of MCT inhibition and molecular mechanism of hypoxia- and angiogenesis-related factors in addition to MCT4. The effect of MCT inhibition was confirmed in mouse xenograft models. MCT4 expression in surgical tissue was evaluated by immunohistochemistry (IHC) and used for survival analysis. Expression of MCTs was demonstrated in CRC cell lines. siRNA-mediated MCT silencing caused significant decline of cell proliferation both in vitro and in vivo. An additive effect of MCT inhibition was induced by combined treatment with chemotherapy or radiotherapy. In particular, the expression of MTC4 was markedly increased in PDCs and MCT4 inhibition significantly decreased PDC proliferation. Hypoxia inducible factor 1-α (HIF1α) was also highly expressed in PDCs, whereas HIF1α knockdown reduced MCT4 expression and of other angiogenesis-related mediators. The patients with high MCT4 expression by IHC showed shorter relapse-free survival compared with low expression. These findings suggest that MCT4 may represent a new therapeutic target for CRC with peritoneal carcinomatosis and serve as a prognostic indicator.

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Preclinical activity of abemaciclib alone or in combination with anti-mitotic and targeted therapies in breast cancer

The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+/HER2- and ER+/HER2+ subtypes. However, a subset of triple negative breast cancer (TNBC) cell lines with intact Rb-signaling were also found to be responsive. Equivalent levels of tumor growth inhibition were observed in ER+/HER2-, ER+/HER2+ as well as biomarker selected TNBC xenografts in response to abemaciclib. In addition, abemaciclib combined with hormonal blockade and/or HER2-targeted therapy induced significantly improved anti-tumor activity. CDK4/6 inhibition with abemaciclib combined with anti-mitotic agents, both in vitro and in vivo, did not antagonize the effect of either agent. Finally, we identified a set of Rb/E2F-regulated genes that consistently track with growth inhibitory response and constitute potential pharmacodynamic-biomarkers of response to abemaciclib. Taken together, these data represent a comprehensive analysis of the preclinical activity of abemaciclib, used alone or in combination, in human breast cancer models. The subtypes most likely to respond to abemaciclib-based therapies can be identified by measurement of a specific set of biomarkers associated with increased dependency on cyclinD:CDK4/6:Rb signaling. These data support the clinical development of abemaciclib as mono-therapy or as a combination partner in selected ER+/HER2-, HER2+/ER+ and TNBCs.

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Characterization of ABBV-221, a Tumor-Selective EGFR Targeting Antibody Drug Conjugate

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR highlighting the need for therapies with activity against tumors with non-amplified EGFR overexpression. Additionally, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR targeting ADC comprised of an affinity matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and anti-tumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR amplified GBM PDX model and is highly effective alone and in combination with standard of care (SOC) temozolomide in an EGFRvIII positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase 1 clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR.

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Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long term growth inhibition in estrogen receptor positive breast cancer

The cyclin dependent kinase (CDK) -retinoblastoma (RB) -E2F pathway plays a critical role in the control of cell cycle in estrogen receptor positive (ER+) breast cancer. Small molecule inhibitors of CDK4/6 have shown promise in this tumour type in combination with hormonal therapies, reflecting the particular dependence of this subtype of cancer on cyclin D1 and E2F transcription factors. mTOR inhibitors have also shown potential in clinical trials in this disease setting. Recent data has suggested cooperation between the phosphatidylinositol 3-kinase (PI3K)/mTOR pathway and CDK4/6 inhibition in preventing early adaptation and eliciting growth arrest, but the mechanisms of the interplay between these pathways have not been fully elucidated. Here we show that profound and durable inhibition of ER+ breast cancer growth is likely to require multiple hits on E2F mediated transcription. We demonstrate that inhibition of mTORC1/2 does not affect ER function directly, but does cause a decrease in cyclin D1 protein, RB phosphorylation and E2F mediated transcription. Combination of an mTORC1/2 inhibitor with a CDK4/6 inhibitor results in more profound effects on E2F dependent transcription, which translates into more durable growth arrest and a delay to the onset of resistance. Combined inhibition of mTORC1/2, CDK4/6 and ER delivers even more profound and durable regressions in breast cancer cell lines and xenografts. Furthermore, we show that CDK4/6 inhibitor resistant cell lines re-activate the CDK-RB-E2F pathway, but remain sensitive to mTORC1/2 inhibition, suggesting that mTORC1/2 inhibitors may represent an option for patients that have relapsed on CDK4/6 therapy.

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Analysis of Tissue and Circulating Tumor DNA by Next Generation Sequencing of Hepatocellular Carcinoma: Implications for Targeted Therapeutics

Hepatocellular carcinoma (HCC) has limited treatment options. Molecular analysis of its mutational landscape may enable the identification of novel therapies. However, biopsy is not routinely performed in HCC. The utility of analyzing cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is not established. We performed 32 ctDNA NGS analyses on 26 patients; 10 of these patients had tissue NGS (236 to 626 genes). ctDNA was evaluated using an assay that detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion alterations in 54 to 70 genes. The ctDNA demonstrated that 23 of 26 patients (88.5%) had ≥ 1 characterized alteration, and all these individuals had ≥ 1 potentially actionable alteration. The most frequently mutated gene was TP53 (16 of 26 patients, 61.5%). There were 47 unique characterized molecular alterations amongst 18 total gene alterations (variants of unknown significance (VUSs) excluded). ctDNA and tissue NGS frequently showed different profiles, perhaps due to length of time between tissue and blood samples (median = 370 days (range, 29 to 876 days)). Serial ctDNA evaluation in an illustrative patient treated with capecitabine demonstrated emergence of a new TP53 alteration after progression. In conclusion, ctDNA profiling is feasible in advanced HCC, and serial assessment using ctDNA NGS can reveal genomic changes with time. NGS of ctDNA provides a minimally invasive alternative for identifying potentially actionable gene alterations and potential molecular targeted therapies. Dynamic changes in molecular portfolio associated with therapeutic pressure in difficult-to-biopsy patients can be observed.

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Impact of chemical-induced mutational load increase on immune checkpoint therapy in poorly responsive murine tumors

A recurring historical finding in cancer drug development is encouraging anti-tumor effects observed in tumor-bearing mice which fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26 and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade. Exome sequencing confirmed an increase in somatic mutations by mutagen treatment, an effect mimicked in EMT-6 variants chronically exposed in vivo to cisplatin or cyclophosphamide. Certain mutagenized variants of B16F1, EMT-6/P, CT26 and MC38 (but not RENCA) were more immunogenic than their parents, yet anti-PD-L1 sensitization developed only in some EMT-6/P and B16F1 variants. Treatment response patterns corresponded with changes in immune cell infiltration and especially increases in CD8+ T cells. Chronically cisplatin-exposed EMT-6 variants were also more responsive to anti-PD-L1 therapy. Though tumor PD-L1 expression was upregulated in in vivo chemotherapy exposed variants, PD-L1 expression levels were not consistently associated with anti-PD-L1 treatment activity across mutagenized or chemotherapy-exposed variants. In summary, mutagenized and more immunogenic mouse tumors were not universally sensitized to PD-L1 blockade. Chemically mutagenized variants may be useful to evaluate the impact of immunologically 'hot' or 'cold' tumors with a high mutational load - to which certain chemotherapy agents may contribute - on immunotherapy outcomes.

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Hyperthermic isolated limb perfusion, preoperative radiotherapy, and surgery (PRS) a new limb saving treatment strategy for locally advanced sarcomas

Background

This feasibility study presents the results of a new intensive treatment regimen for locally advanced extremity soft tissue sarcomas (ESTS), consisting of hyperthermic isolated limb perfusion (HILP), preoperative external beam radiotherapy (EBRT), and surgical resection.

Methods

From 2011 to 2016, 11 high grade locally advanced ESTS patients underwent this treatment regimen. Preoperative EBRT (12 × 3 Gy) started <4 weeks following the HILP (TNF-α and melphalan) and the surgical resection was planned to take place <2 weeks following the end of the EBRT.

Results

All patients completed the treatment. After a median follow-up of 32 (23-50) months, the limb was saved in 10 patients (91%), 1 patient (9%) developed a local recurrence, 5 patients (45%) developed distant metastases, and 3 patients (27%) died of their disease. During follow-up two patients (18%) developed a pathologic fracture of the treated limb and three patients (27%) developed a major wound complication requiring surgical intervention. The median overall treatment time (OTT) was 56 (49-69) days.

Conclusions

This intensive treatment regimen is feasible and safe in locally advanced ESTS, and it achieves oncological results that are comparable with conventional HILP treatment. In addition, the major wound complication risk is comparable and the OTT is reduced.

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Considering the cost of a simultaneous versus staged approach to resection of colorectal cancer with synchronous liver metastases in a publicly funded healthcare model

Background

Simultaneous resection for colorectal cancer with synchronous liver metastases is an established alternative to a staged approach. This study aimed to compare these approaches with regards to economic parameters and short-term outcomes.

Methods

A retrospective cohort analysis was conducted between 2005 and 2016. The primary outcome was cost per episode of care. Secondary measures included 30-day clinical outcomes. A multivariate analysis was performed to determine the adjusted effect of a simultaneous surgical approach on total cost of care.

Results

Fifty-three cases were identified; 27 in the staged approach, and 26 in the simultaneous group. Age (P = 0.49), sex (P = 0.20), BMI (P = 0.74), and ASA class (P = 0.44) were comparable between groups. Total cost ($20297 vs $27522), OR ($6830 vs $10376), PACU ($675 vs $1182), ward ($7586 vs $11603) and pharmacy costs ($728 vs $1075) were significantly less for the simultaneous group (P < 0.05). The adjusted rate ratio for total cost of care in the staged group compared to simultaneous group was 1.51 (95%CI: 1.16-1.97, P < 0.05). The groups had comparable Clavien-Dindo scores (P = 0.89), 30-day readmissions (P = 0.44), morbidity (P = 0.50) and mortality (P = 1.00).

Conclusions

Our study demonstrates that a simultaneous approach is associated with a significantly lower total cost while maintaining comparable short-term outcomes.

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Nasolabial propeller perforator flap: Anatomical study and case series

Purpose

The previous cadaveric studies of facial artery perforators have frequently reported high variability, and those results remain to be validated in the Colombian population. Thus, we aimed to describe the vascular anatomy of the lateral nasal artery cutaneous branches and their clinical applications using Colombian cadavers.

Materials and Methods

Nine hemifaces from six fresh cadavers were included in the study. Terminal branches of the facial artery and cutaneous perforators of the lateral nasal artery were dissected. The quality, number, and distribution of the perforators were assessed. In addition, we present results of seven clinical cases for nasal alar reconstruction.

Results

Cutaneous perforators were found in all hemifaces, and zone 2 was the most common location. In our clinical case series, all flaps used to reconstruct the nasal alar defects survived. There were two cases of venous congestion but no additional procedures were needed.

Conclusions

Although nasal alar reconstruction continues to be a challenging plastic surgery procedure, the nasolabial propeller perforator flap is an excellent choice for such because it allows a precise skin island design, is less bulky, has a wide arc of rotation, and facilitates one-staged reconstruction without increasing the rate of complications.

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Upregulation of lactate-inducible snail protein suppresses oncogene-mediated senescence through p16INK4a inactivation

The preferential use of aerobic glycolysis by tumor cells lead to high accumulation of lactate in tumor microenvironment. Clinical evidence has linked elevated lactate concentration with cancer outcomes. Howev...

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Wilms’ tumor 1-associating protein promotes renal cell carcinoma proliferation by regulating CDK2 mRNA stability

Wilms' tumor 1-associating protein (WTAP) plays an important role in physiological processes and the development of tumor such as cell cycle regulation. The regulation of cell cycle is mainly dependent on cycl...

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The viable circulating tumor cells with cancer stem cells feature, where is the way out?

With cancer stem cells (CSCs) became the research hotspot, emerging studies attempt to reveal the functions of these special subsets in tumorigenesis. Although various approaches have been used in CSCs researc...

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Genomic and functional fidelity of small cell lung cancer patient-derived xenografts [Research Articles]

Small cell lung cancer (SCLC) patient-derived xenografts (PDXs) can be generated from biopsies or circulating tumor cells (CTCs), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC-enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a two-year timeframe, at 89% and 38% efficiency, respectively. Whole exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and cisplatin (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.

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Allele-specific mechanisms of activation of MEK1 mutants determine their properties [Research Articles]

Mutations at multiple sites in MEK1 occur in cancer suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS-RAF dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output and often co-occur with RAS or RAF mutations. They act as amplifiers of RAF signaling. By contrast, another class of mutants delete a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors which bind to the inactivated form of MEK1. All the mutants were sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants.

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Drug Combo Bests Sunitinib in RCC [News in Brief]

Atezolizumab and bevacizumab delayed tumor growth for longer than sunitinib does.

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The combined association of modifiable risk factors with breast cancer risk in the Women's Health Initiative

Although several modifiable risk factors have been independently associated with risk of breast cancer, few studies have investigated their joint association with breast cancer risk. Using a healthy lifestyle index (HLI) score, we assessed the association of a combination of selected modifiable risk factors (diet, alcohol, physical activity, BMI and smoking) with risk of invasive breast cancer in the Women's Health Initiative (WHI). This study comprised 131,833 postmenopausal women, of whom 8168 had breast cancer, who were enrolled in the WHI Observational Study or the WHI clinical trials. Cox proportional hazards regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association of the score with the risk of developing breast cancer overall and according to specific breast cancer clinicopathological characteristics. There was a 4% reduction in the risk of breast cancer per unit increase in the HLI score. Compared to those with an HLI score in the lowest quintile level, those in the highest quintile level had 30%, 37%, and 30% lower risk for overall, ER+/PR+, and HER2+ breast cancer, respectively (HR: 0.70; 95% CI: 0.64-0.76; 0.63, 0.57-0.69; and 0.70; 0.55-0.90, respectively). We also observed inverse associations between the score and risk of breast cancer irrespective of nodal status, tumor grade, and stage of the disease. Most individual lifestyle factors were independently associated with the risk of breast cancer. Our findings support the view that promoting healthy lifestyle practices may be beneficial with respect to lowering risk of breast cancer among postmenopausal women.

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STAT5A/B BLOCKADE SENSITIZES PROSTATE CANCER TO RADIATION THROUGH INHIBITION OF RAD51 AND DNA REPAIR

Purpose: The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double strand DNA break repair in PC, and whether Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy. Experimental Design: Stat5a/b regulation of DNA repair in PC was evaluated by comet and clonogenic survival assays, followed by assays specific to Homologous Recombination (HR) DNA repair and Non-Homologous End-Joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in PC cells, xenograft tumors and patient-derived PCs ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing PC xenograft tumors. Results: Stat5a/b is critical for Rad51 expression in PC via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacological Stat5a/b inhibition potently sensitized PC cell lines and PC tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues. Conclusions: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in PC. Inhibition of Jak2-Stat5a/b signaling sensitizes PC to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues.

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Phase 1 study of LY2940680, a Smo antagonist, in patients with advanced cancer including treatment naive and previously treated basal cell carcinoma

Purpose: To determine a recommended Phase 2 dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer. Experimental Design: This was a Phase 1, multicenter, open-label study of oral LY2940680. The maximum tolerated dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment-naive and previously hedgehog (Hh) inhibitor-treated patients with basal cell carcinoma (BCC) were enrolled. Results: Eighty-four patients were treated (dose escalation, n=25; dose confirmation, n=19; and BCC dose expansion, n=40). Common treatment-emergent adverse events were dysgeusia (41 [48.8%]), fatigue (40 [47.6%]), nausea (38 [45.2%]), and muscle spasms (34 [40.5%]). Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested all doses were biologically active (inhibition median of 92.3% [80.9% to 95.7%]). All clinical responses (per RECIST 1.1) were in patients with BCC (n=47); the overall and estimated response rate was 46.8% (95% CI: 32.1-61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh-treatment-naive (11/16) patients. Conclusions:LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh-treatment-naive patients.

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STAT5A/B BLOCKADE SENSITIZES PROSTATE CANCER TO RADIATION THROUGH INHIBITION OF RAD51 AND DNA REPAIR

Purpose: The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double strand DNA break repair in PC, and whether Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy. Experimental Design: Stat5a/b regulation of DNA repair in PC was evaluated by comet and clonogenic survival assays, followed by assays specific to Homologous Recombination (HR) DNA repair and Non-Homologous End-Joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in PC cells, xenograft tumors and patient-derived PCs ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing PC xenograft tumors. Results: Stat5a/b is critical for Rad51 expression in PC via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacological Stat5a/b inhibition potently sensitized PC cell lines and PC tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues. Conclusions: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in PC. Inhibition of Jak2-Stat5a/b signaling sensitizes PC to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues.

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Phase 1 study of LY2940680, a Smo antagonist, in patients with advanced cancer including treatment naive and previously treated basal cell carcinoma

Purpose: To determine a recommended Phase 2 dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer. Experimental Design: This was a Phase 1, multicenter, open-label study of oral LY2940680. The maximum tolerated dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment-naive and previously hedgehog (Hh) inhibitor-treated patients with basal cell carcinoma (BCC) were enrolled. Results: Eighty-four patients were treated (dose escalation, n=25; dose confirmation, n=19; and BCC dose expansion, n=40). Common treatment-emergent adverse events were dysgeusia (41 [48.8%]), fatigue (40 [47.6%]), nausea (38 [45.2%]), and muscle spasms (34 [40.5%]). Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested all doses were biologically active (inhibition median of 92.3% [80.9% to 95.7%]). All clinical responses (per RECIST 1.1) were in patients with BCC (n=47); the overall and estimated response rate was 46.8% (95% CI: 32.1-61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh-treatment-naive (11/16) patients. Conclusions:LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh-treatment-naive patients.

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Patient-customized Drug Combination Prediction and Testing for T-cell Prolymphocytic Leukemia Patients

The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway crosstalk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients. DCPT used drug-target interaction networks to traverse the massive combinatorial search spaces among 218 compounds (a total of 23,653 pairwise combinations) and identified cancer-selective synergies by using differential single-compound sensitivity profiles between patient cells and healthy controls, hence reducing the likelihood of toxic combination effects. A polypharmacology-based machine learning modeling and network visualization made use of baseline genomic and molecular profiles to guide patient-specific combination testing and clinical translation phases. Using T cell prolymphocytic leukemia (T-PLL) as a first case study, we show how the DCPT platform successfully predicted distinct synergistic combinations for each of the three T-PLL patients, each presenting with different resistance patterns and synergy mechanisms. In total, 10/24 (42%) of selective combination predictions were experimentally confirmed to show synergy in patient-derived samples ex vivo. The identified selective synergies among approved drugs, including tacrolimus and temsirolimus combined with BCL-2 inhibitor venetoclax, may offer novel drug repurposing opportunities for treating T-PLL.

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hPCL3s promotes hepatocellular carcinoma metastasis by activating {beta}-catenin signaling

Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2) with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has however not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells. hPCL3s interacted with components of the cytoplasmic beta-catenin destruction complex, inhibited beta-catenin degradation, and activated beta-catenin/T-cell factor (TCF) signaling. Downstream of the beta-catenin cascade, interleukin 6 (IL-6) mediated the motility-promoting functions of hPCL3s. Forced expression of hPCL3s in the liver of a HCC mouse model promoted tumorigenesis and metastasis. Taken together, these data show that hPCL3s promotes the metastasis of HCC by activating the beta-catenin/IL-6 pathway.

http://ift.tt/2oz9ZyM

A soft microenvironment protects from failure of midbody abscission and multinucleation downstream of the EMT-promoting transcription factor Snail

Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or transforming growth factor-beta (TGFbeta), known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.

http://ift.tt/2Cloakl

IRAK1 augments cancer stemness and drug resistance via the AP-1/AKR1B10 signaling cascade in hepatocellular carcinoma

Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (T-IC) within the tumor bulk. Therefore, targeting liver T-IC may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver T-IC properties including self-renewal, tumorigenicity, and liver T-IC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver T-IC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced T-IC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.

http://ift.tt/2oz9WTC

Patient-customized Drug Combination Prediction and Testing for T-cell Prolymphocytic Leukemia Patients

The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway crosstalk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients. DCPT used drug-target interaction networks to traverse the massive combinatorial search spaces among 218 compounds (a total of 23,653 pairwise combinations) and identified cancer-selective synergies by using differential single-compound sensitivity profiles between patient cells and healthy controls, hence reducing the likelihood of toxic combination effects. A polypharmacology-based machine learning modeling and network visualization made use of baseline genomic and molecular profiles to guide patient-specific combination testing and clinical translation phases. Using T cell prolymphocytic leukemia (T-PLL) as a first case study, we show how the DCPT platform successfully predicted distinct synergistic combinations for each of the three T-PLL patients, each presenting with different resistance patterns and synergy mechanisms. In total, 10/24 (42%) of selective combination predictions were experimentally confirmed to show synergy in patient-derived samples ex vivo. The identified selective synergies among approved drugs, including tacrolimus and temsirolimus combined with BCL-2 inhibitor venetoclax, may offer novel drug repurposing opportunities for treating T-PLL.

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hPCL3s promotes hepatocellular carcinoma metastasis by activating {beta}-catenin signaling

Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2) with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has however not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells. hPCL3s interacted with components of the cytoplasmic beta-catenin destruction complex, inhibited beta-catenin degradation, and activated beta-catenin/T-cell factor (TCF) signaling. Downstream of the beta-catenin cascade, interleukin 6 (IL-6) mediated the motility-promoting functions of hPCL3s. Forced expression of hPCL3s in the liver of a HCC mouse model promoted tumorigenesis and metastasis. Taken together, these data show that hPCL3s promotes the metastasis of HCC by activating the beta-catenin/IL-6 pathway.

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A soft microenvironment protects from failure of midbody abscission and multinucleation downstream of the EMT-promoting transcription factor Snail

Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or transforming growth factor-beta (TGFbeta), known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.

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IRAK1 augments cancer stemness and drug resistance via the AP-1/AKR1B10 signaling cascade in hepatocellular carcinoma

Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (T-IC) within the tumor bulk. Therefore, targeting liver T-IC may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver T-IC properties including self-renewal, tumorigenicity, and liver T-IC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver T-IC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced T-IC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.

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A randomized phase 3 trial comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in Chemoradiotherapy for locally advanced esophageal carcinoma—the ESO-shanghai 1 trial protocol

Abstract

Background

Concurrent chemoradiotherapy is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC) patients. Cisplatin combined with 5-fluorouracil continuous infusion (PF) remains the standard concurrent chemotherapy regimen. However, radiotherapy concurrent with PF showed a high incidence of severe side effects. Paclitaxel showed a promising radiosensitivity enhancement in the treatment of esophageal carcinoma in both vitro and vivo studies. The ESO-Shanghai 1 trial examines the hypothesis that paclitaxel plus 5-fluorouracil (TF) concurrent with radiotherapy has better overall survival and lower toxicity for patients with local advanced ESCC.

Method

Four hundred thirty-six ESCC patients presenting with stage IIa to IVa will be enrolled in a prospective multicenter randomized phase 3 study. Patients will be randomized to either concurrent chemoradiotherapy with PF (cisplatin 25 mg/m²/d, d1–3, plus 5-fluorouracil 1800 mg/m², continuous infusion for 72 h) once every 4 weeks for 2 cycles followed by consolidation chemotherapy for 2 cycles or concurrent chemoradiotherapy with weekly TF (5-fluorouracil 300 mg/m², continuous infusion for 96 h plus paclitaxel 50 mg/m², d1) for 5 weeks followed by consolidation chemotherapy (5-fluorouracil 1800 mg/m², continuous infusion for 72 h, plus paclitaxel 175 mg/m² d1) once every 4 weeks for 2 cycles. The radiotherapy dose is 61.2 Gy delivered in 34 fractions to the primary tumor including lymph nodes. The primary end-point is the 3-yr overall survival analyzed by intention to treat. The secondary endpoints are disease progression-free survival, local progression-free survival, and number and grade of participants with adverse events.

Discussion

The aim of this phase 3 study is to determine whether the TF regimen could replace the standard PF regimen for inoperable ESCC patients. An overall survival benefit of 12% at 3 years should be expected in the TF group to achieve this goal.

Trial registration

ClinicalTrials.gov Identifier: NCT01591135. Registered 18 April 2012.

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