Κυριακή, 2 Απριλίου 2017

Angle PLC: Parsortix enables analysis in head and neck cancer - Yahoo Finance


Angle PLC: Parsortix enables analysis in head and neck cancer
Yahoo Finance
The University of Athens work suggest that, for the first time, it might be possible to assess gene expression of head and neck cancers using a Parsortix non-invasive liquid biopsy. Gene expression of biomarkers such as PD-L1 provides key information ...

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Minimally invasive wire-guided balloon catheter puncture for voice prosthesis insertion

Abstract

Background

Tracheoesophageal puncture is an effective and reliable method for voice restoration after total laryngectomy that may be performed as a primary or secondary procedure.

Methods

We describe our technique for secondary tracheoesophageal puncture using a wire-guided balloon catheter in an office setting. A 72-year-old patient with a total laryngectomy performed 2 years ago was selected for wire-guided balloon catheter puncture and voice prosthesis insertion.

Results

Successful tracheoesophageal puncture placement was achieved without complications and the patient tolerated the procedure well. The voice result was satisfactory and immediate.

Conclusion

We conclude that balloon catheter tracheoesophageal puncture can be a simple and safe option for secondary voice prosthesis insertion in total laryngectomy for selected patients. It can be performed in an office setting using only local anesthetic for secondary puncture.



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Sinonasal adenoid cystic carcinoma: Treatment outcomes and association with human papillomavirus

Abstract

Background

The purpose of this study was to review long-term outcomes of sinonasal adenoid cystic carcinoma (ACC) and to clarify its association with human papillomavirus (HPV).

Methods

The medical records of 23 patients with sinonasal ACC treated with primary surgical resection between 1998 and 2013 were reviewed. Tissue specimens were available for 17 patients. The p16 testing was performed using immunohistochemistry (IHC), and HPV infection was determined using quantitative polymerase chain reaction (PCR) with primers targeting the E6/E7 region.

Results

Two of the 17 samples showed strong and diffuse p16 staining, whereas the remaining 15 cases showed p16-positivity isolated to the luminal cells. Only one of the p16-positive cases was positive for HPV. The 5-year local failure, disease-free survival (DFS), and overall survival (OS) were 51%, 52%, and 62%, respectively.

Conclusion

Local failures are common with advanced sinonasal ACC, and the association of HPV with true sinonasal ACC is low.



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Reviewing the genetic alterations in high-risk cutaneous squamous cell carcinoma: A search for prognostic markers and therapeutic targets

Abstract

Cutaneous squamous cell carcinoma (SCC) is second only in incidence to basal cell carcinoma (BCC), effecting up to 500 000 people in the United States annually. Metastasis to regional lymph nodes occurs in approximately 5% of cases and imparts significant morbidity. Standard treatment in this group involves a combination of surgery and adjuvant radiation. Currently, there are no clinically useful biomarkers of metastatic potential in primary cutaneous SCC and histological predictors can be unreliable. The high level of mutational burden in normal UV-exposed skin has hampered the search for novel drivers of invasive disease, and indeed metastatic potential. This review outlines the clinical problems in high-risk and metastatic cutaneous SCCs, reviews the known genetic events and molecular mechanisms in high-risk primary cutaneous SCC and metastasis, and identifies avenues for further investigation and potential therapy.



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Effectiveness of incorporating cetuximab into docetaxel/cisplatin/fluorouracil induction chemotherapy and chemoradiotherapy for inoperable squamous cell carcinoma of the oral cavity: A phase II study

Abstract

Background

Inoperable oral cavity squamous cell carcinoma (SCC) is a highly invasive disease associated with the extensive destruction of locoregional tissues and a dismal prognosis. Management strategies for these patients are limited.

Methods

This study was a single arm, prospective, open-label phase II trial. A regimen consisting of cetuximab-docetaxel, cisplatin, and fluorouracil (C-TPF) followed by bio-chemoradiotherapy (bio-CRT) with cisplatin and cetuximab was administered to patients who responded to induction chemotherapy. The objective response rate to C-TPF was the primary endpoint.

Results

Forty-three patients were enrolled in this study. The objective response rate of C-TPF was 88.4%; 88.9% (32/36) of the responders completed the full bio-CRT course, and the objective response rate of bio-CRT was 64.7%. The most common grade 3/4 adverse events for induction chemotherapy were leucopenia (32.6%) and febrile neutropenia (14.0%). The 1-year progression-free survival (PFS) and overall survival (OS) rates were 43% and 68%, respectively.

Conclusion

C-TPF is an effective and tolerable induction chemotherapy regimen for inoperable oral cavity SCC.



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Ultra–low-dose radiotherapy for definitive management of ocular adnexal B-cell lymphoma

ABSTRACT

Background

The purpose of this study was to report the response to and toxicity of ultra–low-dose radiotherapy (RT) for B-cell ocular adnexal lymphoma (OAL).

Methods

We conducted a retrospective review of patients with indolent B-cell and mantle cell OAL treated with 4 Gy to the orbit(s) in two 2-Gy fractions. Disease response was assessed clinically and/or radiographically at 2 to 4-month intervals after RT. Data collected included rates of overall response, complete response (CR), partial response (PR), and treatment-related toxic effects.

Results

Twenty-two patients (median age, 65 years) had the following histologic subtypes: mucosa-associated lymphoid tissue (MALT; 14 patients; 64%); follicular lymphoma (5 patients; 23%); mantle cell lymphoma (MCL; 2 patients; 9%); and unclassifiable (1 patient, 4%). The overall response rate was 100%; 19 patients (86%) had a CR and 3 patients (14%) had a PR. The only acute toxic effect was grade 1 dry eye syndrome in 1 patient.

Conclusion

Ultra–low-dose RT in patients with OAL is associated with high response rates and minimal toxic effects, and is much shorter in duration and cost. © 2017 Wiley Periodicals, Inc. Head Neck, 2017



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Systematic review of mammary analog secretory carcinoma of salivary glands at 7 years after description

ABSTRACT

Background

Mammary analog secretory carcinoma of the salivary glands (MASCSG) is a newly introduced malignant tumor of the salivary glands. For decades, it has been confused with acinic cell carcinoma (ACC) of the salivary glands.

Methods

All reported cases of MASCSG were surveyed from 2010 until January 2017. The collected data was compiled and computationally processed to describe the clinical parameters of MASCSG. Its epidemiology was also mapped. Moreover, inaccurate data was highlighted.

Results

Clinically implicating, this article tackles simply the several clinical findings of MASCSG so that our contemporary nosology, at 7 years after description, can be updated. The cytogenetic, histologic, and immunohistochemical details are also defined.

Conclusion

The available data about MASCSG is sufficient enough to diagnose it with no need to investigate the ETV6-NTRK3 translocation. Although high-grade malignancy and distant metastases were rarely reported, a rapt attention should be paid both to the nature of this tumor and to the indicated close follow-up of such cases, especially when necrosis, increased mitotic activity, and other classic caveats are conspicuous. © 2017 Wiley Periodicals, Inc. Head Neck, 2017



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Management of unilateral recurrent laryngeal nerve injury after thyroid surgery: A review

Abstract

Background

Recurrent laryngeal nerve (RLN) damage because of thyroid and parathyroid surgery has been recognized for over a century. Injury rates have been slowly decreasing in this period while effective treatment strategies have been increasing.

Methods

Recent literature was evaluated on the topics of anatomy, pathophysiology, avoidance, and conservative and surgical treatment of RLN injury. Data for this literature review were identified by PubMed and references from relevant articles using the search terms “thyroid,” “laryngeal nerve,” and “injury.” Only articles published in English between 1990 and 2015 were included.

Results

Advances in technique and equipment have made injury less likely. The evidence and role for neuromonitoring is discussed. Treatment strategies may include speech therapy, vocal cord augmentation using injection, laryngeal framework surgery techniques (including laryngoplasty and arytenoid adduction), and reinnervation.

Conclusion

Injury rates in specialist centers are very low. Good to excellent results may be obtained in most cases.



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Why doctors say kids need HPV vaccinations - The Denver Post


The Denver Post

Why doctors say kids need HPV vaccinations
The Denver Post
The number of people diagnosed with HPV-related oropharyngeal cancer, tumors found in the middle of the pharynx or throat including the back of the tongue, soft palate, sides of throat and tonsils – is relatively small – about 12,638 men and 3,100 ...
Ask the Expert: What are the most common causes of oral cancer?The Daily Progress

all 7 news articles »


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NYU Langone Medical Center / New York University School of Medicine - EurekAlert (press release)


NYU Langone Medical Center / New York University School of Medicine
EurekAlert (press release)
Genetic testing of tumor and blood fluid samples from people with and without one of the most aggressive forms of skin cancer has shown that two new blood tests can reliably detect previously unidentifiable forms of the disease. Researchers at NYU ...



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HPV virus leads to increase in oral, throat cancers - The Lawton Constitution


The Lawton Constitution

HPV virus leads to increase in oral, throat cancers
The Lawton Constitution
"Right now it's about 3 percent of the cancers in the world, but it's rising rapidly," Kerley said. "In the U.S. it's about twice the population of Duncan each year. That's about 45,000 people get oral or oropharynx or nasal pharynx or hypopharynx or ...

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Angle PLC: Parsortix enables analysis in head and neck cancer - Benzinga


Angle PLC: Parsortix enables analysis in head and neck cancer
Benzinga
The University of Athens work suggest that, for the first time, it might be possible to assess gene expression of head and neck cancers using a Parsortix non-invasive liquid biopsy. Gene expression of biomarkers such as PD-L1 provides key information ...



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Treatment outcomes of tuberculosis patients in nigist Eleni Mohammed general hospital, hosanna, southern nations, nationalities and peoples region, Ethiopia: a five year (June 2009 to August 2014) retrospective study

Tuberculosis remains to be a major public health problem among under developed world due to delay in detection and treatment of patients with active TB. In Ethiopia, tuberculosis has been recognized as a major...

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MLB PREVIEW - Toronto Sun


Toronto Sun

MLB PREVIEW
Toronto Sun
It's been a hot-button issue since Hall of Famer Tony Gwynn died from salivary gland cancer in 2014 and his family subsequently filed a lawsuit against tobacco companies. 5—The Dodgers are rich. The Los Angeles Dodgers certainly have no problem ...

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Injections with structured diabetes education are as good as pumps, trial shows

Adults with type 1 diabetes who use multiple daily injections of insulin achieved similar reductions in HbA1c and severe hypoglycaemia as those using insulin pumps when both groups were given...
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Insomnia may raise risk of MI and stroke, review finds

Insomnia is associated with increased risk of future myocardial infarction (MI) and stroke, a meta-analysis of prospective cohort studies has found.1Insomnia—characterised by difficulty initiating or...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=ntrEWRi3aqA:UIMVYInEnhI:V_sGLiP recent?d=qj6IDK7rITs recent?i=ntrEWRi3aqA:UIMVYInEnhI:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=ntrEWRi3aqA:UIMVYInEnhI:F7zBnMy recent?i=ntrEWRi3aqA:UIMVYInEnhI:-BTjWOF


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Insulin-Mediated Signaling Facilitates Resistance to PDGFR Inhibition in Proneural hPDGFB-Driven Gliomas

Despite abundant evidence implicating receptor tyrosine kinases (RTK), including the platelet-derived growth factor receptor (PDGFR), in the pathogenesis of glioblastoma (GBM), the clinical use of RTK inhibitors in this disease has been greatly compromised by the rapid emergence of therapeutic resistance. To study the resistance of proneural gliomas that are driven by a PDGFR-regulated pathway to targeted tyrosine kinase inhibitors, we utilized a mouse model of proneural glioma in which mice develop tumors that become resistant to PDGFR inhibition. We found that tumors resistant to PDGFR inhibition required the expression and activation of the insulin receptor (IR)/insulin growth-like factor receptor (IGF1R) for tumor cell proliferation and survival. Cotargeting IR/IGF1R and PDGFR decreased the emergence of resistant clones in vitro. Our findings characterize a novel model of glioma recurrence that implicates the IR/IGF1R signaling axis in mediating the development of resistance to PDGFR inhibition and provide evidence that IR/IGF1R signaling is important in the recurrence of the proneural subtype of glioma in which PDGF/PDGFR is most commonly expressed at a high level. Mol Cancer Ther; 16(4); 705–16. ©2017 AACR.



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Preclinical Evaluation of Sequential Combination of Oncolytic Adenovirus Delta-24-RGD and Phosphatidylserine-Targeting Antibody in Pancreatic Ductal Adenocarcinoma

Delta-24-RGD (DNX-2401) is a conditional replication-competent oncolytic virus engineered to preferentially replicate in and lyse tumor cells with abnormality of p16/RB/E2F pathway. In a phase I clinical trial, Delta-24-RGD has shown favorable safety profile and promising clinical efficacy in brain tumor, which prompted us to evaluate its anticancer activity in pancreatic ductal adenocarcinoma (PDAC), which also has high frequency of homozygous deletion and promoter methylation of CDKN2A encoding the p16 protein. Our results demonstrate that Delta-24-RGD can induce dramatic cytotoxicity in a subset of PDAC cell lines with high cyclin D1 expression. Induction of autophagy and apoptosis by Delta-24-RGD in sensitive PDAC cells was confirmed with LC3B-GFP autophagy reporter and acridine orange staining as well as Western blotting analysis of LC3B-II expression. Notably, we found that Delta-24-RGD induced phosphatidylserine exposure in infected cells independent of cells' sensitivity to Delta-24-RGD, which renders a rationale for combination of Delta-24-RGD viral therapy and phosphatidylserine targeting antibody for PDAC. In a mouse PDAC model derived from a liver metastatic pancreatic cancer cell line, Delta-24-RGD significantly inhibited tumor growth compared with control (P < 0.001), and combination of phosphatidylserine targeting antibody 1N11 further enhanced its anticancer activity (P < 0.01) possibly through inducing synergistic anticancer immune responses. Given that these 2 agents are currently in clinical evaluation, our study warrants further clinical evaluation of this novel combination strategy in pancreatic cancer therapy. Mol Cancer Ther; 16(4); 662–70. ©2016 AACR.



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MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

MET or hepatocyte growth factor (HGF) receptor pathway signaling mediates wound healing and hepatic regeneration, with pivotal roles in embryonic, neuronal, and muscle development. However, dysregulation of MET signaling mediates proliferation, apoptosis, and migration and is implicated in a number of malignancies. In non–small cell lung cancer (NSCLC), aberrant MET signaling can occur through a number of mechanisms that collectively represent a significant proportion of patients. These include MET or HGF protein overexpression, MET gene amplification, MET gene mutation or fusion/rearrangement, or aberrations in downstream signaling or regulatory components. Responses to MET tyrosine kinase inhibitors have been documented in clinical trials in patients with MET-amplified or MET-overexpressing NSCLC, and case studies or case series have shown that MET mutation/deletion is a biomarker that is also predictive of response to these agents. However, other recent clinical data have highlighted an urgent need to elucidate optimal biomarkers based on genetic and/or protein diagnostics to correctly identify patients most likely to benefit in ongoing clinical trials of an array of MET-targeted therapies of differing class. The latest advances in the development of MET biomarkers in NSCLC have been reviewed, toward establishing appropriate MET biomarker selection based on a scientific rationale. Mol Cancer Ther; 16(4); 555–65. ©2017 AACR.



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APC Mutations as a Potential Biomarker for Sensitivity to Tankyrase Inhibitors in Colorectal Cancer

In most colorectal cancers, Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli (APC) gene and plays a critical role in tumorigenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a negative regulator of β-catenin, and upregulate β-catenin signaling. Tankyrase inhibitors downregulate β-catenin and are expected to be promising therapeutics for colorectal cancer. However, colorectal cancer cells are not always sensitive to tankyrase inhibitors, and predictive biomarkers for the drug sensitivity remain elusive. Here we demonstrate that the short-form APC mutations predict the sensitivity of colorectal cancer cells to tankyrase inhibitors. By using well-established colorectal cancer cell lines, we found that tankyrase inhibitors downregulated β-catenin in the drug-sensitive, but not resistant, colorectal cancer cells. The drug-sensitive cells showed higher Tcf/LEF transcriptional activity than the resistant cells and possessed "short" truncated APCs lacking all seven β-catenin-binding 20-amino acid repeats (20-AARs). In contrast, the drug-resistant cells possessed "long" APC retaining two or more 20-AARs. Knockdown of the long APCs with two 20-AARs increased β-catenin, Tcf/LEF transcriptional activity and its target gene AXIN2 expression. Under these conditions, tankyrase inhibitors were able to downregulate β-catenin in the resistant cells. These results indicate that the long APCs are hypomorphic mutants, whereas they exert a dominant-negative effect on Axin-dependent β-catenin degradation caused by tankyrase inhibitors. Finally, we established 16 patient-derived colorectal cancer cells and confirmed that the tankyrase inhibitor–responsive cells harbor the short-form APC mutations. These observations exemplify the predictive importance of APC mutations, the most common genetic alteration in colorectal cancers, for molecular targeted therapeutics. Mol Cancer Ther; 16(4); 752–62. ©2017 AACR.



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AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells

Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect. The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer.

In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3–dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738. Inhibition of ATM in SNU-484 cells enhanced AZD6738 sensitivity to a level comparable with that observed in SNU-601 cells, showing that activation of the ATM-Chk2 signaling pathway attenuates AZD6738 sensitivity. In addition, decreased HDAC1 expression was found to be associated with ATM inactivation in SNU-601 cells, demonstrating the interaction between HDAC1 and ATM can affect sensitivity to AZD6738. Furthermore, in an in vivo tumor xenograft mouse model, AZD6738 significantly suppressed tumor growth and increased apoptosis.

These findings suggest synthetic lethality between ATR inhibition and ATM deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM deficiency are warranted to develop novel treatment strategies for gastric cancer. Mol Cancer Ther; 16(4); 566–77. ©2017 AACR.



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Bispecific Antibodies and Antibody-Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

The properties of cell surface proteins targeted by antibody–drug conjugates (ADCs) have not been fully exploited; of particular importance are the rate of internalization and the route of intracellular trafficking. In this study, we compared the trafficking of HER2, which is the target of the clinically approved ADC ado-trastuzumab emtansine (T-DM1), with that of prolactin receptor (PRLR), another potential target in breast cancer. In contrast to HER2, we found that PRLR is rapidly and constitutively internalized, and traffics efficiently to lysosomes, where it is degraded. The PRLR cytoplasmic domain is necessary to promote rapid internalization and degradation, and when transferred to HER2, enhances HER2 degradation. In accordance with these findings, low levels of cell surface PRLR (~30,000 surface receptors per cell) are sufficient to mediate effective killing by PRLR ADC, whereas cell killing by HER2 ADC requires higher levels of cell surface HER2 (~106 surface receptors per cell). Noncovalently cross-linking HER2 to PRLR at the cell surface, using a bispecific antibody that binds to both receptors, dramatically enhances the degradation of HER2 as well as the cell killing activity of a noncompeting HER2 ADC. Furthermore, in breast cancer cells that coexpress HER2 and PRLR, a HER2xPRLR bispecific ADC kills more effectively than HER2 ADC. These results emphasize that intracellular trafficking of ADC targets is a key property for their activity and, further, that coupling an ADC target to a rapidly internalizing protein may be a useful approach to enhance internalization and cell killing activity of ADCs. Mol Cancer Ther; 16(4); 681–93. ©2017 AACR.



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Suppression of the Growth and Invasion of Human Head and Neck Squamous Cell Carcinomas via Regulating STAT3 Signaling and the miR-21/{beta}-catenin Axis with HJC0152

Signal transducer and activator of transcription 3 (STAT3) is involved in the tumor growth and metastasis of human head and neck squamous cell carcinoma (HNSCC) and is therefore a target with therapeutic potential. In this study, we show that HJC0152, a recently developed anticancer agent and a STAT3 signaling inhibitor, exhibits promising antitumor effects against HNSCC both in vitro and in vivo via inactivating STAT3 and downstream miR-21/β-catenin axis. HJC0152 treatment efficiently suppressed HNSCC cell proliferation, arrested the cell cycle at the G0–G1 phase, induced apoptosis, and reduced cell invasion in both SCC25 and CAL27 cell lines. Moreover, HJC0152 inhibited nuclear translocation of phosphorylated STAT3 at Tyr705 and decreased VHL/β-catenin signaling activity via regulation of miR-21. Loss of function of VHL remarkably compromised the antitumor effect of HJC0152 in both cell lines. In our SCC25-derived orthotopic mouse models, HJC0152 treatment significantly abrogated STAT3/β-catenin expression in vivo, leading to a global decrease of tumor growth and invasion. With its favorable aqueous solubility and oral bioavailability, HJC0152 holds the potential to be translated into the clinic as a promising therapeutic strategy for patients with HNSCC. Mol Cancer Ther; 16(4); 578–90. ©2017 AACR.



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In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance

We previously reported that the EGFR-targeted inhibitor erlotinib induces G1 arrest of squamous cell carcinoma of the head and neck (SCCHN) cell lines without inducing significant apoptosis. Large-scale genomic studies suggest that >50% of SCCHN cases have activation of PI3K pathways. This study investigated whether cotargeting of EGFR and PI3K has synergistic antitumor effects and apoptosis induction. We examined growth suppression, apoptosis, and signaling pathway modulation resulting from single and combined targeting of EGFR and PI3K with erlotinib and BKM120, respectively, in a panel of SCCHN cell lines and a xenograft model of SCCHN. In a panel of 12 cell lines, single targeting of EGFR with erlotinib or PI3K with BKM120 suppressed cellular growth without inducing significant apoptosis. Cotargeting of EGFR and PI3K synergistically inhibited SCCHN cell line and xenograft tumor growth, but induced variable apoptosis; some lines were highly sensitive, others were resistant. Mechanistic studies revealed that the combination inhibited both axes of the mTORC1 (S6 and 4EBP1) pathway in apoptosis-sensitive cell lines along with translational inhibition of Bcl-2, Bcl-xL, and Mcl-1, but failed to inhibit p-4EBP1, Bcl-2, Bcl-xL, and Mcl-1 in an apoptosis-resistant cell line. siRNA-mediated knockdown of eIF4E inhibited Bcl-2 and Mcl-1 and sensitized this cell line to apoptosis. Our results strongly suggest that cotargeting of EGFR and PI3K is synergistic and induces apoptosis of SCCHN cell lines by inhibiting both axes of the AKT–mTOR pathway and translational regulation of antiapoptotic Bcl-2 proteins. These findings may guide the development of clinical trials using this combination of agents. Mol Cancer Ther; 16(4); 729–38. ©2017 AACR.



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Combining Chk1/2 Inhibition with Cetuximab and Radiation Enhances In Vitro and In Vivo Cytotoxicity in Head and Neck Squamous Cell Carcinoma

EGFR inhibition and radiotherapy are potent inducers of DNA damage. Checkpoint kinases 1 and 2 (Chk1/2) are critical regulators of the DNA-damage response, controlling cell-cycle checkpoints that may permit recovery from therapy-associated genomic stress. We hypothesized that Chk1/2 inhibition (CHKi) with prexasertib may enhance cytotoxicity from EGFR inhibition plus radiotherapy in head and neck squamous cell carcinoma (HNSCC). In this study, we found that the addition of CHKi to the EGFR inhibitor cetuximab with and without radiotherapy significantly decreased cell proliferation and survival fraction in human papillomavirus virus (HPV)-positive and HPV-negative HNSCC cell lines. Reduced proliferation was accompanied by decreased checkpoint activation, induced S-phase accumulation, persistent DNA damage, and increased caspase cleavage and apoptosis. Importantly, a significant tumor growth delay was observed in vivo in both HPV-positive and HPV-negative cell line xenografts receiving triple combination therapy with CHKi, cetuximab, and radiotherapy without a concomitant increase in toxicity as assessed by mouse body weight. Taken together, the combination of CHKi with cetuximab plus irradiation displayed significant antitumor effects in HNSCCs both in vitro and in vivo, suggesting that this combination therapy may increase clinical benefit. A clinical trial to test this treatment for patients with head and neck cancer is currently ongoing (NCT02555644). Mol Cancer Ther; 16(4); 591–600. ©2017 AACR.



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Highlights of This Issue



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15{alpha}-methoxypuupehenol Induces Antitumor Effects In Vitro and In Vivo against Human Glioblastoma and Breast Cancer Models

Studies with 15α-methoxypuupehenol (15α-MP), obtained from the extracts of Hyrtios species, identified putative targets that are associated with its antitumor effects against human glioblastoma and breast cancer. In the human glioblastoma (U251MG) or breast cancer (MDA-MB-231) cells, treatment with 15α-MP repressed pY705Stat3, pErk1/2, pS147CyclinB1, pY507Alk (anaplastic lymphoma kinase), and pY478ezrin levels and induced pS10merlin, without inhibiting pJAK2 (Janus kinase) or pAkt induction. 15α-MP treatment induced loss of viability of breast cancer (MDA-MB-231, MDA-MB-468) and glioblastoma (U251MG) lines and glioblastoma patient–derived xenograft cells (G22) that harbor aberrantly active Stat3, with only moderate or little effect on the human breast cancer, MCF7, colorectal adenocarcinoma Caco-2, normal human lung fibroblast, WI-38, or normal mouse embryonic fibroblast (MEF Stat3fl/fl) lines that do not harbor constitutively active Stat3 or the Stat3-null (Stat3–/–) mouse astrocytes. 15α-MP–treated U251MG cells have severely impaired F-actin organization and altered morphology, including the cells rounding up, and undergo apoptosis, compared with a moderate, reversible morphology change observed for similarly treated mouse astrocytes. Treatment further inhibited U251MG or MDA-MB-231 cell proliferation, anchorage-independent growth, colony formation, and migration in vitro while only moderately or weakly affecting MCF7 cells or normal mouse astrocytes. Oral gavage delivery of 15α-MP inhibited the growth of U251MG subcutaneous tumor xenografts in mice, associated with apoptosis in the treated tumor tissues. Results together suggest that the modulation of Stat3, CyclinB1, Alk, ezrin, merlin, and Erk1/2 functions contributes to the antitumor effects of 15α-MP against glioblastoma and breast cancer progression. Mol Cancer Ther; 16(4); 601–13. ©2017 AACR.



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Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression

The receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types, including gastrointestinal stromal tumors, in which constitutively active mutant forms of KIT represent an actionable target for small-molecule tyrosine kinase inhibitors. There is also considerable potential for KIT to influence tumor growth indirectly based on its expression and function in cell types of the innate immune system, most notably mast cells. We have evaluated syngeneic mouse tumor models for antitumor effects of an inhibitory KIT mAb, dosed either alone or in combination with immune checkpoint inhibitors. Anti-KIT mAb treatment enhanced the antitumor activity of anti–CTLA-4 and anti–PD-1 mAbs, and promoted immune responses by selectively reducing the immunosuppressive monocytic myeloid-derived suppressor cell population and by restoring CD8+ and CD4+ T-cell populations to levels observed in naïve mice. These data provide a rationale for clinical investigation of the human KIT-specific mAb KTN0158 in novel immuno-oncology combinations with immune checkpoint inhibitors and other immunotherapeutic agents across a range of tumor types. Mol Cancer Ther; 16(4); 671–80. ©2017 AACR.



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Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398

Activation of FGFR signaling through mutations, amplifications, or fusions involving FGFR1, 2, 3, or 4 is seen in multiple tumors, including lung, bladder, and cholangiocarcinoma. Currently, several clinical trials are evaluating the role of novel FGFR inhibitors in solid tumors. As we move forward with FGFR inhibitors clinically, we anticipate the emergence of resistance with treatment. Consequently, we sought to study the mechanism(s) of acquired resistance to FGFR inhibitors using annotated cancer cell lines. We identified cancer cell lines that have activating mutations in FGFR1, 2, or 3 and treated them chronically with the selective FGFR inhibitor, BGJ398. We observed resistance to chronic BGJ398 exposure in DMS114 (small-cell lung cancer, FGFR1 amplification) and RT112 (urothelial carcinoma, FGFR3 fusion/amplification) cell lines based on viability assays. Reverse-phase protein array (RPPA) analysis showed increased phosphorylation of Akt (T308 and S473) and its downstream target GSK3 (S9 and S21) in both the resistant cell lines when compared with matching controls. Results of RPPA were confirmed using immunoblots. Consequently, the addition of an Akt inhibitor (GSK2141795) or siRNA was able to restore sensitivity to BGJ398 in resistant cell lines. These data suggest a role for Akt pathway in mediating acquired resistance to FGFR inhibition. Mol Cancer Ther; 16(4); 614–24. ©2017 AACR.



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Ras-MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells

Cancer cell line profiling to identify previously unrecognized kinase dependencies revealed a novel nonmutational dependency on the DNA damage response checkpoint kinase Chk1. Although Chk1 is a promising therapeutic target in p53-deficient cancers, we found that Ras–MEK signaling engages Chk1 in a subset of osteosarcoma, ovarian, and breast cancer cells to enable their survival upon DNA damage, irrespective of p53 mutation status. Mechanistically, Ras–MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras–MEK signaling, thereby limiting DNA damage. Furthermore, exogenous DNA damage promotes Chk1 dependency, and pharmacologic Chk1 inhibition combined with genotoxic chemotherapy potentiates a DNA damage response and tumor cell killing. These findings reveal a mechanism-based diagnostic strategy to identify cancer patients that may benefit from Chk1-targeted therapy. Mol Cancer Ther; 16(4); 694–704. ©2017 AACR.



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A Prodrug of Two Approved Drugs, Cisplatin and Chlorambucil, for Chemo War Against Cancer

Cancer cells maintain normal mitochondrial glutathione as one of the defense mechanisms to inhibit mitochondrial membrane polarization and hence apoptosis. A combinational therapeutic modality Platin-Cbl, a prodrug of FDA-approved chemotherapeutic agents, cisplatin and chlorambucil (Cbl), was synthesized and characterized to explore the potential of this compound to initiate chemo war on cancer cells using the active drugs, cisplatin and Cbl, when delivered to the cellular power house mitochondrion using a targeted nanoparticle designed to get associated with this organelle. Platin-Cbl demonstrated significantly high cytotoxic activity across a number of tumor cell lines as well as in a cisplatin-resistant cancer cell line compared with cisplatin or its mixture with Cbl suggesting its unique potency in cisplatin-resistant tumors. A mitochondria-targeted nanoparticle formulation of Platin-Cbl allowed for its efficacious mitochondrial delivery. In vitro studies documented high potency of Platin-Cbl nanoparticle formulations. Cisplatin-resistant cells upon treatment with Platin-Cbl were still able to manage energy production to a certain extent via fatty acid pathway; the advantage of using T-Platin-Cbl-NP is that this nanoparticle treatment causes impairment of all metabolic pathways in cisplatin-resistant cells forcing the cells to undergo efficient apoptosis. This study highlights a combination of several beneficial effects for a cascade of events to overcome resistance associated with single drug therapy. Mol Cancer Ther; 16(4); 625–36. ©2017 AACR.



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Nuclear Export of Ubiquitinated Proteins Determines the Sensitivity of Colorectal Cancer to Proteasome Inhibitor

Although proteasome inhibitors such as bortezomib had significant therapeutic effects in multiple myeloma and mantel cell lymphoma, they exhibited minimal clinical activity as a monotherapy for solid tumors, including colorectal cancer. We found in this study that proteasome inhibition induced a remarkable nuclear exportation of ubiquitinated proteins. Inhibition of CRM1, the nuclear export carrier protein, hampered protein export and synergistically enhanced the cytotoxic action of bortezomib on colon cancer cells containing wild-type p53, which underwent G2–M cell-cycle block and apoptosis. Further analysis indicated that tumor suppressor p53 was one of the proteins exported from nuclei upon proteasome inhibition, and in the presence of CRM1 inhibitor KPT330, nuclear p53, and expression of its target genes were increased markedly. Moreover, knockdown of p53 significantly reduced the synergistic cytotoxic action of bortezomib and KPT330 on p53+/+ HCT116 cells. In mice, KPT330 markedly augmented the antitumor action of bortezomib against HCT116 xenografts as well as patient-derived xenografts that harbored functional p53. These results indicate that nuclear p53 is a major mediator in the synergistic antitumor effect of bortezomib and KPT330, and provides a rationale for the use of proteasome inhibitor together with nuclear export blocker in the treatment of colorectal cancer. It is conceivable that targeting nuclear exportation may serve as a novel strategy to overcome resistance and raise chemotherapeutic efficacy, especially for the drugs that activate the p53 system. Mol Cancer Ther; 16(4); 717–28. ©2016 AACR.



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PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers

Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer. Endometrial cancers display hyperactivation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA, and PIK3R1. The FGFR2 and PI3K pathways, have emerged as potential therapeutic targets in endometrial cancer. Activation of the PI3K pathway is seen in more than 90% of FGFR2mutant endometrial cancers. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719. We assessed synergy in three FGFR2mutant endometrial cancer cell lines (AN3CA, JHUEM2, and MFE296), and the combination of BGJ398 and GDC-0941 or BYL719 showed strong synergy. A significant increase in cell death and decrease in long-term survival was seen when PI3K inhibitors were combined with BGJ398. Importantly, these effects were seen at low concentrations correlating to only partial inhibition of AKT. The combination of BGJ398 and GDC-0941 showed tumor regressions in vivo, whereas each drug alone only showed moderate tumor growth inhibition. BYL719 alone resulted in increased tumor growth of AN3CA xenografts but in combination with BGJ398 resulted in tumor regression in both AN3CA- and JHUEM2-derived xenografts. These data provide evidence that subtherapeutic doses of PI3K inhibitors enhance the efficacy of anti-FGFR therapies, and a combination therapy may represent a superior therapeutic treatment in patients with FGFR2mutant endometrial cancer. Mol Cancer Ther; 16(4); 637–48. ©2017 AACR.



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MALAT1 Is Associated with Poor Response to Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients and Promotes Chemoresistance through EZH2

A major reason for oxaliplatin chemoresistance in colorectal cancer is the acquisition of epithelial–mesenchymal transition (EMT) in cancer cells. The long noncoding RNA (lncRNA), MALAT1, is a highly conserved nuclear ncRNA and a key regulator of metastasis development in several cancers. However, its role in oxaliplatin-induced metastasis and chemoresistance is not well known. In this study, we aim to investigate the prognostic and therapeutic role of lncRNA MALAT1 in colorectal cancer patients receiving oxaliplatin-based therapy and further explore the potential transcriptional regulation through interaction with EZH2 based on the established HT29 oxaliplatin-resistant cells. Our results showed that high MALAT1 expression was associated with reduced patient survival and poor response to oxaliplatin-based chemotherapy in advanced colorectal cancer patients. Oxaliplatin-resistant colorectal cancer cells exhibited high MALAT1 expression and EMT. LncRNA MALAT1 knockdown enhances E-cadherin expression and inhibits oxaliplatin-induced EMT in colorectal cancer cells. EZH2 is highly expressed and associated with the 3' end region of lncRNA MALAT1 in colorectal cancer, and this association suppressed the expression of E-cadherin. Furthermore, targeted inhibition of MALAT1 or EZH2 reversed EMT and chemoresistance induced by oxaliplatin. Finally, the interaction between lncRNA MALAT1 and miR-218 was observed, which further indicated its prognostic value in patients who received standard FOLFOX (oxaliplatin combine with 5-fluorouracil and leucovorin) treatment. In conclusion, this study illuminates the prognostic role of lncRNA MALAT1 in colorectal cancer patients receiving oxaliplatin-based treatment and further demonstrates how lncRNA MALAT1 confers a chemoresistant function in colorectal cancer. Thus, lncRNA MALAT1 may serve as a promising prognostic and therapeutic target for colorectal cancer patients. Mol Cancer Ther; 16(4); 739–51. ©2017 AACR.



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Reactive Oxygen Species-Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies

T-cell lymphoid malignancies (TCLM) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitor romidepsin and the synthetic cytotoxic retinoid fenretinide both have achieved durable clinical responses in T-cell lymphomas as single agents. We investigated the potential for using these two agents in combination in TCLMs. We demonstrated cytotoxic synergy between romidepsin and fenretinide in 15 TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for nonmalignant cells (fibroblasts and blood mononuclear cells). In vivo, romidepsin + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous and disseminated TCLM xenograft models than single-agent romidepsin or fenretinide + ketoconazole. Fenretinide + romidepsin caused a reactive oxygen species (ROS)–dependent increase in proapoptotic proteins (Bim, tBid, Bax, and Bak), apoptosis, and inhibition of HDAC enzymatic activity, which achieved a synergistic increase in histone acetylation. The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + romidepsin were abrogated by antioxidants (vitamins C or E). Romidepsin + fenretinide activated p38 and JNK via ROS, and knockdown of p38 and JNK1 significantly decreased the synergistic cytotoxicity. Romidepsin + fenretinide also showed synergistic cytotoxicity for B-lymphoid malignancy cell lines, but did not increase ROS, acetylation of histones, activation of p38 + JNK, or cytotoxicity in nonmalignant cells. Romidepsin + fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in nonmalignant cells, via a novel molecular mechanism. These data support conducting clinical trials of romidepsin + fenretinide in relapsed and refractory TCLMs. Mol Cancer Ther; 16(4); 649–61. ©2017 AACR.



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Targeted Treatment of Metastatic Breast Cancer by PLK1 siRNA Delivered by an Antioxidant Nanoparticle Platform

Metastatic breast cancer is developed in about 20% to 30% of newly diagnosed patients with early-stage breast cancer despite treatments. Herein, we report a novel nanoparticle platform with intrinsic antimetastatic properties for the targeted delivery of Polo-like kinase 1 siRNA (siPLK1). We first evaluated it in a triple-negative breast cancer (TNBC) model, which shows high metastatic potential. PLK1 was identified as the top therapeutic target for TNBC cells and tumor-initiating cells in a kinome-wide screen. The platform consists of a 50-nm mesoporous silica nanoparticle (MSNP) core coated layer-by-layer with bioreducible cross-linked PEI and PEG polymers, conjugated with an antibody for selective uptake into cancer cells. siRNA is loaded last and fully protected under the PEG layer from blood enzymatic degradation. The material has net neutral charge and low nonspecific cytotoxicity. We have also shown for the first time that the MSNP itself inhibited cancer migration and invasion in TNBC cells owing to its ROS- and NOX4-modulating properties. In vivo, siPLK1 nanoconstructs (six doses of 0.5 mg/kg) knocked down about 80% of human PLK1 mRNA expression in metastatic breast cancer cells residing in mouse lungs and reduced tumor incidence and burden in lungs and other organs of an experimental metastasis mouse model. Long-term treatment significantly delayed the onset of death in mice and improved the overall survival. The platform capable of simultaneously inhibiting the proliferative and metastatic hallmarks of cancer progression is unique and has great therapeutic potential to also target other metastatic cancers beyond TNBC. Mol Cancer Ther; 16(4); 763–72. ©2017 AACR.



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Highlights of This Issue



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Bone Microenvironment Changes in Latexin Expression Promote Chemoresistance

Although docetaxel is the standard of care for advanced prostate cancer, most patients develop resistance to docetaxel. Therefore, elucidating the mechanism that underlies resistance to docetaxel is critical to enhance therapeutic intervention. Mining cDNA microarray from the PC-3 prostate cancer cell line and its docetaxel-resistant derivative (PC3-TxR) revealed decreased latexin (LXN) expression in the resistant cells. LXN expression was inversely correlated with taxane resistance in a panel of prostate cancer cell lines. LXN knockdown conferred docetaxel resistance to prostate cancer cells in vitro and in vivo, whereas LXN overexpression reduced docetaxel resistance in several prostate cancer cell lines. A mouse model of prostate cancer demonstrated that prostate cancer cells developed resistance to docetaxel in the bone microenvironment, but not the soft tissue microenvironment. This was associated with decreased LXN expression in prostate cancer cells in the bone microenvironment compared with the soft tissue microenvironment. It was identified that bone stromal cells decreased LXN expression through methylation and induced chemoresistance in prostate cancer in vitro. These findings reveal that a subset of prostate cancer develops docetaxel resistance through loss of LXN expression associated with methylation and that the bone microenvironment promotes this drug resistance phenotype.

Implications: This study suggests that the LXN pathway should be further explored as a viable target for preventing or reversing taxane resistance in prostate cancer. Mol Cancer Res; 15(4); 457–66. ©2017 AACR.



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Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis

Metastasis is the consequence of a cancer cell that disperses from the primary tumor, travels throughout the body, and invades and colonizes a distant site. On the basis of Paget's 1889 hypothesis, the majority of modern metastasis research focuses on the properties of the metastatic "seed and soil," but the implications of the primary tumor "soil" have been largely neglected. The rare lethal metastatic "seed" arises as a result of the selective pressures in the primary tumor. Optimal foraging theory describes how cancer cells adopt a mobile foraging strategy to balance predation risk and resource reward. Further selection in the dispersal corridors leading out of the primary tumor enhances the adaptive profile of the potentially metastatic cell. This review focuses on the selective pressures of the primary tumor "soil" that generate lethal metastatic "seeds" which is essential to understanding this critical component of prostate cancer metastasis.

Implication: Elucidating the selective pressures of the primary tumor "soil" that generate lethal metastatic "seeds" is essential to understand how and why metastasis occurs in prostate cancer. Mol Cancer Res; 15(4); 361–70. ©2017 AACR.



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Metabolic Profiling in Formalin-Fixed and Paraffin-Embedded Prostate Cancer Tissues

Metabolite profiling has significantly contributed to a deeper understanding of the biochemical metabolic networks and pathways in cancer cells. Metabolomics-based biomarker discovery would greatly benefit from the ability to interrogate retrospective annotated clinical specimens archived as formalin-fixed, paraffin-embedded (FFPE) material. Mass spectrometry–based metabolomic analysis was performed in matched frozen and FFPE human prostate cancers as well as isogenic prostate cancer cell lines. A total of 352 and 460 metabolites were profiled in human tissues and cell lines, respectively. Classes and physical–chemical characteristics of the metabolites preserved in FFPE material were characterized and related to their preservation or loss following fixation and embedding. Metabolite classes were differentially preserved in archival FFPE tissues, regardless of the age of the block, compared with matched frozen specimen, ranging from maximal preservation of fatty acids (78%) to loss of the majority of peptides and steroids. Generally, FFPE samples showed a decrease of metabolites with functional groups, such as carboxamide. As an adjunct technique, metabolic profiles were also obtained in situ from FFPE tissue sections where metabolites were extracted in a manner that preserves tissue architecture. Despite the fact that selected metabolites were not retained after processing, global metabolic profiles obtained from FFPE can be used to predict biologic states and study biologic pathways. These results pave the way for metabolomics-based biomarker discovery/validation utilizing retrospective and clinically annotated FFPE collections.

Implications: Metabolic profiles can be performed in archival tissue and may be used to complement other profiling methods such as gene expression for biomarker discovery or pathway analysis in the assessment of biologic states. Mol Cancer Res; 15(4); 439–47. ©2017 AACR.



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A Systematic Analysis of Negative Growth Control Implicates the DREAM Complex in Cancer Cell Dormancy

Epithelial ovarian cancer (EOC) generates multicellular aggregates called spheroids that detach from the primary tumor and disseminate through ascites. Spheroids possess a number of characteristics of tumor dormancy including withdrawal from the cell cycle and resistance to chemotherapeutics. This report systematically analyzes the effects of RNAi depletion of 21 genes that are known to contribute to negative regulation of the cell cycle in 10 ovarian cancer cell lines. Interestingly, spheroid cell viability was compromised by loss of some cyclin-dependent kinase inhibitors such as p57Kip2, as well as Dyrk1A, Lin52, and E2F5 in most cell lines tested. Many genes essential for EOC spheroid viability are pertinent to the mammalian DREAM repressor complex. Mechanistically, the data demonstrate that DREAM is assembled upon the induction of spheroid formation, which is dependent upon Dyrk1A. Loss of Dyrk1A results in retention of the b-Myb–MuvB complex, elevated expression of DREAM target genes, and increased DNA synthesis that is coincident with cell death. Inhibition of Dyrk1A activity using pharmacologic agents Harmine and INDY compromises viability of spheroids and blocks DREAM assembly. In addition, INDY treatment improves the response to carboplatin, suggesting this is a therapeutic target for EOC treatment.

Implications: Loss of negative growth control mechanisms in cancer dormancy lead to cell death and not proliferation, suggesting they are an attractive therapeutic approach. Mol Cancer Res; 15(4); 371–81. ©2016 AACR.



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Potent EMT and CSC Phenotypes Are Induced By Oncostatin-M in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is referred to as a silent killer due to the lack of clear symptoms, a lack of early detection methods, and a high frequency of metastasis at diagnosis. In addition, pancreatic cancer is remarkably resistant to chemotherapy, and clinical treatment options remain limited. The tumor microenvironment (TME) and associated factors are important determinants of metastatic capacity and drug resistance. Here, oncostatin M (OSM), an IL6 cytokine family member, was identified as an important driver of mesenchymal and cancer stem cell (CSC) phenotypes. Furthermore, the generation of cells that harbor mesenchymal/CSC properties following OSM exposure resulted in enhanced tumorigenicity, increased metastasis, and resistance to gemcitabine. OSM induced the expression of ZEB1, Snail (SNAI1), and OSM receptor (OSMR), engaging a positive feedback loop to potentiate the mesenchymal/CSC program. Suppression of JAK1/2 by ruxolitinib prevented STAT3-mediated transcription of ZEB1, SNAI1 and OSMR, as well as the emergence of a mesenchymal/CSC phenotype. Likewise, ZEB1 silencing, by shRNA-mediated knockdown, in OSM-driven mesenchymal/CSC reverted the phenotype back to an epithelial/non-CSC state. Importantly, the generation of cells with mesenchymal/CSC properties was unique to OSM, and not observed following IL6 exposure, implicating OSMR and downstream effector signaling as a distinct target in PDAC. Overall, these data demonstrate the capacity of OSM to regulate an epithelial–mesenchymal transition (EMT)/CSC plasticity program that promotes tumorigenic properties.

Implications: Therapeutic targeting the OSM/OSMR axis within the TME may prevent or reverse the aggressive mesenchymal and CSC phenotypes associated with poor outcomes in patients with PDAC. Mol Cancer Res; 15(4); 478–88. ©2017 AACR.



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A Genome-Wide Loss-of-Function Screen Identifies SLC26A2 as a Novel Mediator of TRAIL Resistance

TRAIL is a potent death-inducing ligand that mediates apoptosis through the extrinsic pathway and serves as an important endogenous tumor suppressor mechanism. Because tumor cells are often killed by TRAIL and normal cells are not, drugs that activate the TRAIL pathway have been thought to have potential clinical value. However, to date, most TRAIL-related clinical trials have largely failed due to the tumor cells having intrinsic or acquired resistance to TRAIL-induced apoptosis. Previous studies to identify resistance mechanisms have focused on targeted analysis of the canonical apoptosis pathway and other known regulators of TRAIL receptor signaling. To identify novel mechanisms of TRAIL resistance in an unbiased way, we performed a genome-wide shRNA screen for genes that regulate TRAIL sensitivity in sublines that had been selected for acquired TRAIL resistance. This screen identified previously unknown mediators of TRAIL resistance including angiotensin II receptor 2, Crk-like protein, T-Box Transcription Factor 2, and solute carrier family 26 member 2 (SLC26A2). SLC26A2 downregulates the TRAIL receptors, DR4 and DR5, and this downregulation is associated with resistance to TRAIL. Its expression is high in numerous tumor types compared with normal cells, and in breast cancer, SLC26A2 is associated with a significant decrease in relapse-free survival.

Implication: Our results shed light on novel resistance mechanisms that could affect the efficacy of TRAIL agonist therapies and highlight the possibility of using these proteins as biomarkers to identify TRAIL-resistant tumors, or as potential therapeutic targets in combination with TRAIL. Mol Cancer Res; 15(4); 382–94. ©2017 AACR.



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Immunophenotyping and Transcriptomic Outcomes in PDX-Derived TNBC Tissue

Cancer tissue functions as an ecosystem of a diverse set of cells that interact in a complex tumor microenvironment. Genomic tools applied to biopsies in bulk fail to account for this tumor heterogeneity, whereas single-cell imaging methods limit the number of cells which can be assessed or are very resource intensive. The current study presents methods based on flow cytometric analysis and cell sorting using known cell surface markers (CXCR4/CD184, CD24, THY1/CD90) to identify and interrogate distinct groups of cells in triple-negative breast cancer clinical biopsy specimens from patient-derived xenograft (PDX) models. The results demonstrate that flow cytometric analysis allows a relevant subgrouping of cancer tissue and that sorting of these subgroups provides insights into cancer cell populations with unique, reproducible, and functionally divergent gene expression profiles. The discovery of a drug resistance signature implies that uncovering the functional interaction between these populations will lead to deeper understanding of cancer progression and drug response.

Implications: PDX-derived human breast cancer tissue was investigated at the single-cell level, and cell subpopulations defined by surface markers were identified which suggest specific roles for distinct cellular compartments within a solid tumor. Mol Cancer Res; 15(4); 429–38. ©2016 AACR.



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TNF Signaling through RIP1 Kinase Enhances SN38-Induced Death in Colon Adenocarcinoma

Elucidation of TNF-directed mechanisms for cell death induction and maintenance of tumor growth has revealed a role for receptor-interacting protein kinases 1 and 3 (RIPK1/RIP1 and RIPK3/RIP3), components of the necrosome complex, as determinants of cell fate. Here, the participation of TNF signaling was analyzed with regard to the cytotoxic action of different DNA-damaging agents in a panel of colon cancer cells. While most of these cell lines were insensitive to TNF, combination with these drugs increased sensitivity by inducing cell death and DNA damage, especially in the case of the topoisomerase inhibitor SN38. Changes in levels of RIP1 and RIP3 occurred following monotherapy with SN38 or in combination with TNF. Downregulation of RIP1 resulted in increased resistance to SN38, implying a requirement for RIP1 in mediating cytotoxicity through the TNF/TNFR signaling pathway. Downregulation of RIP1 in a xenograft model impaired tumor growth inhibition from SN38 treatment, suggesting the potential of RIP1 to determine the clinical outcome of irinotecan treatment. These results indicate that TNF plays a key role in determining the cytotoxic effectiveness of SN38 in colorectal cancer and suggests a re-evaluation of TNF-based interventions to enhance therapeutic efficacy.

Implications: The capacity of RIP1 to influence drug sensitivity suggests RIP1 may have biomarker potential. Mol Cancer Res; 15(4); 395–404. ©2017 AACR.



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miR-211-5p Suppresses Metastatic Behavior by Targeting SNAI1 in Renal Cancer

The Snail family transcriptional repressor 1 (SNAI1) is known to promote metastatic phenotypes in renal cell carcinoma (RCC). However, the mechanism by which SNAI1 promotes RCC metastasis remains largely unexplored. Here, bioinformatics and quantitative validation revealed that miR-211-5p was downregulated in metastatic RCC clinical specimens compared with nonmetastatic RCC tissues. Overexpression of miR-211-5p suppressed RCC cell migration and invasion via downregulation of SNAI1 expression. Luciferase reporter assays demonstrated that miR-211-5p directly targeted 3'-UTR of SNAI1. Furthermore, miR-211-5p decreased xenograft tumor weight and reduced in vivo tumor metastasis in mice. These findings indicate that miR-211-5p-mediated inhibition of SNAIL1 expression contributes to the suppression of RCC progression.

Implications: Targeting the miR-211-5p/SNAI1 signaling pathway may be a novel therapeutic approach for the treatment of RCC metastasis. Mol Cancer Res; 15(4); 448–56. ©2017 AACR.



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EZH2 or HDAC1 Inhibition Reverses Multiple Myeloma-Induced Epigenetic Suppression of Osteoblast Differentiation

In multiple myeloma, osteolytic lesions rarely heal because of persistent suppressed osteoblast differentiation resulting in a high fracture risk. Herein, chromatin immunoprecipitation analyses reveal that multiple myeloma cells induce repressive epigenetic histone changes at the Runx2 locus that prevent osteoblast differentiation. The most pronounced multiple myeloma–induced changes were at the Runx2-P1 promoter, converting it from a poised bivalent state to a repressed state. Previously, it was observed that multiple myeloma induces the transcription repressor GFI1 in osteoblast precursors, which correlates with decreased Runx2 expression, thus prompting detailed characterization of the multiple myeloma and TNFα-dependent GFI1 response element within the Runx2-P1 promoter. Further analyses reveal that multiple myeloma–induced GFI1 binding to Runx2 in osteoblast precursors and recruitment of the histone modifiers HDAC1, LSD1, and EZH2 is required to establish and maintain Runx2 repression in osteogenic conditions. These GFI1-mediated repressive chromatin changes persist even after removal of multiple myeloma. Ectopic GFI1 is sufficient to bind to Runx2, recruit HDAC1 and EZH2, increase H3K27me3 on the gene, and prevent osteogenic induction of endogenous Runx2 expression. Gfi1 knockdown in MC4 cells blocked multiple myeloma–induced recruitment of HDAC1 and EZH2 to Runx2, acquisition of repressive chromatin architecture, and suppression of osteoblast differentiation. Importantly, inhibition of EZH2 or HDAC1 activity in pre-osteoblasts after multiple myeloma exposure in vitro or in osteoblast precursors from patients with multiple myeloma reversed the repressive chromatin architecture at Runx2 and rescued osteoblast differentiation.

Implications: This study suggests that therapeutically targeting EZH2 or HDAC1 activity may reverse the profound multiple myeloma–induced osteoblast suppression and allow repair of the lytic lesions. Mol Cancer Res; 15(4); 405–17. ©2017 AACR.



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Inflammatory Molecule, PSGL-1, Deficiency Activates Macrophages to Promote Colorectal Cancer Growth through NF{kappa}B Signaling

P-selectin glycoprotein ligand 1 (SELPLG/PSGL-1) is an inflammatory molecule that is functionally related to immune cell differentiation and leukocyte mobilization. However, the role of PSGL-1 in tumor development remains unknown. Therefore, this study investigates the mechanistic role of PSGL-1 in the development of intestinal tumors in colorectal cancer. ApcMin/+ mice are highly susceptible to spontaneous intestinal adenoma formation, and were crossbred with PSGL1-null mice to generate compound transgenic mice with a ApcMin/+;PSGL-1–/– genotype. The incidence and pathologic features of the intestinal tumors were compared between the ApcMin/+ mice and ApcMin/+;PSGL-1–/– mice. Importantly, PSGL-1–deficient mice showed increased susceptibility to develop intestinal tumors and accelerated tumor growth. Mechanistically, increased production of the mouse chemokine ligand 9 (CCL9/MIP-1) was found in the PSGL-1–deficient mice, and the macrophages are likely the major source of macrophage inflammatory protein-1 gamma (MIP-1). Studies in vitro demonstrated that macrophage-derived MIP-1 promoted colorectal cancer tumor cell growth through activating NFB signaling. Conversely, restoration of the PSGL-1 signaling via bone marrow transplantation reduced MIP-1 production and attenuated the ability of ApcMin/+;PSGL-1–/– mice to generate intestinal tumors. In human colorectal cancer clinical specimens, the presence of PSGL-1–positive cells was associated with a favorable tumor–node–metastasis staging and decreased lymph node metastasis.

Implications: PSGL-1 deficiency and inflammation render intestinal tissue more vulnerable to develop colorectal tumors through a MIP-1/NFB signaling axis. Mol Cancer Res; 15(4); 467–77. ©2017 AACR.



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14-3-3{sigma} Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

14-3-3 has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3 contributes to these resistances via inhibiting apoptosis and arresting cells in G2–M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3 causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2–M phase following DNA-damaging treatments. We showed that 14-3-3 contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2–M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSB). The increased NHEJ repair activity was due to 14-3-3–mediated upregulation of PARP1 expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G2–M arrest following IR was due to 14-3-3–induced Chk2 expression.

Implications: These findings reveal an important molecular basis of 14-3-3 function in cancer cell resistance to chemo/radiation therapy and in poor prognosis of human cancers. Mol Cancer Res; 15(4); 418–28. ©2017 AACR.



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IGF-1 Receptor Modulates FoxO1-Mediated Tamoxifen Response in Breast Cancer Cells

Tamoxifen is a common adjuvant treatment for estrogen receptor (ER)α-positive patients with breast cancer; however, acquired resistance abrogates the efficacy of this therapeutic approach. We recently demonstrated that G protein–coupled estrogen receptor 1 (GPER1) mediates tamoxifen action in breast cancer cells by inducing insulin-like growth factor–binding protein-1 (IGFBP-1) to inhibit IGF-1–dependent signaling. To determine whether dysregulation of IGFBP-1 induction is associated with tamoxifen resistance, IGFBP-1 transcription was measured in tamoxifen-resistant MCF-7 cells (TamR) after tamoxifen (Tam) treatment. IGFBP-1 transcription was not stimulated in tamoxifen-treated TamR cells whereas decreased expression of FoxO1, a known modulator of IGFBP-1, was observed. Exogenous expression of FoxO1 rescued the ability of tamoxifen to induce IGFBP-1 transcription in TamR cells. As decreased IGF-1R expression is observed in tamoxifen-resistant cells, the requirement for IGF-1R expression on tamoxifen-stimulated IGFBP-1 transcription was investigated. In TamR and SK-BR-3 cells, both characterized by low IGF-1R levels, exogenous IGF-1R expression increased FoxO1 levels and IGFBP-1 expression, whereas IGF-1R knockdown in MCF-7 cells decreased tamoxifen-stimulated IGFBP-1 transcription. Interestingly, both 17β-estradiol (E2)-stimulated ERα phosphorylation and progesterone receptor (PR) expression were altered in TamR. PR is a transcription factor known to modulate FoxO1 transcription. In addition, IGF-1R knockdown decreased FoxO1 protein levels in MCF-7 cells. Furthermore, IGF-1R or FoxO1 knockdown inhibited the ability of tamoxifen to induce IGFBP-1 transcription and tamoxifen sensitivity in MCF-7 cells. These data provide a molecular mechanistic connection between IGF-1R expression and the FoxO1-mediated mechanism of tamoxifen action in breast cancer cells.

Implications: Loss of IGF-1R expression is associated with decreased tamoxifen efficacy in patients with breast cancer and the development of tamoxifen resistance. This contribution identifies potential molecular mechanisms of altered tamoxifen sensitivity in breast cancer cells resulting from decreased IGF-1R expression. Mol Cancer Res; 15(4); 489–97. ©2017 AACR.



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Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma

Purpose: Aberrant activation of the NF-B transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-B inhibitors are not yet available. Because NF-B transcription factors can be activated by the interleukin-1 receptor-associated kinases (IRAKs) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAKs in the pathobiology of PDAC.

Experimental Design: We examined the phosphorylation status of IRAK4 (p-IRAK4), the master regulator of TLR signaling, in PDAC cell lines, in surgical samples and commercial tissue microarray. We then performed functional studies using small-molecule IRAK1/4 inhibitor, RNA-interference, and CRISPR/Cas9n techniques to delineate the role of IRAK4 in NF-B activity, chemoresistance, cytokine production, and growth of PDAC cells in vitro and in vivo.

Results: p-IRAK4 staining was detectable in the majority of PDAC lines and about 60% of human PDAC samples. The presence of p-IRAK4 strongly correlated with phospho-NF-B/p65 staining in PDAC samples and is predictive of postoperative relapse and poor overall survival. Inhibition of IRAK4 potently reduced NF-B activity, anchorage-independent growth, chemoresistance, and secretion of proinflammatory cytokines from PDAC cells. Both pharmacologic suppression and genetic ablation of IRAK4 greatly abolished PDAC growth in mice and augmented the therapeutic effect of gemcitabine by promoting apoptosis, reducing tumor cell proliferation and tumor fibrosis.

Conclusions: Our data established IRAK4 as a novel therapeutic target for PDAC treatment. Development of potent IRAK4 inhibitors is needed for clinical testing. Clin Cancer Res; 23(7); 1748–59. ©2016 AACR.



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Nivolumab in the Treatment of Hodgkin Lymphoma

Despite an extensive immune infiltrate that is recruited to the tumor by malignant Reed–Sternberg cells in Hodgkin lymphoma, the antitumor immune response is ineffective and unable to eradicate the malignant cells. The ineffective immune response is in part due to PD-1 signaling that renders intratumoral immune cells anergic. Reed–Sternberg cells have been shown to upregulate expression of the PD-1 ligands, PD-L1 and PD-L2, due to either genetic alterations at chromosome 9p24.1 or Epstein–Barr virus infection, and these ligands suppress the function of PD-1+ intratumoral T cells. Blockade of PD-1 signaling has proven to be a highly successful therapeutic approach, and the use of the anti-PD-1 mAb nivolumab recently received accelerated approval by the FDA for patients with classical Hodgkin lymphoma that has relapsed or progressed after autologous stem cell transplant and posttransplantation brentuximab vedotin. Initial clinical trials using nivolumab in this patient population resulted in high response rates that were durable. Adverse events associated with nivolumab included immune-mediated adverse reactions and infusion reactions, but these were well tolerated, allowing for continued nivolumab administration. Clinical trials are now in progress to test the use of nivolumab in combination with standard chemotherapy or with novel agents with a goal of improving the outcome of patients with Hodgkin lymphoma. Clin Cancer Res; 23(7); 1623–6. ©2016 AACR.



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Landscape of Genomic Alterations in Pituitary Adenomas

Purpose: Pituitary adenomas are the second most common primary brain tumor, yet their genetic profiles are incompletely understood.

Experimental Design: We performed whole-exome sequencing of 42 pituitary macroadenomas and matched normal DNA. These adenomas included hormonally active and inactive tumors, ones with typical or atypical histology, and ones that were primary or recurrent.

Results: We identified mutations, insertions/deletions, and copy-number alterations. Nearly one-third of samples (29%) had chromosome arm-level copy-number alterations across large fractions of the genome. Despite such widespread genomic disruption, these tumors had few focal events, which is unusual among highly disrupted cancers. The other 71% of tumors formed a distinct molecular class, with somatic copy number alterations involving less than 6% of the genome. Among the highly disrupted group, 75% were functional adenomas or atypical null-cell adenomas, whereas 87% of the less-disrupted group were nonfunctional adenomas. We confirmed this association between functional subtype and disruption in a validation dataset of 87 pituitary adenomas. Analysis of previously published expression data from an additional 50 adenomas showed that arm-level alterations significantly impacted transcript levels, and that the disrupted samples were characterized by expression changes associated with poor outcome in other cancers. Arm-level losses of chromosomes 1, 2, 11, and 18 were significantly recurrent. No significantly recurrent mutations were identified, suggesting no genes are altered by exonic mutations across large fractions of pituitary macroadenomas.

Conclusions: These data indicate that sporadic pituitary adenomas have distinct copy-number profiles that associate with hormonal and histologic subtypes and influence gene expression. Clin Cancer Res; 23(7); 1841–51. ©2016 AACR.



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Pancreatic Cancer: Challenge and Inspiration



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Targeting Hypoxic Prostate Tumors Using the Novel Hypoxia-Activated Prodrug OCT1002 Inhibits Expression of Genes Associated with Malignant Progression

Purpose: To understand the role of hypoxia in prostate tumor progression and to evaluate the ability of the novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the antitumor effect of bicalutamide.

Experimental Design: The effect of OCT1002 on prostate cancer cells (LNCaP, 22Rv1, and PC3) was measured in normoxia and hypoxia in vitro. In vivo, tumor growth and lung metastases were measured in mice treated with bicalutamide, OCT1002, or a combination. Dorsal skin fold chambers were used to image tumor vasculature in vivo. Longitudinal gene expression changes in tumors were analyzed using PCR.

Results: Reduction of OCT1002 to its active form (OCT1001) decreased prostate cancer cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo, treatment with OCT1002 alone, or with bicalutamide, showed significantly greater tumor growth control and reduced lung metastases compared with controls. Reestablishment of the tumor microvasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the upregulation of RUNX2 and its targets caused by bicalutamide alone was blocked by OCT1002.

Conclusions: OCT1002 selectively targets hypoxic tumor cells and enhances the antitumor efficacy of bicalutamide. Furthermore, bicalutamide caused changes in gene expression, which indicated progression to a more malignant genotype; OCT1002 blocked these effects, emphasizing that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumor growth and malignant progression. This is of importance for the design and refinement of existing androgen-deprivation regimens in the clinic. Clin Cancer Res; 23(7); 1797–808. ©2016 AACR.



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Pancreatic Cancer: "A Riddle Wrapped in a Mystery inside an Enigma"

Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult-to-treat cancers. With an increasing incidence and inability to make major progress, it represents the very definition of unmet medical need. Progress has been made in understanding the basic biology—systematic genomic sequencing has led to the recognition that PDAC is not typically a heavily mutated tumor, although there are exceptions. The most consistently mutated genes are KRAS, CDKN2A, TP53, and SMAD4/DPC4. Study of familial PDAC has led to the recognition that a variety of defects in DNA repair genes can be associated with the emergence of pancreatic cancer. Recent studies suggest that epigenetics may play a larger role than previously recognized. A major new understanding is the recognition that PDAC should be considered a composite of tumor cells, as well as pancreatic stellate cells, immune cells, and extracellular matrix. The individual components contribute to metabolic aberration, immune dysfunction, and chemotherapy resistance, and therapeutic innovations may be needed to address them individually. It has also been recognized that metastatic seeding from PDAC occurs very early in the disease course—in an estimated 73% of cases, once the tumor reaches 2 cm. The implication of this is that therapies directed toward micrometastatic disease and increasing fractional cell kill are most needed. Neoadjuvant approaches have been taken to increase resectability and improve outcome. So much work remains, and most critical is the need to understand how this tumor originates and develops. Clin Cancer Res; 23(7); 1629–37. ©2017 AACR.

See all articles in this CCR Focus section, "Pancreatic Cancer: Challenge and Inspiration."



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【News Release】Toshiba Medical introduces the new 1.5T MRI Systems Zen Edition Delivering intelligent, quiet and comfortable technology for daily examinations to meet newly evolving clinical requirements



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Prolactin Receptor-Mediated Internalization of Imaging Agents Detects Epithelial Ovarian Cancer with Enhanced Sensitivity and Specificity

Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack high sensitivity to detect small tumors and high specificity to distinguish malignant from benign tissue, both impeding diagnosis of early and metastatic cancer stages and leading to costly and invasive surgeries. Tissue microarray analysis revealed that >98% of ovarian cancers express the prolactin receptor (PRLR), forming the basis of a new molecular imaging strategy. We fused human placental lactogen (hPL), a specific and tight binding PRLR ligand, to magnetic resonance imaging (gadolinium) and near-infrared fluorescence imaging agents. Both in tissue culture and in mouse models, these imaging bioconjugates underwent selective internalization into ovarian cancer cells via PRLR-mediated endocytosis. Compared with current clinical MRI techniques, this targeted approach yielded both enhanced signal-to-noise ratio from accumulation of signal via selective internalization and improved specificity conferred by PRLR upregulation in malignant ovarian cancer. These features endow PRLR-targeted imaging with the potential to transform ovarian cancer detection. Cancer Res; 77(7); 1684–96. ©2017 AACR.

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Precancer Atlas to Drive Precision Prevention Trials

Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. In this Perspective, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity – basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. Emerging genetic and pharmacologic (metformin) disruption of mitochondrial (mt) respiration increased autophagy to prevent cancer in a Li-Fraumeni mouse model (biology reproduced in clinical pilot) and revealed profound influences of subtle changes in mt DNA background variation on obesity, aging, and cancer risk. The elaborate communication between the immune system and neoplasia includes an increasingly complex cellular microenvironment and dynamic interactions between host genetics, environmental factors, and microbes in shaping the immune response. Cancer vaccines are in early murine and clinical precancer studies, building on the recent successes of immunotherapy and HPV vaccine immune prevention. Molecular monitoring in Barrett's esophagus to avoid overdiagnosis/treatment highlights an important PCA theme. Next generation sequencing (NGS) discovered age-related clonal hematopoiesis of indeterminate potential (CHIP). Ultra-deep NGS reports over the past year have redefined the premalignant landscape remarkably identifying tiny clones in the blood of up to 95% of women in their 50s, suggesting that potentially premalignant clones are ubiquitous. Similar data from eyelid skin and peritoneal and uterine lavage fluid provide unprecedented opportunities to dissect the earliest phases of stem/progenitor clonal (and microenvironment) evolution/diversity with new single-cell and liquid biopsy technologies. Cancer mutational signatures reflect exogenous or endogenous processes imprinted over time in precursors. Accelerating the prevention of cancer will require a large-scale, longitudinal effort, leveraging diverse disciplines (from genetics, biochemistry, and immunology to mathematics, computational biology, and engineering), initiatives, technologies, and models in developing an integrated multi-omics and immunity PCA – an immense national resource to interrogate, target, and intercept events that drive oncogenesis. Cancer Res; 77(7); 1510–41. ©2017 AACR.

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EGFR-Dependent Regulated Intramembrane Proteolysis of EpCAM—Letter



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The Role of PIAS SUMO E3-Ligases in Cancer

SUMOylation modifies the interactome, localization, activity, and lifespan of its target proteins. This process regulates several cellular machineries, including transcription, DNA damage repair, cell-cycle progression, and apoptosis. Accordingly, SUMOylation is critical in maintaining cellular homeostasis, and its deregulation leads to the corruption of a plethora of cellular processes that contribute to disease states. Among the proteins involved in SUMOylation, the protein inhibitor of activated STAT (PIAS) E3-ligases were initially described as transcriptional coregulators. Recent findings also indicate that they have a role in regulating protein stability and signaling transduction pathways. PIAS proteins interact with up to 60 cellular partners affecting several cellular processes, most notably immune regulation and DNA repair, but also cellular proliferation and survival. Here, we summarize the current knowledge about their role in tumorigenesis and cancer-related processes. Cancer Res; 77(7); 1542–7. ©2017 AACR.

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Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer

The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1–induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer. Cancer Res; 77(7); 1730–40. ©2017 AACR.

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Surgery for Cancer: A Trigger for Metastases

Surgery is a crucial intervention and provides a chance of cure for patients with cancer. The perioperative period is characterized by an increased risk for accelerated growth of micrometastatic disease and increased formation of new metastatic foci. The true impact for cancer patients remains unclear. This review summarizes the often fragmentary clinical and experimental evidence supporting the role of surgery and inflammation as potential triggers for disease recurrence. Surgery induces increased shedding of cancer cells into the circulation, suppresses antitumor immunity allowing circulating cells to survive, upregulates adhesion molecules in target organs, recruits immune cells capable of entrapping tumor cells, and induces changes in the target tissue and in the cancer cells themselves to enhance migration and invasion to establish at the target site. Surgical trauma induces local and systemic inflammatory responses that can also contribute to the accelerated growth of residual and micrometastatic disease. Furthermore, we address the role of perioperative factors, including anesthesia, transfusions, hypothermia, and postoperative complications, as probable deleterious factors contributing to early recurrence. Through the admittedly limited understanding of these processes, we will attempt to provide suggestions for potential new therapeutic approaches to target the protumorigenic perioperative window and ultimately improve long-term oncological outcomes. Cancer Res; 77(7); 1548–52. ©2017 AACR.

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Highlights from Recent Cancer Literature



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Therapeutic Potential of Bacteria against Solid Tumors

Intentional bacterial infections can produce efficacious antitumor responses in mice, rats, dogs, and humans. However, low overall success rates and intense side effects prevent such approaches from being employed clinically. In this work, we titered bacteria and/or the proinflammatory cytokine TNFα in a set of established murine models of cancer. To interpret the experiments conducted, we considered and calibrated a tumor–effector cell recruitment model under the influence of functional tumor-associated vasculature. In this model, bacterial infections and TNFα enhanced immune activity and altered vascularization in the tumor bed. Information to predict bacterial therapy outcomes was provided by pretreatment tumor size and the underlying immune recruitment dynamics. Notably, increasing bacterial loads did not necessarily produce better long-term tumor control, suggesting that tumor sizes affected optimal bacterial loads. Short-term treatment responses were favored by high concentrations of effector cells postinjection, such as induced by higher bacterial loads, but in the longer term did not correlate with an effective restoration of immune surveillance. Overall, our findings suggested that a combination of intermediate bacterial loads with low levels TNFα administration could enable more favorable outcomes elicited by bacterial infections in tumor-bearing subjects. Cancer Res; 77(7); 1553–63. ©2017 AACR.

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Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair

Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+ availability. Targeting the PARP DNA repair pathway extensively sensitized IDH1-mutated glioma cells to TMZ. Our findings demonstrate a novel molecular mechanism that defines chemosensitivity in IDH-mutated gliomas. Targeting PARP-associated DNA repair may represent a novel therapeutic strategy for gliomas. Cancer Res; 77(7); 1709–18. ©2017 AACR.

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Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation

Abnormal metabolism is a hallmark of cancer, yet its regulation remains poorly understood. Cancer cells were considered to utilize primarily glycolysis for ATP production, referred to as the Warburg effect. However, recent evidence suggests that oxidative phosphorylation (OXPHOS) plays a crucial role during cancer progression. Here we utilized a systems biology approach to decipher the regulatory principle of glycolysis and OXPHOS. Integrating information from literature, we constructed a regulatory network of genes and metabolites, from which we extracted a core circuit containing HIF-1, AMPK, and ROS. Our circuit analysis showed that while normal cells have an oxidative state and a glycolytic state, cancer cells can access a hybrid state with both metabolic modes coexisting. This was due to higher ROS production and/or oncogene activation, such as RAS, MYC, and c-SRC. Guided by the model, we developed two signatures consisting of AMPK and HIF-1 downstream genes, respectively, to quantify the activity of glycolysis and OXPHOS. By applying the AMPK and HIF-1 signatures to The Cancer Genome Atlas patient transcriptomics data of multiple cancer types and single-cell RNA-seq data of lung adenocarcinoma, we confirmed an anticorrelation between AMPK and HIF-1 activities and the association of metabolic states with oncogenes. We propose that the hybrid phenotype contributes to metabolic plasticity, allowing cancer cells to adapt to various microenvironments. Using model simulations, our theoretical framework of metabolism can serve as a platform to decode cancer metabolic plasticity and design cancer therapies targeting metabolism. Cancer Res; 77(7); 1564–74. ©2017 AACR.

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