ACR Inhibits Lipogenesis to Prevent Hepatocellular Carcinoma

Acyclic retinoid (ACR) is a promising drug under clinical trials for preventing recurrence of hepatocellular carcinoma. The objective of this study was to gain insights into molecular basis of the antitumorigenic action of ACR from a metabolic point of view. To achieve this, comprehensive cationic and lipophilic liver metabolic profiling was performed in mouse diethylnitrosamine (DEN)-induced hepatic tumorigenesis model using both capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. ACR significantly counteracted against acceleration of lipogenesis but not glucose metabolism in DEN-treated mice liver, suggesting an important role of lipid metabolic reprogramming in the initiation step of hepatic tumorigenesis. Knowledge-based pathway analysis suggested that inhibition of linoleic acid metabolites such as arachidonic acid, a proinflammatory precursor, played a crucial role in the prevention by ACR of DEN-induced chronic inflammation–mediated tumorigenesis of the liver. As a molecular mechanism of the ACR's effect to prevent the aberrant lipogenesis, microarray analysis identified that a key transcription regulator of both embryogenesis and tumorigenesis, COUP transcription factor 2, also known as NR2F2, was associated with the metabolic effect of ACR in human hepatocellular carcinoma cells. Our study provided potential therapeutic targets for the chemoprevention of hepatocellular carcinoma as well as new insights into the mechanisms underlying prevention of hepatic tumorigenesis. Cancer Prev Res; 9(3); 205–14. ©2016 AACR.

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Alkylation Damage Protects against Hepatocellular Carcinoma

Hepatocellular carcinoma is increasingly important in the United States as the incidence rate rose over the last 30 years. C3HeB/FeJ mice serve as a unique model to study hepatocellular carcinoma tumorigenesis because they mimic human hepatocellular carcinoma with delayed onset, male gender bias, approximately 50% incidence, and susceptibility to tumorigenesis is mediated through multiple genetic loci. Because a human O⁶-methylguanine-DNA methyltransferase (hMGMT) transgene reduces spontaneous tumorigenesis in this model, we hypothesized that hMGMT would also protect from methylation-induced hepatocarcinogenesis. To test this hypothesis, wild-type and hMGMT transgenic C3HeB/FeJ male mice were treated with two monofunctional alkylating agents: diethylnitrosamine (DEN; 0.025 μmol/g body weight) on day 12 of life with evaluation for glucose-6-phosphatase-deficient (G6PD) foci at 16, 24, and 32 weeks or N-methyl-N-nitrosurea (MNU; 25 mg MNU/kg body weight) once monthly for 7 months starting at 3 months of age with evaluation for liver tumors at 12 to 15 months of age. No difference in abundance or size of G6PD foci was measured with DEN treatment. In contrast, it was unexpectedly found that MNU reduces liver tumor prevalence in wild-type and hMGMT transgenic mice despite increased tumor prevalence in other tissues. hMGMT and MNU protections were additive, suggesting that MNU protects through a different mechanism, perhaps through the cytotoxic N7-alkylguanine and N3-alkyladenine lesions which have low mutagenic potential compared with O⁶-alkylguanine lesions. Together, these results suggest that targeting the repair of cytotoxic lesions may be a good preventative for patients at high risk of developing hepatocellular carcinoma. Cancer Prev Res; 9(3); 245–52. ©2015 AACR.

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Inhibition of Akt Potentiates Rapamycin Skin Chemoprevention

The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared with those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here, we explored the use of topical rapamycin as a chemopreventive agent in the context of solar-simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared with controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared with vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC. Cancer Prev Res; 9(3); 215–24. ©2016 AACR.

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Piperlongumine and Gemcitabine in Pancreatic Cancer

Pancreatic cancer is an aggressive malignancy, which generally respond poorly to chemotherapy. Hence, novel agents that are safe and effective are highly needed. The aim of this study was to investigate whether piperlongumine, a natural product isolated from the fruit of the pepper Piper longum, has any efficacy against human pancreatic cancer when used either alone or in combination with gemcitabine in vitro and in a xenograft mouse model. In vitro, piperlongumine inhibited the proliferation of pancreatic cancer cell lines, potentiated the apoptotic effects of gemcitabine, inhibited the constitutive and inducible activation of NF-B, and suppressed the NF-B–regulated expression of c-Myc, cyclin D1, Bcl-2, Bcl-xL, Survivin, XIAP, VEGF, and matrix metalloproteinase-9 (MMP-9). Furthermore, in an in vivo xenograft model, we found piperlongumine alone significantly suppressed tumor growth and enhanced the antitumor properties of gemcitabine. These results were consistent with the downregulation of NF-B activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that piperlongumine alone exhibits significant antitumor effects against human pancreatic cancer and it further enhances the therapeutic effects of gemcitabine, possibly through the modulation of NF-B– and NF-B–regulated gene products. Cancer Prev Res; 9(3); 234–44. ©2015 AACR.

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Efficacy and Safety of Exemestane in the Prevention Setting

This phase II trial evaluated clinical markers of efficacy and safety of exemestane in postmenopausal women at increased risk for breast cancer. Postmenopausal women (n = 42) at risk for invasive breast cancer received 25 mg exemestane daily for 2 years along with calcium and vitamin D. The primary outcome was change in mammographic density (MD) after one year. Secondary outcomes included change in serum steroid hormones as well as change in trefoil protein 1 (TFF1) and proliferating cell nuclear antigen (PCNA) in breast tissue. Safety and tolerability were also assessed. MD decreased at 1 year and was significant at 2 years [mean change = –4.1%; 95% confidence intervals (CI), –7.2 to –1.1; P = 0.009]. Serum estradiol and testosterone levels significantly decreased at 3 months and remained suppressed at 12 months. After 1 year of treatment, TFF1 intensity decreased (mean change –1.32; 95% CI, –1.87 to –0.76; P < 0.001). Exemestane was safe and well tolerated. Exemestane decreased MD and expression of breast tissue TFF1. It was well tolerated with few clinically relevant side effects. MD and breast tissue TFF1 are potential biomarkers of breast cancer–preventive effects of exemestane in high-risk postmenopausal women. Cancer Prev Res; 9(3); 225–33. ©2016 AACR.

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MyD88 and Inflammation in Gastric Tumorigenesis

It has been established that COX-2 and downstream signaling by prostaglandin E₂ (PGE₂) play a key role in tumorigenesis through generation of inflammatory microenvironment. Toll-like receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) also regulates inflammatory responses in tumors. However, the relationship between these distinct pathways in tumorigenesis is not yet fully understood. We herein investigated the role of MyD88 in gastric tumorigenesis using Gan mice, which develop inflammation-associated gastric tumors due to the simultaneous activation of the COX-2/PGE₂ pathway and Wnt signaling. Notably, the disruption of Myd88 in Gan mice resulted in the significant suppression of gastric tumorigenesis with the inhibition of inflammatory responses, even though COX-2/PGE₂ pathway is constitutively activated. Moreover, Myd88 disruption in bone marrow–derived cells (BMDCs) in Gan mice also suppressed inflammation and tumorigenesis, indicating that MyD88 signaling in BMDCs regulates the inflammatory microenvironment. We also found that expression of Tlr2 and its coreceptor Cd14 was induced in tumor epithelial cells in Gan mice, which was suppressed by the disruption of Myd88. It has already been shown that TLR2/CD14 signaling is important for stemness of intestinal epithelial cells. These results indicate that MyD88 in BMDCs, together with COX-2/PGE₂ pathway, plays an essential role in the generation of the inflammatory microenvironment, which may promote tumorigenesis through induction of TLR2/CD14 pathway in tumor epithelial cells. These results suggest that inhibition of TLR/MyD88 signaling together with COX-2/PGE₂ pathway will be an effective preventive strategy for gastric cancer. Cancer Prev Res; 9(3); 253–63. ©2016 AACR.

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ReCAP: Assessing the Quality of a Radiation Oncology Case-based Peer-review Program in an Integrated Academic and Community Cancer Center Network [Focus on Quality]

QUESTION ASKED:

How can academic centers assess the quality of a comprehensive peer-review program in an integrated academic and community cancer center network?

SUMMARY ANSWER:

Of a total of 104 peer-reviewed cases from four community cancer network centers that were quality audited by expert academic faculty, 17% (18/104) of cases were not concordant with any of the following: national standards, MD Anderson Cancer Center institutional guidelines, or expert review of individual case variations (Figure 1). Deficiencies included incomplete staging work-up, incorrect target and normal tissue delineation, and non-adherence to accepted dose-volume constraints.

METHODS:

An electronic tool was used by community cancer network centers to enter clinical treatment information on patients undergoing peer-review, and at least 10% of the case-load for each community radiation oncology physician was selected for quality audit. Quality metrics included review of the management plan, technical plan, and other indicators.

BIAS, CONFOUNDING FACTOR(S), DRAWBACKS:

Data from only four of 13 current community network sites were available for this analysis. Since quality auditing was conducted on a retrospective sampling of cases, sampling error could result in either a higher or lower non-concordance rate. Although a primary goal of the quality audit program is to educate community network physicians and improve the level of care for future cases, longitudinal assessment of changes in physician treatment plans based on previous feedback is not yet available. Finally, most quality metrics assessed in this study are process metrics, and future efforts will require incorporation of outcomes and cost measurement.

REAL-LIFE IMPLICATIONS:

Given the high rate of non-concordance in the integrated community network, prospective pre-radiotherapy peer review of all cases, in particular expert case review of low-volume or complex disease sites, is recommended. An integrated approach to peer review may help improve the quality, safety, and value of cancer therapy in the community setting.

FIG 1.

Non-concordance rates of peer-reviewed cases, stratified by disease site. Rates represent the number of non-concordant cases divided by the number of peer-reviewed cases in that disease site.

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ReCAP: Cancer Screening Patterns and Concerns in Caregivers of Patients Undergoing Radiation Therapy [Care Delivery]

QUESTION ASKED:

What is the compliance with recommended cancer screening in caregivers who accompany patients to radiation oncology consultations, and are there specific barriers and deficiencies?

SUMMARY ANSWER:

The results revealed that younger participants (≤ 49 years) were less likely to report PCP discussion of cancer screening than older participants, and nearly half of the participants had one or more concerns regarding cancer screening (Fig 2B). Notable decreases in mammography and colonoscopy were seen in younger screening-eligible caregivers.

METHODS:

Over a 9-month period, 209 English-speaking men and women caregivers at an urban and two suburban radiation oncology treatment centers voluntarily completed the 21-question-item surveys designed to assess cancer screening.

BIAS, CONFOUNDING FACTOR(S), DRAWBACKS:

Limitations of this study include potential selection bias and inherent bias from a self-reported survey given to caregivers who accompany patients to radiation oncology consultation. Participant responses regarding screening practices were not independently verified. In this surveyed group, we report higher compliance rates than state and national rates, potentially limiting the effect of cancer screening discussion in this group.

REAL-LIFE IMPLICATIONS:

With the frequently shifting cancer screening recommendations, deficiencies and concerns remain prevalent. Radiation oncology consultations may serve as potential avenues for oncologists to address concerns and encourage compliance, thereby improving detection and outcomes. Further investigation of this methodology is warranted, particularly in underserved communities.

FIG 2B.

Reported reasons for concerns about cancer screening.

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Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression Summary [Guideline Summary]

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