Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR)

High rates of cell proliferation and protein synthesis in pancreatic cancer are among many factors leading to endoplasmic reticulum (ER) stress. To restore cellular homeostasis, the unfolded protein response (UPR) activates as an adaptive mechanism through either the IRE1α, PERK, or ATF6 pathways to reduce the translational load and process unfolded proteins, thus enabling tumor cells to proliferate. Under severe and prolonged ER stress, however, the UPR may promote adaptation, senescence, or apoptosis under these same pathways if homeostasis is not restored. In this review, we present evidence that high levels of ER stress and UPR activation are present in pancreatic cancer. We detail the mechanisms by which compounds activate one or many of the three arms of the UPR and effectuate downstream apoptosis and examine available data on the pre-clinical and clinical-phase ER stress inducers with the potential for anti-tumor efficacy in pancreatic cancer. Finally, we hypothesize a potential new approach to targeting pancreatic cancer by increasing levels of ER stress and UPR activation to incite apoptotic cell death

Disparities in Metabolic Conditions and Cancer Characteristics among Hispanic Women with Breast Cancer: A Multi-Institutional Study

While the associations of common metabolic conditions with ethnicity have been previously described, disparity among Hispanic individuals based on country of origin is understudied. This multi-institutional analysis explored the prevalence of metabolic conditions and their association with cancer subtypes among Mexican and non-Mexican Hispanics. After IRB approval, we conducted a cross-sectional study at two academic medical centers with a significant Hispanic patient population (Texas Tech University Health Sciences Center, El Paso, TX (TTUHSC-EP) and Cleveland Clinic Florida in Weston, FL (CCF)). A total of n = 1020 self-identified Hispanic patients with breast cancer consecutively diagnosed between 2005 and 2014 were selected from the two institutional databases. Comparisons between Mexican and Non-Mexican Hispanics revealed variations in tumor types and metabolic conditions. Mexican Hispanics were found to have a higher prevalence of diabetes mellitus (27.8% vs. 14.2%, p < 0.001), obesity (51.0% vs. 32.5%, p < 0.001), and ductal carcinoma type (86.6 vs. 73.4%, p < 0.001). On the other hand, hormone-receptor-positive breast cancer was more common in non-Mexicans, while Mexicans had more triple-negative breast cancer, especially in premenopausal women. In addition to highlighting these variations among Hispanic patients with breast cancer, this study supports a more focused approach to addressing obesity and other metabolic conditions prevalent in the Hispanic population with breast cancer. Moreover, Hispanic individuals with breast cancer are diverse and should not be lumped under one category without reference to their country of origin regarding the impact of race and ethnicity

Precision Medicine Targeting FGFR2 Genomic Alterations in Advanced Cholangiocarcinoma: Current State and Future Perspectives

Although a relatively uncommon tumor, cholangiocarcinoma is on the rise globally. Of note, most patients are diagnosed with metastatic disease, and the prognosis is poor with cytotoxic chemotherapy. Strategies targeting specific genomic alterations have demonstrated promising activity in recent years and could represent a new therapeutic avenue for these patients. In this review, we will address the biology and clinical results of FGFR inhibition in intrahepatic cholangiocarcinoma, highlighting limitations associated with treatment and discussing the use of circulating tumor DNA to detect mechanisms of resistance.</jats:p

Disparities in Metabolic Conditions and Cancer Characteristics among Hispanic Women with Breast Cancer: A Multi-Institutional Study

While the associations of common metabolic conditions with ethnicity have been previously described, disparity among Hispanic individuals based on country of origin is understudied. This multi-institutional analysis explored the prevalence of metabolic conditions and their association with cancer subtypes among Mexican and non-Mexican Hispanics. After IRB approval, we conducted a cross-sectional study at two academic medical centers with a significant Hispanic patient population (Texas Tech University Health Sciences Center, El Paso, TX (TTUHSC-EP) and Cleveland Clinic Florida in Weston, FL (CCF)). A total of n = 1020 self-identified Hispanic patients with breast cancer consecutively diagnosed between 2005 and 2014 were selected from the two institutional databases. Comparisons between Mexican and Non-Mexican Hispanics revealed variations in tumor types and metabolic conditions. Mexican Hispanics were found to have a higher prevalence of diabetes mellitus (27.8% vs. 14.2%, p &lt; 0.001), obesity (51.0% vs. 32.5%, p &lt; 0.001), and ductal carcinoma type (86.6 vs. 73.4%, p &lt; 0.001). On the other hand, hormone-receptor-positive breast cancer was more common in non-Mexicans, while Mexicans had more triple-negative breast cancer, especially in premenopausal women. In addition to highlighting these variations among Hispanic patients with breast cancer, this study supports a more focused approach to addressing obesity and other metabolic conditions prevalent in the Hispanic population with breast cancer. Moreover, Hispanic individuals with breast cancer are diverse and should not be lumped under one category without reference to their country of origin regarding the impact of race and ethnicity.</jats:p

Abstract 3594: Impact of metformin on HCC prognosis

Abstract Concurrent with the increase in hepatocellular carcinoma (HCC) incidence, the prevalence of metabolic syndrome has increased in the USA. Metabolic syndrome is currently considered a major health problem. Moreover, long term diabetes mellitus is an independent risk factor for HCC. We have previously shown that use of metformin among diabetics was associated with 70% risk reduction of HCC as compare to the use of other types of antidiabetic treatment. It is not known, however, if diabetic patients with HCC who used metformin had a better prognosis. Between 2001 and 2010 we interviewed 438 patients with pathologically confirmed HCC for multiple risk factors of HCC including prior history of diabetes and type of antidiabetic treatment. Survival times were calculated from the date of pathology diagnosis and were censored for patients who were alive at the last follow up. Median survival was calculated using Kaplan Meier product-limit method and survival rates were compared using the log rank test. Cox proportional hazards model (CPHM) was used to estimate the multivariate Hazard Risk Ratios (HRR) and 95% Confidence Interval (CI). Total of 130 HCC patients (29.7%) recalled prior history of diabetes with more than 1 year prior to HCC diagnosis. Most subjects were considered to have type 2 diabetes mellitus and were on an oral antidiabetic regimen. The survival duration for HCC patients with diabetes did not significantly differs from those without diabetes in men and women. However, HCC diabetic men who received metformin had a better survival outcome. The median survival was 14.9 months (95% CI, 1.3-28.9) for metformin users compared to 12.7 months (95% CI. 6.2-10.1) among HCC diabetic men who received other treatments, Log Rank p value=.04. CPHM, which included age, hepatitis C virus infection, alcohol consumption, treatment of HCC (chemotherapy and surgical treatment), history of cirrhosis, and Liver Italian Program (CLIP) staging score yielded 40% improvement of overall survival in HCC men with diabetes who received metformin as compared to other treatments. The estimated HRR (95% CI) was 0.56 (.35-.91), P =.02. These results suggest a possible beneficial role of metformin in diabetic men with HCC. Such observations need to be confirmed in other populations and with correlation with duration of metformin intake. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3594. doi:1538-7445.AM2012-3594</jats:p

Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR)

High rates of cell proliferation and protein synthesis in pancreatic cancer are among many factors leading to endoplasmic reticulum (ER) stress. To restore cellular homeostasis, the unfolded protein response (UPR) activates as an adaptive mechanism through either the IRE1α, PERK, or ATF6 pathways to reduce the translational load and process unfolded proteins, thus enabling tumor cells to proliferate. Under severe and prolonged ER stress, however, the UPR may promote adaptation, senescence, or apoptosis under these same pathways if homeostasis is not restored. In this review, we present evidence that high levels of ER stress and UPR activation are present in pancreatic cancer. We detail the mechanisms by which compounds activate one or many of the three arms of the UPR and effectuate downstream apoptosis and examine available data on the pre-clinical and clinical-phase ER stress inducers with the potential for anti-tumor efficacy in pancreatic cancer. Finally, we hypothesize a potential new approach to targeting pancreatic cancer by increasing levels of ER stress and UPR activation to incite apoptotic cell death.</jats:p