Vitamin E δ-tocotrienol Sensitizes Human Pancreatic Cancer Cells to TRAIL-induced Apoptosis Through Proteasome-Mediated Down-Regulation of c-FLIP

Background: Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects. Methods: We report a novel function of VEDT in augmenting tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in pancreatic cancer cells. The effects of VEDT were shown by its ability to trigger caspase-8-dependent apoptosis in pancreatic cancer cells. Results: When combined with TRAIL, VEDT significantly augmented TRAIL-induced apoptosis of pancreatic cancer cells. VEDT decreased cellular FLICE inhibitory protein (c-FLIP) levels without consistently modulating the expression of decoy death receptors 1, 2, 3 or death receptors 4 and 5. Enforced expression of c-FLIP substantially attenuated VEDT/TRAIL-induced apoptosis. Thus, c-FLIP reduction plays an important part in mediating VEDT/TRAIL-induced apoptosis. Moreover, VEDT increased c-FLIP ubiquitination and degradation but did not affect its transcription, suggesting that VEDT decreases c-FLIP levels through promoting its degradation. Of note, degradation of c-FLIP and enhanced TRAIL-induced apoptosis in pancreatic cancer cells were observed only with the anticancer bioactive vitamin E compounds δ-, γ-, and β-tocotrienol but not with the anticancer inactive vitamin E compounds α-tocotrienol and α-, β-, γ-, and δ-tocopherol. Conclusions: c-FLIP degradation is a key event for death receptor-induced apoptosis by anticancer bioactive vitamin E compounds in pancreatic cancer cells. Moreover, VEDT augmented TRAIL inhibition of pancreatic tumor growth and induction of apoptosis in vivo. Combination therapy with TRAIL agonists and bioactive vitamin E compounds may offer a novel strategy for pancreatic cancer intervention

Greco-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer

Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks. Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide. Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety. In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization

Proceedings of the I ndo‐ U.S. bilateral workshop on accelerating botanicals/biologics agent development research for cancer chemoprevention, treatment, and survival

With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, an Indo‐U.S. collaborative Workshop focusing on “Accelerating Botanicals Agent Development Research for Cancer Chemoprevention and Treatment” was conducted at the Moffitt Cancer Center, 29–31 May 2012. Funded by the Indo‐U.S. Science and Technology Forum, a joint initiative of Governments of India and the United States of America and the Moffitt Cancer Center, the overall goals of this workshop were to enhance the knowledge (agents, molecular targets, biomarkers, approaches, target populations, regulatory standards, priorities, resources) of a multinational, multidisciplinary team of researcher's to systematically accelerate the design, to conduct a successful clinical trials to evaluate botanicals/biologics for cancer chemoprevention and treatment, and to achieve efficient translation of these discoveries into the standards for clinical practice that will ultimately impact cancer morbidity and mortality. Expert panelists were drawn from a diverse group of stakeholders, representing the leadership from the National Cancer Institute's Office of Cancer Complementary and Alternative Medicine (OCCAM), NCI Experimental Therapeutics (NExT), Food and Drug Administration, national scientific leadership from India, and a distinguished group of population, basic and clinical scientists from the two countries, including leaders in bioinformatics, social sciences, and biostatisticians. At the end of the workshop, we established four Indo‐U.S. working research collaborative teams focused on identifying and prioritizing agents targeting four cancers that are of priority to both countries. Presented are some of the key proceedings and future goals discussed in the proceedings of this workshop. With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, the proceedings of the Indo‐U.S. collaborative Workshop represent one of the most contemporary issues in Cancer Medicine .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96353/1/cam442.pd

Proceedings of the I ndo‐ U.S. bilateral workshop on accelerating botanicals/biologics agent development research for cancer chemoprevention, treatment, and survival

With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, an Indo‐U.S. collaborative Workshop focusing on “Accelerating Botanicals Agent Development Research for Cancer Chemoprevention and Treatment” was conducted at the Moffitt Cancer Center, 29–31 May 2012. Funded by the Indo‐U.S. Science and Technology Forum, a joint initiative of Governments of India and the United States of America and the Moffitt Cancer Center, the overall goals of this workshop were to enhance the knowledge (agents, molecular targets, biomarkers, approaches, target populations, regulatory standards, priorities, resources) of a multinational, multidisciplinary team of researcher's to systematically accelerate the design, to conduct a successful clinical trials to evaluate botanicals/biologics for cancer chemoprevention and treatment, and to achieve efficient translation of these discoveries into the standards for clinical practice that will ultimately impact cancer morbidity and mortality. Expert panelists were drawn from a diverse group of stakeholders, representing the leadership from the National Cancer Institute's Office of Cancer Complementary and Alternative Medicine (OCCAM), NCI Experimental Therapeutics (NExT), Food and Drug Administration, national scientific leadership from India, and a distinguished group of population, basic and clinical scientists from the two countries, including leaders in bioinformatics, social sciences, and biostatisticians. At the end of the workshop, we established four Indo‐U.S. working research collaborative teams focused on identifying and prioritizing agents targeting four cancers that are of priority to both countries. Presented are some of the key proceedings and future goals discussed in the proceedings of this workshop. With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, the proceedings of the Indo‐U.S. collaborative Workshop represent one of the most contemporary issues in Cancer Medicine .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96353/1/cam442.pd

Evaluating the quality of psychosocial care in outpatient medical oncology settings using performance indicators

Abstract Objective: An American Psychosocial Oncology Society workgroup has developed indicators of the quality of psychosocial care that can be measured through review of medical records. The present report describes the first large-scale use of these indicators to evaluate psychosocial care in outpatient medical oncology settings. Methods: Medical records of 1660 colorectal, breast and non-small cell cancer patients first seen by a medical oncologist in 2006 at 11 practice sites in Florida were reviewed for performance on indicators of the quality of psychosocial care. Results: Assessment of emotional well-being was significantly less likely to be documented than assessment of pain (52 vs 87%, po0.001). A problem with emotional well-being was documented in 13% of records and evidence of action taken was documented in 58% of these records. Ten of eleven practice sites performed below an 85% threshold on each indicator of psychosocial care. Variability in assessment of emotional-well being was associated (po0.02) with practice site and patient gender and age while variability in assessment of pain was associated (po0.001) with practice site and cancer type. Conclusions: Findings illustrate how use of the psychosocial care indicators permits identification of specific practice sites and processes of care that should be targeted for quality improvement efforts. Additionally, findings demonstrate the extent to which routine assessment of emotional well-being lags behind routine assessment of pain in cancer patients

Murine Pancreatic Adenocarcinoma Reduces Ikaros Expression and Disrupts T Cell Homeostasis

Background Maintenance of T cell immune homeostasis is critical for adequate anti-tumor immunity. The transcription factor Ikaros is essential for lymphocyte development including T cells. Alterations in Ikaros expression occur in blood malignancies in humans and mice. In this study, we investigated the role of Ikaros in regulating T cell immune balance in pancreatic cancer mouse models. Methodology and Principal Findings Using our Panc02 tumor-bearing (TB) mouse model, western blot analysis revealed a reduction in Ikaros proteins while qRT-PCR showed no differences in Ikaros mRNA levels in TB splenocytes compared to control. Treatment of naïve splenocytes with the proteasomal inhibitor, MG132, stabilized Ikaros expression and prevented Ikaros downregulation by Panc02 cells, in vitro. Western blot analyses showed a reduction in protein phosphatase 1 (PP1) and protein kinase CK2 expression in TB splenocytes while CK2 activity was increased. Immunofluorescence microscopy revealed altered punctate staining of Ikaros in TB splenocytes. Flow cytometry revealed a significant decrease in effector CD4+ and CD8+ T cell percentages but increased CD4+CD25+ regulatory T cells in TB splenocytes. Similar alterations in T cell percentages, as well as reduced Ikaros and CK2 but not PP1 expression, were observed in a transgenic, triple mutant (TrM) pancreatic cancer model. Ikaros expression was also reduced in enriched TB CD3+ T cells. MG132 treatment of naïve CD3+ T cells stabilized Ikaros expression in the presence of Panc02 cells. Western blots showed reduced PP1 and CK2 expression in TB CD3+ T cells. Conclusions/Significance The results of this study suggest that the pancreatic tumor microenvironment may cause proteasomal degradation of Ikaros, possibly via dysregulation of PP1 and CK2 expression and activity, respectively. This loss of Ikaros expression may contribute to an imbalance in T cell percentages. Ikaros may potentially be a therapeutic target to restore T cell homeostasis in pancreatic cancer hosts, which may be critical for effective anti-tumor immunity

Delta-tocotrienol treatment and prevention of pancreatic cancer

Methods are disclosed for treating neoplastic disorders, such as pancreatic cancer, using tocotrienols; namely, gamma-tocotrienol and delta tocotrienol. The antitumorogenic effects of these compounds are shown both in vitro and in vivo using several human pancreatic cancer cell lines and MIA-PACA2 human pancreatic cancer cells xenografted in nude mice. Also disclosed are methods of testing the efficacy of potential chemotherapeutic agents by measuring their effect on surrogate endpoint biomarkers, such as Ki-67 and p27. Associated compounds are also disclosed

Delta-tocotrienol treatment and prevention of pancreatic cancer

Methods are disclosed for treating neoplastic disorders, such as pancreatic cancer, using tocotrienols; namely, gamma-tocotrienol and delta tocotrienol. The antitumorogenic effects of these compounds are shown both in vitro and in vivo using several human pancreatic cancer cell lines and MIA-PACA2 human pancreatic cancer cells xenografted in nude mice. Also disclosed are methods of testing the efficacy of potential chemotherapeutic agents by measuring their effect on surrogate endpoint biomarkers, such as Ki-67 and p27. Associated compounds are also disclosed