PanCa Patients Research Articles

Deoxyribonucleic acid methylation driven aberrations in pancreatic cancer-related pathways.

Pancreatic cancer (PanCa) presents a catastrophic disease with poor overall survival at advanced stages, with immediate requirement of new and effective treatment options. Besides genetic mutations, epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target. Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails. Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients. Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies. Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance. Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions, and novel pharmacological strategies that target these components could potentially lead to breakthroughs. We aim to highlight the possibilities that exist and the potential therapeutic interventions.

Sugar Sweetened and Artificially Sweetened Beverage Consumption and Pancreatic Cancer: A Retrospective Study.

Pancreatic cancer (PanCa) is a highly fatal malignancy with few modifiable risk and prognostic factors. This study investigates the association between cola, diet cola, and non-cola soft drink consumption and PanCa risk and mortality. A retrospective study was conducted using data from the Patient Epidemiology Data System (1982-1998) at Roswell Park Comprehensive Cancer Center (Buffalo, NY, USA), including 213 PanCa patients and 852 cancer-free controls. Data were collected using a self-administered questionnaire, including a 46-item food frequency questionnaire (FFQ). Multivariable logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) of cola, diet cola, and non-cola soft drink consumption and PanCa risk. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CIs of cola, diet cola, and non-cola soft drink consumption and PanCa mortality. Stratified analyses were conducted by sex, body mass index (BMI), and smoking status. We observed significant 55% increased odds of PanCa among patients consuming ≥1 regular cola per day (OR: 1.55, 95% CI: 1.01-2.39). We also observed non-significant 38% increased hazard of mortality among patients consuming ≥1 regular cola per day (HR: 1.38, 95% CI: 0.91-2.07). We conclude that regular cola consumption is a modifiable lifestyle that may be associated with PanCa risk and mortality following diagnosis.

Interstitial lung disease in microscopic polyangiitis and granulomatosis with polyangiitis: demographic, clinical, serological and radiological features of an Italian cohort from the Italian Society for Rheumatology.

Interstitial lung disease (ILD) has been described as a possible pulmonary involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV), mainly granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Aim of this cross-sectional Italian national study was to describe demographic, clinical and serological profile of ILD related to MPA and GPA and investigate possible correlations between radiologic patterns of ILD and vasculitis features. We enrolled 95 consecutive patients with AAV-ILD, 56 affected by MPA (58.9%) and 39 by GPA (41.1%). NSIP was the most frequently detected ILD pattern, observed in c-ANCA patients in 60.9% of cases, followed by UIP pattern mainly observed in p-ANCA patients (47.7%, p=0.03). ILD represented the first clinical manifestation, preceding vasculitis diagnosis in 22.1% of cases and, globally, ILD was already detectable at AAV diagnosis in 66.3% of patients. The diagnosis of ILD preceded that of AAV in 85.7% of p-ANCA positive-patients, while only one patient with c-ANCA developed ILD before AAV (p= 0.039). Multivariate analysis confirmed the correlation of UIP pattern with p-ANCA-positivity and a diagnosis of ILD before AAV, also when adjusted for age and sex. Our study confirms that UIP is a frequent pattern of lung disease in AAVILD patients. Our results also suggest that ILD can represent an early complication of AAV but also occur in the course of the disease, suggesting the need of a careful evaluation by both pulmonologist and rheumatologist to achieve an early diagnosis. Further prospective studies are needed to define ILD prevalence and evolution in AAV patients.

Novel Paclitaxel Nanoformulation Impairs De Novo Lipid Synthesis in Pancreatic Cancer Cells and Enhances Gemcitabine Efficacy.

Pancreatic cancer (PanCa) is a highly lethal disease with a poor 5 year survival rate, less than 7%. It has a dismal prognosis, and more than 50% of cases are detected at an advanced and metastatic stage. Gemcitabine (GEM) is a gold standard chemotherapy used for PanCa treatment. However, GEM-acquired resistance in cancer cells is considered as a major setback for its continued clinical implementation. This phenomenon is evidently linked to de novo lipid synthesis. PanCa cells rely on de novo lipid synthesis, which is a prime event in survival and one of the key drivers for tumorigenesis, cancer progression, and drug resistance. Thus, the depletion of lipogenesis or lipid metabolism can not only improve treatment outcomes but also overcome chemoresistance, which is an unmet clinical need. Toward this effort, our study reports a unique paclitaxel–poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PPNPs) formulation which can target lipid metabolism and improve anticancer efficacy of GEM in PanCa cells. PPNPs inhibit excessive lipid formation and alter membrane stability with compromised membrane integrity, which was confirmed by Fourier transform infrared and zeta potential measurements. The effective interference of PPNPs in lipid metabolic signaling was determined by reduction in the expression of FASN, ACC, lipin, and Cox-2 proteins. This molecular action profoundly enhances efficacy of GEM as evident through enhanced inhibitory effects on the tumorigenic and metastasis assays in PanCa cells. These data clearly suggest that the ablation of lipid metabolism might offer an innovative approach for the improved therapeutic outcome in PanCa patients.

ROS/KRAS/AMPK Signaling Contributes to Gemcitabine-Induced Stem-like Cell Properties in Pancreatic Cancer

Poor prognosis in pancreatic cancer (PanCa) is partially due to chemoresistance to gemcitabine (GEM). Glucose metabolism has been revealed to contribute to the therapeutic resistance and pluripotent state of PanCa cells. However, few studies have focused on the effects of GEM on cancer cell metabolism, stemness of tumor cells, and molecular mechanisms that critically influence PanCa treatment. We demonstrate that GEM treatment induces metabolic reprogramming, reducing mitochondrial oxidation and upregulating aerobic glycolysis, and promotes stem-like behaviors in cancer cells. Inhibiting aerobic glycolysis suppresses cancer cell stemness and strengthens GEM’s cytotoxicity. GEM-induced metabolic reprogramming is KRAS dependent, as knockdown of KRAS reverses the metabolic shift. GEM-induced metabolic reprogramming also activates AMP-activated protein kinase (AMPK), which promotes glycolytic flux and cancer stemness. In addition, GEM-induced reactive oxygen species (ROS) activate the KRAS/AMPK pathway. This effect was validated by introducing exogenous hydrogen peroxide (H2O2). Taken together, these findings reveal a counterproductive GEM effect during PanCa treatment. Regulating cellular redox, targeting KRAS/AMPK signaling, or reversing metabolic reprogramming might be effective approaches to eliminate cancer stem cells (CSCs) and enhance chemosensitivity to GEM to improve the prognosis of PanCa patients.

The Relationship Between Nutritional Status, Performance Status, and Survival Among Pancreatic Cancer Patients

Aim: The purpose of this study was to identify the nutritional and performance status of Pancreatic Cancer (PanCa) patients and to determine the relationship between these parameters and their survival time.Material and Methods: Ninety-six PanCa patients [59.6% F, 61.4% M; mean age: 60.7 (min:28, max:80) years] were followed up for 6–24 months. The Patient Generated Subjective Global Assessment (PG-SGA) and Eastern Comparative Oncology Group (ECOG) scale were performed. Anthropometric measurements [height, weight, mid-upper arm circumference (MUAC), calf circumference (CC) and triceps skin fold thickness (TSF)], hand grip strength (HGS) were recorded. Survival analyses were conducted using Kaplan–Meier curves.Results: Malnutrition was observed in 85.5% (n = 82) and 54.2% of all patients had poor performance status. A positive correlation was observed between malnutrition and ECOG scale of the patients (P < .01). Antropometric measurements for women and men, respectively, were 34.4 ± 3.03–34.6 ± 3.43 cm for CC; 26.9 ± 3.47–26.05 ± 3.37 cm for MUAC; 20.5 ± 6.3–13.02 ± 7.7 mm for TSF; – 31.02 ± 7.64–20.13 ± 6.04 kg for HGS. Survival time of patients with SGA-A and B was 38.0 ± 6.6 months and of those with SGA-C was 12.0 ± 3.1 months (P = .000).Conclusion: Malnutrition negatively affected both performance status and survival time among PanCa patients.

Abstract 5534: Novel pluronic F127-coated paclitaxel nanoparticles formulation for pancreatic cancer

Abstract Pancreatic cancer (PanCa) is one of the deadliest cancers which accounts for 46,420 new cancer cases and almost 39,590 deaths in the United States in 2014. There is no effective treatment modality for PanCa that can significantly improve the overall survival rate of patients. Paclitaxel is a mitotic inhibitor widely used in chemotherapy. Recent FDA approved treatment regimen of Abraxane® (paclitaxel nanoformulation) with gemcitabine has been increased overall survival of PanCa patients from 6.7 months (Gemcitabine) to 8.5 months (Abraxane® + Gemcitabine). Targeted delivery of paclitaxel may lead to significant improvement in treating pancreatic cancer. For this purpose, we have engineered a unique, pluronic F127-coated paclitaxel loaded nanoparticles (PPNPs) formulation. This formulation is composed of a PLGA core that is subsequently coated with poly(vinyl alcohol) (PVA), poly(l-lysine) (PLL), and pluronic polymer (F127) for efficient drug delivery and active tumors targeting. This formulation has several unique properties: (a) the PLGA core is capable of loading paclitaxel and its sustained release (b) pluronic-polymer layer coating provides stability and also reverses multi-drug resistance in cancer cells (c) the polyethylene glycol chains of pluronic F127 polymer act as a stealth polymer which diminishes the nonspecific uptake of formulation, and (d) amine functional groups on NPs (PLL) are useful for antibody conjugation through a PEG-linker for specific targeting of tumor/cancer cells. The PPNPs formulation was characterized for particle size, chemical composition, and thermal characteristics. The PPNPs exhibited superior dose-dependent inhibition effects on the proliferation of Colo-357, HPAF-II, BxPC-3, MiaPaca-2, Panca-1, and AsPC-1 pancreatic cancer cell lines, over free PTX and other conventional PTX nanoformulation (Abraxane®). Similar inhibition effects were also observed in colony formation assay in BxPC-3 cells. The improved anti-cancer effects of this formulation was achieved due to its accumulation in the cytosolic compartment and less presence in early endosome/late endosome/lysosome indicates their escape from lysosomal degradation. In addition, our data suggest that F127-stabilized PPNPs exhibit superior anti-cancer potential and is capable of regulating proteins associated with sonic hedgehog, multi drug resistance and miR-21 signaling pathways and inducing apoptosis which, eventually lead to the gemcitabine chemo-sensitization. Interestingly, MUC13-conjugated nanoformulation exhibited efficient targeting in HPAF-II cells. In conclusion, our data suggest that the PPNPs nanoformulation can be used for the efficient, targeted delivery of paclitaxel to tumors and may useful for treatment of pancreatic cancer alone and/or in combination with gemcitabine. Citation Format: Murali M. Yallapu, Neeraj Chauhan, Sheema Khan, Meena Jaggi, Aditya Ganju, Diane M. Maher, Mara C. Ebeling, Subhash C. Chauhan. Novel pluronic F127-coated paclitaxel nanoparticles formulation for pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5534. doi:10.1158/1538-7445.AM2015-5534

Endoscopic Ultrasonography for Tumor Node Staging and Vascular Invasion in Pancreatic Cancer: A Meta-Analysis

Background/Aims: The accurate staging of pancreatic cancer (PanCa) is crucial in the development of a stage-specific treatment plan for PanCa patients. We aimed to perform a meta-analysis of endoscopic ultrasonography (EUS) in the tumor node (TN) staging and evaluation of vascular invasion in PanCa. Methods: A meta-analysis of diagnostic accuracy parameters was performed to evaluate the EUS-based TN staging, and vascular invasion by PanCa was compared to the results of intraoperative staging or to the histopathology of resected specimens. Results: Twenty studies with 726 PanCa cases were identified from 281 articles. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were 0.72, 0.90, 6.27, 0.28, and 24.69, respectively, for T1-2 staging and 0.90, 0.72, 3.58, 0.16, and 24.69, respectively, for T3-4 staging. The overall sensitivity, specificity, PLR, NLR, and DOR were 0.62, 0.74, 2.54, 0.51, and 6.67, respectively, for N staging (positive vs. negative) and 0.87, 0.92, 7.16, 0.20, and 56.19, respectively, for vascular invasion. The area under the curve was 0.90, 0.90, 0.79, and 0.94 for T1-2 staging, T3-4 staging, N staging, and vascular invasion, respectively. Conclusions: EUS is a reliable and accurate diagnostic tool for the TN staging and evaluation of vascular invasion in PanCa. The nodal staging accuracy using EUS is less satisfactory. i 2014 S. Karger AG, Basel

Impact of a multidisciplinary cancer care program and nurse navigation on pancreatic adenocarcinoma treatment.

200 Background: Treatment of pancreatic adenocarcinoma (PanCa) is complex and requires input from multiple physicians. We developed a unique gastrointestinal (GI) cancer program utilizing a multidisciplinary conference, a multidisciplinary clinic (MDC), a GI nurse navigator (NN) and continuous quality assessment with a nurse clinical auditor. The impact of this program, which requires significant additional resources, on adherence to evidence based cancer treatment for newly diagnosed PanCa patients is unknown. Methods: The GI (NN) interviews patients, coordinates staging and biopsies, physician visits and subsequent adjuvant care in the first year of diagnosis. A clinical quality specialist abstracted all treatment received (surgical, radiation, chemotherapy, palliative), and data was entered into a GI Quality database. Treatment received by patients in first year of diagnosis was compared to NCCN guidelines. Results: From January 2010 to April 2012, 68 patients with newly diagnosed PanCA were evaluated/treated. Overall compliance with NCCN treatment guidelines was 83.4%. Compliance was highest for stage I (almost all underwent surgical resection) and stage IV (none underwent surgery). Utilization of adjuvant therapies was 80% (16/20) for patients with stageI/II disease. Eight patients with stage I/II disease did not undergo surgery, due to comorbidities or disease progression. Conclusions: A novel GI cancer program utilizing a multispecialty MDC and a dedicated GI NN demonstrates very high compliance with evidence based therapy for first line treatment for PanCa patients. Although resource intensive, this level of adherence to evidence-based medicine is encouraging and higher than prior reports for PanCa. The relative contribution of the GI MDC clinic format versus the NN warrants further study. [Table: see text]

447PD - Preclinical and Clinical Evaluation of the Combination of Sorafenib and Everolimus in Patients with Advanced Solid Tumors

ABSTRACT Background Using a patient-derived primary pancreatic cancer (PanCa) xenograft SCID mouse model, we found synergistic anti-tumor effects of sorafenib (S) 20 mg/kg + everolimus (E) 1 mg/kg, and greater efficacy than either drug alone. No significant mouse toxicity was observed (weight loss, fur quality, GI toxicity). Here, we conducted a phase I and pharmacokinetic (PK) study of S + E in patients with advanced solid tumors, intending to expand to a phase II PanCa trial. Methods: Patients with advanced solid tumors were treated at dose levels (DL): [DL1] S 400 mg bid + E 5 mg daily; [DL2] S 400 mg bid + E 10 mg daily every 28-day cycle using a 3 + 3 dose escalation design. Patients started treatment with either S or E alone during a 1-week run-in, and the other agent added from Cycle 1 Day 1 onwards. Plasma samples were collected and analyzed for S and E, and PK was compared to preclinical studies. Results Ten of 22 patients were evaluable for dose-limiting toxicity (DLT). Two of 6 and 3 of 4 patients developed DLT at DL1 and 2 respectively, including grade (G) 3 diarrhea, rash, hypophosphatemia, hand-foot syndrome and G4 fistula. Median cycles received were 1.5. Clinical E exposure (AUC profile) was significantly lower (1/100th) than in preclinical combination studies whereas S exposure was comparable. Best response was stable disease for 6 cycles (168 days) in a uterine carcinosarcoma patient at DL1 (prior therapy PFS 114 days). Intention-to-treat analysis of 12 advanced gemcitabine-refractory (GR) PanCa patients showed median survival of 2.7 mo (95%CI 0, 6.8 mo). No PK interaction between S and E was observed. Conclusions E at doses 5 mg and 10 mg daily combined with S 400 mg bid were not tolerable in patients. S toxicity appeared accentuated by E co- administration with no drug-drug PK interaction observed. Efficacy was observed in uterine carcinosarcoma but no significant efficacy in GR-PanCa. Although our preclinical model indicated efficacy of S + E in PanCa, it failed to predict the clinical toxicity profile. Disclosure All authors have declared no conflicts of interest.

Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen.

4034 Background: TGF-β2 overexpression in solid tumors triggers key cancer pathomechanisms, i.e. suppression of antitumor immune responses system and metastasis. Trabedersen specifically inhibits TGF-β2 expression. In the clinical Phase I/II study we evaluate MTD, safety, pharmakokinetics (PK), and efficacy of i.v. trabedersen in patients with advanced tumors. Methods: A total of 61 patients with pancreatic cancer (PancCa, n=37), malignant melanoma (MM, n=19), or colorectal carcinoma (n=5) were treated with i.v. trabedersen as 2nd to 4th-line therapy with escalating doses in 2 treatment schedules. (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles). Within the 1st schedule, the MTD was established at 160 mg/m2/d. In the 2nd schedule dose-escalation was stopped before reaching MTD. In the Phase II-part of the study further PancCa and MM patients were treated with 140 mg/m2/d. For assessment of PK parameters, plasma time profiles were analyzed for trabedersen and its n-1 to n-5 metabolites by non-compartimental analysis. Results: Trabedersen was safe and well-tolerated. The only expected adverse reaction identified is non-serious and transient thrombocytopenia. Only 2 SAEs (gastrointestinal hemorrhage und pyrexia) were considered as possibly related to study medication. Further clinical development will focus on PancCa patients receiving 140 mg/m2/d trabedersen as 2nd-line treatment. Survival analysis of these patients revealed a mOS of 13.4 months (n=9; 95% CI: 2.2, 39.7). One PanCa patient had a complete response of liver metastases and is still alive after 75 months. Promising efficacy data were also seen in MM patients enrolled into the last cohort (140 mg/m2/day) with a current mOS of 9.3 months (n=14; 95% CI: 6.5, 12.2). PK analyses showed for both treatment schedules that exposure to trabedersen was in the expected range for all doses and half-life of trabedersen (1.12 to 2.08 hrs) as well as clearance (2.22-4.37 L/h*m2) were independent of dose. Conclusions: Trabedersen showed excellent safety and encouraging survival results in the Phase I/II clinical study. A randomized, active-controlled study in 2nd line stage IV PanCa patients is in preparation.

Phase I/II study with trabedersen (AP 12009) monotherapy for the treatment of patients with advanced pancreatic cancer, malignant melanoma, and colorectal carcinoma.

2513 Background: TGF-β2 regulates key cancer mechanisms, particularly immunosuppression and metastasis. The antisense oligonucleotide trabedersen (AP 12009) specifically inhibits TGF-β2 expression. A randomized, active-controlled Phase IIb study in high-grade glioma patients showed a clear survival benefit for trabedersen over standard chemotherapy. This study evaluates the maximum tolerated dose (MTD), safety, pharmakokinetics, and efficacy of intravenous trabedersen treatment in patients with advanced solid tumors. Methods: This open label, multicenter, Phase I/II study enrolled 33 patients with advanced pancreatic carcinoma (PanCa, stage III/IV, N=23), malignant melanoma (stage III/IV, N=5), or colorectal carcinoma (stage III/IV, N=5) into the dose-escalation part of the study. Patients were treated in cohorts with i.v. trabedersen monotherapy as 2nd to 4th-line therapy with escalating doses in 2 treatment schedules (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles). Results: Trabedersen was safe and well-tolerated. The only expected adverse reaction identified is non-serious and transient thrombocytopenia. In the Phase II-part of the study further PanCa and melanoma patients were treated with the 4d on, 10d off schedule with a dose of 140 mg/m2/d. The median overall survival of PanCa patients treated 2nd-line with the 2nd schedule-140 mg/m2/d regimen (N=9) has not yet been reached (12.9 months as of Dec 2010). One PanCa patient had a complete response of liver metastases and is still alive after 61 months (status Oct 2010). Further promising efficacy data from the dose-escalation are: one patient with metastatic and DTIC-resistant melanoma who is still alive 19.7 months after start of treatment (status Dec 2010); 3 other patients with stage IV melanoma, treated 3rd or 4th-line with trabedersen, who survived for 11.4, 13.8, and 18.6 months. Conclusions: Trabedersen showed excellent safety and encouraging survival results. The evaluation of 14 melanoma patients treated with the 4d on, 10d off-140 mg/m2/d regimen is ongoing. A randomized, active-controlled study in PanCA patients is in preparation.

C-antineutrophil cytoplasmic antibody positivity in vasculitis patients is associated with the Z allele of alpha-1-antitrypsin, and P-antineutrophil cytoplasmic antibody positivity with the S allele

Antineutrophil cytoplasmic antibodies (ANCA) in vasculitis have either cANCA or pANCA patterns as defined by immunofluorescence. The target autoantigen of cANCA is usually proteinase 3 (PR3), whereas that of pANCA is usually myeloperoxidase (MPO). Alpha-1-antitrypsin (alpha 1AT) is the major physiological inhibitor of PR3, while MPO is an inhibitor of alpha 1AT. To determine whether there was an association between ANCA positive vasculitis, ANCA pattern, and alpha 1AT deficiency alleles, we studied alpha 1AT phenotypes of 99 cANCA and 99 pANCA positive vasculitis patients by isoelectric focusing and immunoblotting, and compared them with 2310 controls from the same geographical area. C-ANCA patients showed an increased frequency of the Z allele (0.055 versus 0.018 in controls), conferring a relative risk of 3. They showed no increase in frequency of the S allele. P-ANCA patients showed an increased frequency of the S allele (0.091 versus 0.046 in controls) conferring a relative risk of 2. The frequency of the Z allele also appeared to be increased (0.030 versus 0.018 in controls), but this was not statistically significant. These findings demonstrate an association between ANCA-positive vasculitis and deficiency phenotypes of alpha 1AT, and suggest a role for alpha 1AT in the development of systemic vasculitis.