Treatment Of Pancreatic Cancer Patients Research Articles

Abstract 3907: Human pancreatic cancer stem cells utilized to generate an in-vivo mouse/rat model system for screening potential drug candidates for treatment of pancreatic cancer patients

Abstract Cancer stem cells (CSCs) are critical for engraftment and long-term growth of many tumors, including pancreatic cancer. The Cancer Stem cells are less sensitive to conventional chemotherapies and radiation therapies, and treatments that can target CSCs are critically needed. Human Pancreatic Cancer is a heterogeneous tumor composed of tumor cells and small fraction of cancer stem cells, with high tumorigenic potential. Pancreatic cancer stem cells are phenotypically similar to the normal stem cells, they express CD133 gene and other genes characteristic of neural stem cells (Nestin) and posses self-renewal potential. The CD133+ Pancreatic CSCs have been isolated with Celprogen Media and ECM and characterized as chemo-/radio-resistant tumor-initiating cells which are responsible as one of the major factors involved in post-treatment recurrence. In order to explore the molecular properties of tumorigenic CD133+ Pancreatic CSCs that resist treatment, we isolated CD133+ Pancreatic CSCs from tumors that are recurrent and have previously received chemo-/radio-therapy. We found that the purified CD133+ Pancreatic CSCs sorted from the CD133+ Pancreatic CSC spheres express SOX2 ,CD44, Nestin and are capable of clonal self-renewal. We generated in-vivo model systems in mice and rats with these cells to screen potential drug agents for the treatment of Pancreatic Cancer patients. We were capable of generating Pancreatic tumors in mice and rats within 20 days by subcutaneously injecting 1000 Pancreatic CSCs at the hind limbs of the rodents. Within day 5 the Pancreatic CSCs were already present in the rodent's pancreas. At days 10, 15 & 20 the Pancreatic CSCs labeled with GFP were located in the rodent's pancreas. We tested various compound candidates in this model system and we were able to show decrease in Pancreatic tumor when the treatment was started at day 10. We were able to demonstrate gene signatures associated with Pancreatic CSCs in this model system. We do see a down regulation of certain cancer promoter genes in the treatment group when compared to non-treatment groups. Citation Format: Cristian Sharma, Patrick Cleary, Esteban Gomez, Shruthi Satish, Michael Sharma, Michael Perez, Natalee Amecuza, Jitesh Jani, Rubio Punzalan, Jay P. Sharma. Human pancreatic cancer stem cells utilized to generate an in-vivo mouse/rat model system for screening potential drug candidates for treatment of pancreatic cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3907. doi:10.1158/1538-7445.AM2014-3907

URG11 predicts poor prognosis of pancreatic cancer by enhancing epithelial-mesenchymal transition-driven invasion.

The poor prognosis and high recurrent rate of pancreatic cancer (PC) necessitates the discovery of new predictive markers of PC invasion and prognosis. In this study, we evaluated the expression pattern of up-regulated gene 11 (URG11) in a tissue microarray with 18 pairs of PC and adjacent normal tissues. It was shown that URG11 was significantly up-regulated in PC tissues. High expression levels of URG11 were detected in all PC specimens, but were rarely detected in adjacent non-tumorous tissues. In addition, high expression of URG11 was correlated to poor prognosis. Furthermore, it was discovered that URG11 was correlated to epithelial-mesenchymal transition (EMT) markers and clinical pathological parameters indicative of high PC invasion, while knockdown of URG11 significantly changed the expression pattern of EMT markers and decreased the invasion of PC cells. These findings indicate that URG11 might enhance the invasion of PC by inducing EMT and thus lead to poor PC prognosis. Thus, URG11 has the potential to be a new predictive biomarker of PC invasion and prognosis, which may help in the diagnosis and treatment of PC patients.

Gemcitabine and tegafur combination in adjuvant treatment of pancreatic cancer patients with low expression of hENT1

Gemcitabine and tegafur combination in adjuvant treatment of pancreatic cancer patients with low expression of hENT1

Pancreatic cancer stem cells: association with cell surface markers, prognosis, resistance, metastasis and treatment.

In this review, we will discuss the recent advances in understanding the pancreatic cancer stem cells. Identification and characterization of pancreatic cancer stem cells may aid our ability to improve diagnosis and treatment of pancreatic cancer. Novel approaches are necessary for the earlier diagnosis of pancreatic cancer as well as improved treatment to prevent distal metastasis. Key markers for the identification of pancreatic cancer stem cells include CD133, ALDH, side population cells and the triplet combination CD44+ CD24+ESA+. The roles of these proteins as markers for stemness in pancreatic cancer as well as recent studies with the c-Met proto-oncogene will be discussed. The ability of these markers to predict survival of pancreatic cancer patients is being examined clinically. Stemness and resistance to chemotherapy and radiotherapy may be linked. Expression of some of these markers may be associated with distant metastasis. Treatment of pancreatic cancer patients by targeting the pancreatic cancer stem cells holds promise.

Phase I/II trial of autophagy inhibition in combination with neoadjuvant gemcitabine in patients with high-risk pancreatic adenocarcinoma: Safety, clinical response, and correlative studies.

218 Background: Autophagy is a cell survival mechanism, upregulated in pancreatic ductal adenocarcinoma, correlating adversely with response to therapy and prognosis. The autophagy inhibitor hydroxychloroquine (HCQ) is a novel treatment. Methods: A Phase I/II trial examined pre-operative gemcitabine with HCQ in the treatment of pancreatic cancer patients. Eligibility was restricted to those predicted to have limited survival following surgical resection. Two doses of gemcitabine (1500mg/m2) were administered with oral HCQ (200-1200mg/day) for 31 days until operation in a Storer phase 1 design. Primary endpoint was the safety and tolerability of HCQ. Secondary endpoints were clinical response as assessed by CA 19-9 and R0 resection rates. LC3 and cleaved caspase 3 staining were assessed as biologic correlates to clinical response. Additional exploratory endpoints included serum levels of HMGB1, IL-6, and DNA DAMPs. Results: Thirty-five patients were enrolled in the safety phase of the trial. Two patients withdrew consent prior to treatment and two others were removed due to a stroke and allergic rash, resulting in 31 patients completing treatment. There were no dose limiting toxicities and no treatment delays. 14 patients (45%) had a decrease in CA19-9 of >50% following treatment. 29 patients (94%) underwent surgical resection with an R0 resection rate of 81%. There was one peri-operative mortality (3.2%) with significant morbidity (Grade 3/4) affecting 29% of patients. Increases in pancreatic LC3 staining were consistent with autophagy inhibition. There was a statistically non significant trend towards increased apoptosis with increasing doses of HCQ. Both mitochondrial and nuclear DNA (p = .09) decreased. During treatment, HMGB1 and IL-6 levels rose and then returned to normal levels. Conclusions: Pre-operative autophagy inhibition with HCQ in combination with gemcitabine is safe and tolerable and associated with biomarkers of response. This regimen has promise as a biologically active strategy and future trials will examine HCQ in combination with Nab-paclitaxol/Gemcitabine combinations. Clinical trial information: NCT01128296.

Capture, release and culture of circulating tumor cells from pancreatic cancer patients using an enhanced mixing chip

Circulating tumor cells (CTCs) from peripheral blood hold important information for cancer diagnosis and disease monitoring. Analysis of this "liquid biopsy" holds the promise to usher in a new era of personalized therapeutic treatments and real-time monitoring for cancer patients. But the extreme rarity of CTCs in blood makes their isolation and characterization technologically challenging. This paper reports the development of a geometrically enhanced mixing (GEM) chip for high-efficiency and high-purity tumor cell capture. We also successfully demonstrated the release and culture of the captured tumor cells, as well as the isolation of CTCs from cancer patients. The high-performance microchip is based on geometrically optimized micromixer structures, which enhance the transverse flow and flow folding, maximizing the interaction between CTCs and antibody-coated surfaces. With the optimized channel geometry and flow rate, the capture efficiency reached >90% with a purity of >84% when capturing spiked tumor cells in buffer. The system was further validated by isolating a wide range of spiked tumor cells (50-50,000) in 1 mL of lysed blood and whole blood. With the combination of trypsinization and high flow rate washing, captured tumor cells were efficiently released. The released cells were viable and able to proliferate, and showed no difference compared with intact cells that were not subjected to the capture and release process. Furthermore, we applied the device for detecting CTCs from metastatic pancreatic cancer patients' blood; and CTCs were found from 17 out of 18 samples (>94%). We also tested the potential utility of the device in monitoring the response to anti-cancer drug treatment in pancreatic cancer patients, and the CTC numbers correlated with the clinical computed tomograms (CT scans) of tumors. The presented technology shows great promise for accurate CTC enumeration, biological studies of CTCs and cancer metastasis, as well as for cancer diagnosis and treatment monitoring.

Dendritic cell immunotherapy combined with gemcitabine chemotherapy enhances survival in a murine model of pancreatic carcinoma

Pancreatic cancer is an extremely aggressive malignancy with a dismal prognosis. Cancer patients and tumor-bearing mice have multiple immunoregulatory subsets including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) that may limit the effectiveness of anti-tumor immunotherapies for pancreatic cancer. It is possible that modulating these subsets will enhance anti-tumor immunity. The goal of this study was to explore depletion of immunoregulatory cells to enhance dendritic cell (DC)-based cancer immunotherapy in a murine model of pancreatic cancer. Flow cytometry results showed an increase in both Tregs and MDSC in untreated pancreatic cancer-bearing mice compared with control. Elimination of Tregs alone or in combination with DC-based vaccination had no effect on pancreatic tumor growth or survival. Gemcitabine (Gem) is a chemotherapeutic drug routinely used for the treatment for pancreatic cancer patients. Treatment with Gem led to a significant decrease in MDSC percentages in the spleens of tumor-bearing mice, but did not enhance overall survival. However, combination therapy with DC vaccination followed by Gem treatment led to a significant delay in tumor growth and improved survival in pancreatic cancer-bearing mice. Increased MDSC were measured in the peripheral blood of patients with pancreatic cancer. Treatment with Gem also led to a decrease of this population in pancreatic cancer patients, suggesting that combination therapy with DC-based cancer vaccination and Gem may lead to improved treatments for patients with pancreatic cancer.

Inhibition of the Growth of Patient-Derived Pancreatic Cancer Xenografts with the MEK Inhibitor Trametinib Is Augmented by Combined Treatment with the Epidermal Growth Factor Receptor/HER2 Inhibitor Lapatinib

Mutations of the oncogene KRAS are important drivers of pancreatic cancer progression. Activation of epidermal growth factor receptor (EGFR) and human EGFR2 (HER2) is observed frequent in pancreatic adenocarcinomas. Because of co-activation of these two signaling pathways, we assessed the efficacy of inhibition of EGFR/HER2 receptors and the downstream KRAS effector, mitogen-activated protein kinase/extracellular-signal regulated kinase (ERK) kinase 1 and 2 (MEK1/2), on pancreatic cancer proliferation in vitro and in a murine orthotopic xenograft model. Treatment of established and patient-derived pancreatic cancer cell lines with the MEK1/2 inhibitor trametinib (GSK1120212) inhibited proliferation, and addition of the EGFR/HER2 inhibitor lapatinib enhanced the inhibition elicited by trametinib in three of eight cell lines. Importantly, in the orthotopic xenograft model, treatment with lapatinib and trametinib resulted in significantly enhanced inhibition of tumor growth relative to trametinib treatment alone in four of five patient-derived tumors tested and was, in all cases, significantly more effective in reducing the size of established tumors than treatment with lapatinib or trametinib alone. Acute treatment of established tumors with trametinib resulted in an increase in AKT2 phosphorylation that was blunted in mice treated with both trametinib and lapatinib. These data indicate that inhibition of the EGFR family receptor signaling may contribute to the effectiveness of MEK1/2 inhibition of tumor growth possibly through the inhibition of feedback activation of receptor tyrosine kinases in response to inhibition of the RAS-RAF-MEK-ERK pathway. These studies provide a rationale for assessing the co-inhibition of these pathways in the treatment of pancreatic cancer patients.

Response evaluation following neoadjuvant treatment of pancreatic cancer patients

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplastic entities, with a very poor prognosis characterized by a high mortality rate and short survival. This is due both to its aggressive biological behaviour and the high incidence of locally advanced stages at the time of the initial diagnosis. The limits of resectability and the role of neoadjuvant (radio) chemotherapy for PDAC management are still unclear. A recently published article by Kats et al compared the radiological, surgical and histopathological results of 129 patients with borderline resectable tumors undergoing neoadjuvant treatment followed by surgery. Although post-neoadjuvant treatment imaging implied a low response rate, a high rate of complete resections was achieved. This seems to confirm that, though radiology has made a significant progress in defining locally advanced PDAC, there is place for further improvement. In particular, the differentiation between radiotherapy-induced scarring/fibrosis and cancer-associated desmoplasia remains a clinical/radiological challenge. Though selection of patients with occult systemic disease is possible with neoadjuvant treatment, downstaging does not seem to occur frequently. Thus, development of novel, more aggressive (radio) chemotherapy regimens is required to improve prognosis of patients with locally unresectable but not systemically micro-metastasized tumors.

Effects of porcine pancreatic enzymes on the pancreas of hamsters. Part 1: basic studies.

Porcine pancreatic enzymes (PPE) extracted from glandular stomach has been used for the treatment of pancreatic cancer patients. Unfortunately, no information is available on the in vitro and in vivo effect on the pancreas and other tissues.We used Syrian Golden hamsters, a unique pancreatic cancer model, to obtain basic information on PPE for its eventual use for the treatment of pancreatic cancer.PPE was used in different concentrations in vitro and in vivo. The stability of the enzyme in the water solution was investigated. It was given to the hamsters by gavage in concentrations of 1g/kg and 400 mg/kg for short periods and in aqueous solution for 65 days. Plasma enzyme and insulin, the size of islets and the number of the insulin cells per islet were examined.The enzyme activity of PPE was maintained in water solution for at least 24 hours. Due to its content of calcium chloride it showed a high toxicity to normal and malignant hamster pancreatic cancer cells and human pancreatic cancer cell lines in vitro. PPE did not alter the plasma pancreatic enzyme levels regardless of the dose, duration and application route. On the contrary, PPE reduced their levels significantly. Remarkably, it also reduced the level of insulin, the size of the islets and the number of insulin cells in the islets significantly.The results imply that PPE does not enter the blood circulation but it appears to slow down the function of both the exocrine and endocrine pancreas.

The effect of depression on stage at diagnosis, treatment, and survival in pancreatic adenocarcinoma

Depression has been associated with delayed presentation, inadequate treatment, and poor survival in patients with cancer. Using Surveillance, Epidemiology and End Results and Medicare linked data (1992-2005), we identified patients with pancreatic adenocarcinoma (N = 23,745). International classification of diseases, 9th edition, clinical modification codes were used to evaluate depression during the 3 to 27 months before the diagnosis of cancer. The effect of depression on receipt of therapy and survival was evaluated in univariate and multivariate models. Of patients with pancreatic cancer in our study, 7.9% had a diagnosis of depression (N = 1,868). Depression was associated with increased age, female sex, white race, single or widowed status, and advanced stage disease (P < .0001). In an adjusted model, patients with locoregional disease and depression had 37% lower odds of undergoing surgical resection (odds ratio, 0.63; 95% confidence interval, 0.52-0.76). In patients with locoregional disease, depression was associated with lower 2-year survival (hazard ratio, 1.20; 95% confidence interval, 1.09-1.32). After adjusting for surgical resection, this association was attenuated (hazard ratio, 1.14; 95% confidence interval, 1.04-1.26). In patients who underwent surgical resection, depression was a significant predictor of survival (hazard ratio, 1.34; 95% confidence interval, 1.04-1.73). Patients with distant disease and depression had 21% lower odds of receiving chemotherapy (odds ratio, 0.79; 95% confidence interval, 0.70-0.90). After adjusting for chemotherapy for distant disease, depression was no longer a significant predictor of survival (hazard ratio, 1.03; 95% confidence interval, 0.97-1.09). The decreased survival associated with depression appears to be mediated by a lower likelihood of appropriate treatment in depressed patients. Accurate recognition and treatment of pancreatic cancer patients with depression may improve treatment rates and survival.

Abstract 4959: Osteoprotegerin mediates resistance to TRAIL-induced apoptosis in pancreatic ductal adenocarcinoma

Abstract [Purpose] Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) has been shown to have great potential for the treatment of most human tumor cells without harming normal cells. However, some cancers show resistance to TRAIL induced apoptosis. The poor prognosis of both pancreatic ductal adenocarcinoma (PDAC) is likely due to the absence of valid approaches for early detection, the frequency of its metastases at the time of diagnosis, frequent recurrence after surgery, and poor responsiveness to chemotherapy. PDAC is also known as the most common resistant cells to TRAIL. Since osteoprotegerin (OPG) is known as a decoy receptor that binds to TRAIL and inhibits TRAIL-induced apoptosis, we hypothesized that OPG might play a role in mediating resistance to apoptosis in PDAC cells. [Methods and Results] To investigate the expression of OPG in PDAC cells, RT-PCR, Western blot and ELISA were performed. From the results, we found significant expression of OPG in both cell and cell culture medium. To investigate the apoptotic activity of TRAIL, we performed cell viability assay and apoptosis assay with or without siRNA against OPG. We found that PDAC cells showed significantly resistance to TRAIL induced apoptosis and knocking down of OPG sensitized TRAIL induced apoptosis in PDAC cells. [Conclusion] This study demonstrated that OPG played a role in resistance to TRAIL-induced apoptosis in PDAC cells. Expression of OPG might provide PDAC cells with an essential growth advantage through resistance to TRAIL-induced apoptosis. Inhibition of OPG expression and blocking OPG function might be a new therapeutic approach for the treatment of pancreatic cancer patients. 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 4959. doi:1538-7445.AM2012-4959

Abstract 1776: Antitumor activity of Chk1 inhibitor LY2606368 as a single agent in SW1990 human pancreas orthotopic tumor model

Abstract ChK1 is a key kinase in the DNA damage response signaling network, including cell cycle checkpoints, DNA repair, apoptosis and transcription, thus emerging as an attractive target in anti-cancer therapy. LY2606368, a potent and selective ATP competitive inhibitor of the Chk1 protein kinase, is currently in clinical development. LY2606368 has been reported to inhibit Chk1 auto-phosphorylation activated by DNA damaging agents, and induce phosphorylation of H2AX, a DNA damage maker in multiple cancer cell lines in vitro. In addition, LY2606368 has demonstrated potent single agent activity and potentiates the anti-tumor activity of DNA damaging agents in vivo. Pancreatic cancer is one of the least curable cancers, with an approximate 5% overall 5-year survival for all patients. In the current study, we evaluated the efficacy of LY2606368 (as its methanesulfonate salt, hydrate; LY2606368.MeSO3H.H2O = LY2940930) in pancreatic cancer cell lines in vitro and xenograft tumors (including subcutaneous and orthotopic models) in vivo. LY2606368 alone significantly inhibited the cell proliferation in a variety of pancreatic cell lines (SW1990, SU86.86, Bx-PC3, AsPC-1, CFPAC-1, Capan-2, HPAF-II) with SW1990 being the most sensitive (IC50=1.5 nM). In SW1990 subcutaneous xenograft model, LY2606368 showed substantial dose-dependent inhibition of tumor growth. In SW1990 pancreas orthotopic model, which represents the local and metastatic growth pattern seen in pancreas cancer patients, LY2606368 treatment resulted in over 92% inhibition of primary tumor growth as well as 100% inhibition of metastasis to lymph node, spleen and intestine. The anti-tumor effect of LY2606368 treatment was further demonstrated in comparing with gemcitabine (the standard of care for pancreas cancer patient) in SW1990 orthotopic model. The anti-tumor and/or anti-metastasis mechanism of LY2606368 was also investigated, including phosphorylation of H2AX, cell proliferation, cell survival, and soft agar anchorage-independent growth. Together, our findings demonstrate the therapeutic potential of LY2606368 as a single agent in the treatment of pancreatic cancer patients. 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 1776. doi:1538-7445.AM2012-1776

A phase I/II, non-randomized, feasibility/safety and efficacy study of the combination of everolimus, cetuximab and capecitabine in patients with advanced pancreatic cancer

Summary Background Improvements in knowledge of molecular mechanisms in cancer are the basis for new studies combining chemotherapy with targeted drugs. Inhibition of the epidermal growth factor receptor (EGFR) by erlotinib or cetuximab has limited or no activity, respectively, in pancreatic cancer. The crosstalk between EGFR and mammalian target of rapamycin (mTOR) pathways is a potential mechanism of resistance; therefore we conducted a study to explore safety and efficacy of multiple pathway inhibition by cetuximab and everolimus in combination with capecitabine. Methods Safety and efficacy of fixed standard dose cetuximab in combination with various dose levels of everolimus (5–10 mg/day) and capecitabine (600–800 mg/m2 bid, 2 weeks every 3 weeks) were investigated in a phase I/II study in patients with advanced pancreatic cancer. The primary endpoint was objective response. Results Sixteen patients were treated in the phase I part at two dose levels. Mucositis, rash and hand-foot syndrome were dose-limiting toxicities. Dose level 1 (everolimus 5 mg/day, capecitabine 600 mg/m2 bid for 2 weeks every 3 weeks and cetuximab 250 mg/m2 weekly) was considered the maximum tolerated dose (MTD). Of 31 patients in the phase II part, partial response was documented in two patients (6.5%) and five (16.1%) had stable disease. Median overall survival was 5.0 months (CI 3.1–6.8). Conclusion The schedule of capecitabine, everolimus and cetuximab resulted in considerable epidermal and mucosal toxicities and prevented escalation to optimal dose levels. Because of toxicity and low efficacy this treatment combination cannot be recommended for treatment in pancreatic cancer patients.

Intervention effect of palliative treatment of patients with pancreatic cancer and their families to implement the same period nursing

Objective To explore intervention effect of palliative treatment of pancreatic cancer patients and their families to implement the same period nursing. Methods 48 cases of patients with pancreatic cancer were divided into intervention group and control group by odd and even numbers in hospital, each group was 24 cases, the intervention group implemented the same period nursing to the patients with pancreatic cancer and their families, the control group took the whole patient-centered nursing intervention, Before and after the intervention, the questionnaire survey was conducted to the patients by Hamilton Depression Rating Scale and the Perceived Social Support Scale, Patients were evaluated for depression and social support. Results After the nursing intervention to palliative treatment of patients with pancreatic cancer and their families to implement the same period nursing, patients with depression had significantly improved than that of the control group, the difference was significant [(10. 17 ± 2.41) vs (14.46 ± 1. 25), t = -7. 750, P ＜ 0. 01]; Intervention group in improving the perception of social support group was better than that in the control group [61.79±7.40) vs (51.08 ±4.94) ,t =5. 894,P ＜0. 0l]. Also it found, the control group scores after the intervention to support the family has declined compared with that before intervention, the intervention group scores after the intervention to support the family has increased compared with that before intervention, and differences were statistically significant (P ＜0. 01). Conclusions The methods of palliative treatment of patients with pancreatic cancer and their families to implement the same period nursing were feasible, help alleviate depression in patients and improve their quality of lives. Key words: Palliative care; Pancreatic neoplasms; Nursing; Depression; Social support

First-line treatment of pancreatic cancer patients with the combination of 5-fluorouracil/folinic acid plus gemcitabine: a multicenter phase II trial by the CONKO-study group

This open-label, multi-center phase II study investigated the efficacy and safety of the combination of 5-fluorouracil (5-FU)/folinic acid (FA) plus gemcitabine (GFF) in patients with advanced pancreatic cancer. The study is based on our completed dose finding phase I trial. A total of 90 patients (pts) were recruited between 02/2000 and 04/2002 to receive 5-FU 750mg/m(2) (24h, i.v.), FA 500mg/m(2) (2h, i.v.) and gemcitabine 1,000mg/m(2) (30min, i.v.) on days 1, 8, 15, and 22. Treatment was repeated on day 43 until disease progression. The primary objective was the 1-year survival rate. The trial was conducted in compliance with the Declaration of Helsinki. The 1-year survival rate was 25% [95% CI: 16-34], median overall survival was 6.8months [95% CI: 5.13-8.45], 9 patients showed partial responses (PR) so that the overall response rate was 10.3%. Overall control rate (PR+stable disease for at least 6months) was 56%. Median time to progression was 4.6months [95% CI: 3.68-5.52]. In 402 GFF cycles, we observed adverse events grade 3 in up to 10% of patients and grade 4 below 5% of patients. The GFF combination appears to be effective and well tolerated. This intravenous regimen represents an intensified therapy with low frequency of toxicities and seems to be convenient for patients who are unable to get oral anti-neoplastic medication. After these encouraging results, the German CONKO-002 trial investigated the GFF regimen versus single-agent gemcitabine.

Pancreatic cancers require autophagy for tumor growth

Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.

Abstract B17: PDL192, a humanized antibody to TweakR exhibits potent antitumor activity in pancreatic cancer models

Abstract Approximately 42,000 new cases of pancreatic cancer were diagnosed in the United States in 2009, and the 5-year survival rate for this disease is exceedingly low (approximately 5%). Given the lack of therapeutic success with current standards of care, new therapies are clearly needed to treat this disease. We have generated PDL192, a humanized IgG1 antibody to TweakR (Fn14, TNFRSF12A, CD266), a cell surface protein and member of the TNF receptor superfamily. PDL192 has been shown to exhibit antitumor activity in xenograft models on a range of solid tumor types via both direct tumor cell growth inhibition and by antibody-dependent cellular cytotoxicity. In this study, we explored the activity of PDL192 in pancreatic cancer models. Approximately 60% of primary pancreatic cancers express TweakR protein at high levels, as determined by immunohistochemistry. PDL192 exhibited potent anti-tumor activity in two cell line xenograft models, Panc1 and MiaPaCa2. PDL192 also exhibited significant anti-tumor activity against 3 of 6 primary tumor xenograft models derived from pancreatic patients. PDL192 was also tested in combination with gemcitabine, the most common treatment for pancreatic cancer patients. In the Panc1 and MiaPaCa2 xenograft models, the combination of PDL192 and gemcitabine exhibited more potent activity than either agent alone. In three of five primary tumor xenograft models tested, combining PDL192 and gemcitabine also resulted in greater anti-tumor activity than either agent alone. In one of the primary tumor models, where neither PDL192 nor gemcitabine alone exhibited significant anti-tumor activity, the combination completely inhibited tumor growth. The activity of PDL192 in multiple pancreatic xenograft models using both cell lines and primary tumors is supportive of the use of PDL192 for the treatment of pancreatic cancer. PDL192 is currently being evaluated in a phase1 safety study in patients with solid tumors. Citation Information: Clin Cancer Res 2010;16(14 Suppl):B17.

Impact of 18-Fluorodeoxyglucose Positron Emission Tomography on the Management of Pancreatic Cancer

BackgroundWe compared the usefulness of positron emission tomography with the glucose analogue 2-deoxy-2-[18F]-fluoro-d-glucose (FDG-PET) and multidetector-row computed tomography (MD-CT) in diagnosing pancreatic cancer and in determining the patients’ suitability for surgery. MethodsWe reviewed the clinical FDG-PET data of 103 consecutive pancreatic cancer patients between July 2004 and March 2009. ResultsThe detection rates of pancreatic cancer by MD-CT (89%) and FDG-PET (91%) were similar. From the MD-CT findings, 38 patients were judged as operable, and 65, inoperable. Among the inoperable patients, noncurative factors (metastasis to the liver, peritoneum, remote lymph nodes, bones, and other organs and major arterial invasion) were detected by MD-CT and/or FDG-PET. Detection rates of liver metastasis and arterial invasion by FDG-PET were significantly inferior to those of MD-CT (neither was detected by FDG-PET alone). Remote lymph nodes and bone metastasis were detected in 20 lesions by FDG-PET alone; however, MD-CT indicated other noncurative factors in these patients. All 65 patients could be diagnosed as inoperable without FDG-PET. ConclusionsFDG-PET is not a suitable imaging modality for either diagnosis or preoperative treatment in pancreatic cancer patients. Since it is expensive, FDG-PET as a routine diagnostic tool in pancreatic cancer patients must be used with caution.

Abstract 5420: Multi-targeted approach for inhibiting pancreatic tumor growth in vivo consistent with in vitro results

Abstract Inactivation of survival pathways such as NF-κB, cyclooxygenase (COX-2) or epidermal growth factor receptor (EGFR) signaling individually may not be sufficient for the treatment of advanced pancreatic cancer (PC). Since these pathways are well known in the pathogenesis and aggressiveness of PC, we hypothesized that a multitargeted approach for the inhibition of NF-κB, COX-2 and EGFR may therefore be useful to improve the outcome of anti-EGFR therapies and will also potentiate the anti-tumor effects of gemcitabine. In this study, we determined the cell viability in seven PC cell lines with 3,3′-diindolylmethane (B-DIM), erlotinib or gemcitabine alone or in combination using MTT assay. Significant inhibition in cell viability and induction in apoptosis was observed in PC cells expressing high levels of COX-2, EGFR, and NF-κB proteins. A significant down-regulation in the expression of COX-2, NF-κB and EGFR in BxPC-3, COLO-357 and HPAC cells was observed, suggesting that multi-targeting of EGFR, NF-κB and COX-2 is more effective than targeting either signaling pathway separately. Most importantly, our in vivo results using animal model showed that B-DIM in combination with erlotinib and gemcitabine was significantly more effective than individual agents and these results were consistent with in vitro findings. Based on our pre-clinical in vitro and in vivo results, we conclude that this multi-targeted combination could be developed for the treatment of PC patients whose tumors express high levels of COX-2, EGFR and NF-κB. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5420.