Current Status in Chemotherapy for Advanced Pancreatic Adenocarcinoma

Radiobiology Laboratory, California Pacific Medical Center Research Institute, #602, OPR Bldg, 3801 Sacramento Street, San Francisco, CA 94118, U.S.A. .
Anticancer research (Impact Factor: 1.83). 05/2013; 33(5):1785-91.
Source: PubMed


Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer in the United States. Surgical resection remains the only curative treatment, but fewer than 20% of patients qualify as candidates. The past two decades saw major changes in the treatment of advanced PDA, a shift of standard protocol from 5-fluorouracil to gemcitabine and gemcitabine-based combinations, the introduction of molecular target therapy and multi-agent regimens. However, even with advancements in medicine, PDA is still extremely resistant to currently available regimens, which results in poor prognosis, with only 5.2% of patients alive at three years. This provides a challenge to scientists as they seek to find the best active regimen with the least side-effects. In this article, we review the current recommended guidelines from the National Comprehensive Cancer Network. In addition, we highlight major clinical trials since 2011.

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    • "Cancer poses a major public health problem worldwide, and chemotherapy remains one of the most effective approaches to clinical cancer treatment (Siegel et al., 2013). In spite of recent improvements made in early diagnosis and treatment of various cancers, the mortality rates are still high for most advanced cancers such as pancreatic cancer (Cao et al., 2013). There is an urgent need to develop novel agents for these cancer types that respond poorly to currently available therapies (Paulson et al., 2013). "
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    ABSTRACT: There is an increasing interest in targeting the MDM2 oncogene for cancer therapy. SP-141, a novel designed small molecule MDM2 inhibitor, exerts excellent in vitro and in vivo anticancer activity. To facilitate the preclinical development of this candidate anticancer agent, we have developed an HPLC method for the quantitative analysis of SP-141. The method was validated to be precise, accurate, and specific, with a linear range of 16.2–32,400 ng/mL in plasma, 16.2–6480 ng/mL in homogenates of brain, heart, liver, kidneys, lungs, muscle and tumor, and 32.4–6480 ng/mL in spleen homogenates. The lower limit of quantification was 16.2 ng/mL in plasma and all the tissue homogenates, except for spleen homogenates, where it was 32.4 ng/mL. The intra- and inter-assay precisions (coefficient of variation) were between 0.86 and 13.39%, and accuracies (relative errors) ranged from −8.50 to 13.92%. The relative recoveries were 85.6–113.38%. SP-141 was stable in mouse plasma, modestly plasma bound and metabolized by S9 microsomal enzymes. We performed an initial pharmacokinetic study in tumor-bearing nude mice, demonstrating that SP-141 has a short half-life in plasma and wide tissue distribution. In summary, this HPLC method can be used in future preclinical and clinical investigations of SP-141. Copyright © 2014 John Wiley & Sons, Ltd.
    Full-text · Article · Oct 2014 · Biomedical Chromatography
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    • "Pancreatic ductal adenocarcinoma (PDAC), which is the most common form of this extremely aggressive cancer, is highly invasive and metastatic and is highly resistant to all forms of existing therapies [3]. Patients who are diagnosed with PDAC at advanced stages have little hope of effective surgical resection [1] and other treatments like radiation, chemotherapy (Gemcitabine, 5-flurouracil, cisplatin, paclitaxel, docetaxel, etc.) or targeted therapies (Erlotinib-Tarceva) [4] do not currently offer much benefit either. The asymptomatic nature of the disease in its early stages has ensured that PDAC still remains a deadly and nearly untreatable cancer despite multiple attempts to find better treatment strategies [5]. "
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    ABSTRACT: Pancreatic cancer is one of the most lethal cancers. Increasing incidence and mortality indicates that there is still much lacking in detection and management of the disease. This is partly due to a lack of specific symptoms during early stages of the disease. Several growth factor receptors have been associated with pancreatic cancer. Here, we have investigated if an RNA interference approach targeted to IGF-IR could be effective and efficient against pancreatic cancer growth and metastasis. For that, we evaluated the effects of IGF-1R inhibition using small interfering RNA (siRNAs) on tumor growth and metastasis in HPAC and PANC-1 pancreatic cancer cell lines. We found that silencing IGF-1R inhibits pancreatic cancer growth and metastasis by blocking key signaling pathways such AKT/PI3K, MAPK, JAK/STAT and EMT. Silencing IGF-1R resulted in an anti-proliferative effect in PANC-1 and HPAC pancreatic cancer cell lines. Matrigel invasion, transwell migration and wound healing assays also revealed a role for IGF-1R in metastatic properties of pancreatic cancer. These results were further confirmed using Western blotting analysis of key intermediates involved in proliferation, epithelial mesenchymal transition, migration, and invasion. In addition, soft agar assays showed that silencing IGF-1R also blocks the colony forming capabilities of pancreatic cancer cells in vitro. Western blots, as well as, flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R also suppressed the expression of insulin receptor β. All these effects together significantly control pancreatic cancer cell growth and metastasis. To conclude, our results demonstrate the significance of IGF-1R in pancreatic cancer.
    Full-text · Article · May 2014 · PLoS ONE
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    • "The 5-year survival rate is about 3% and the median survival is <6 months [1]. Less than 20% of PDAC patients are eligible for surgery because the disease is often in the late stage when diagnosed [2]. However, even in most cases where surgery is available, the recurrence rate after curative resection of PDAC is up to 93.6% on account of metastasis [3]. "
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    ABSTRACT: The membrane mucin MUC4 is aberrantly expressed in multiple cancers and is of clinical significance to diagnosis and prognosis in pancreatic cancer. However, the role of MUC4 in angiogenesis and the potential association among these malignant capabilities have not been explored. In this study, we investigated the collective signaling mechanisms associated with MUC4-induced growth, metastasis and angiogenesis in pancreatic cancer. Knockdown of MUC4 in two pancreatic cancer cell lines led to downregulation of lysosomal degradation of E-cadherin by Src kinase through downregulation of pFAK and pSrc pathway. The downregulation of lysosomal degradation of E-cadherin in turn induced the formation of E-cadherin/β-catenin complex and membrane translocation of β-catenin, resulting in the downregulation of Wnt/β-catenin signaling pathway. Thus, the Wnt/β-catenin target genes c-Myc, Cyclin D1, CD44 and VEGF were down-regulated and their malignant functions proliferation, metastasis and angiogenesis were reduced. Taken together, MUC4-induced nuclear translocation of β-catenin is a novel mechanism for growth, metastasis and angiogenesis of pancreatic cancer.
    Full-text · Article · Dec 2013 · Cancer letters
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