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Published online before print February 7, 2008
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From The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Abstract |
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Introduction |
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Molecular Abnormalities of Pancreatic Cancer |
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Copy Number Aberrations
Due to chromosomal instability, a common feature of most solid tumors, almost every pancreatic cancer harbors several numerical or structural chromosomal alterations revealed by cytogenetic analysis.4, 5
The most common numerical changes observed in pancreatic cancer are losses on chromosomes 6, 12, 13, and 18, as well as gains on chromosomes 7 and 20; chromosomal breaks and rearrangements most frequently occur in regions involving 1p, 1q, 3p, 6q, 7q, 11p, 17p, and 19q.
Another technique that is commonly applied to identify regions of genomic losses at a "higher resolution" by means of polymorphic microsatellite markers is called allelotyping. In a recent study Iacobuzio-Donahue et al analyzed 
80 pancreatic cancer xenografts by means of 386 microsatellite markers.6
Allelic losses found most commonly involved chromosomal regions 9p, 17p, and 18q, covering the tumor suppressor genes CDKN2A, TP53, and DPC4/SMAD4/MADH4, respectively. Additional losses were frequently found in 3p, 4q, 5q, 6q, 8p, 12q, 14q, 21q, and 22q. Many of these regions have been linked to candidate tumor suppressor genes, eg, the stress-activated protein kinase MKK4 (17p), which has been suggested to be involved in metastatic spread,7
or receptors of the transforming growth factor (TGF)-β signaling pathway TGFBR1 (9q), TGFBR2 (3p),8
and ACVR1B (12q).9
Interestingly, allelotype analysis of microdissected pancreatic intraepithelial neoplasia (PanIN) samples revealed loss of heterozygosity in several of the chromosomal regions also found in pancreatic cancer, including 9p, 17p, and 18q.10, 11
Comparative genomic hybridization (CGH) can be used to discover genomic deletions as well as amplifications, providing the potential to uncover both potential tumor suppressor genes and oncogenes. For CGH, samples of non-neoplastic and tumor cell DNA are labeled with different dyes and hybridized against each other. Subsequently, the relative ratio of the two dyes indicates regions of cancer-associated gains or losses. Conventional CGH was originally performed using metaphase spreads, with the major drawbacks of relatively low resolution and frequent difficulties to map precisely the regions of genomic amplifications or losses.12 More recently, several array-based CGH techniques have been developed, using microarrays that are spotted with bacterial artificial chromosomes (BAC arrays),13 cDNAs (cDNA microarrays),14 or stretches of oligonucleotides (representational oligonucleotide microarray analysis),15 providing a significantly higher resolution than conventional CGH (up to 30 kb) and often allowing for precise mapping of deleted or amplified regions and genes included therein. In the setting of pancreatic cancer, array CGH revealed several genomic amplifications, including C-MYC (8q), EGFR (7p), KRAS22 (12p), AKT2 (19q), and AIB1 (20q), as well as deletions, including DPC4/SMAD4/MADH4 (18q), CDKN2A (9p), FHIT (3p), and MKK4 (17p).16, 17 Using the example of thymidylate synthase, which has previously been linked to responsiveness to 5-fluorouracil treatment, a recent report by Brody et al suggests that results from studies examining copy number aberrations should be interpreted with particular caution, since copy numbers determined in tumor cells are not necessarily identical throughout the whole tumor and might vary over time, in response to chemotherapeutic agents or in metastatic foci as compared to primary tumors.18
Nuclear DNA Mutations: Oncogenes
Activating point mutations within the KRAS oncogene (12p) are present in 80 to 90% of pancreatic cancers, most commonly affecting codon 12 but also 13 or 61.19
The activating mutations abolish the intrinsic GTPase activity of KRAS, resulting in constitutive activation of intracellular signal transduction (Figure 1)
. Of note, activating KRAS mutations are not only the most frequently found genetic abnormalities in pancreatic cancer but also seem to be among the earliest changes observed in nonmalignant precursor-lesions, already being present in about 30% of PanIN-1 lesions.21, 22
Rare pancreatic cancers with wild-type KRAS usually harbor mutations of BRAF.23
Since both KRAS and BRAF function in activating the same Ras/Raf/MAP kinase signaling pathway, it explains why mutations of these two genes occur in a virtually exclusive pattern and further underscores the extraordinary importance of this signaling pathway in the genesis of pancreatic cancer. Other oncogenes involved in pancreatic cancer include CMYC, AKT2, and EGFR. CMYC amplifications and concomitant overexpression of CMYC can be detected in 50 to 60% of pancreatic cancers,17, 24
providing a potential target for the development of future therapeutic options due to the recent development of compounds specifically inhibiting Myc signaling.25
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Tumor Suppressor Genes
The cyclin-dependent kinase CDKN2A/p16 on chromosome 9p inhibits cell cycle progression through the G1-S checkpoint and constitutes the most frequently inactivated gene in pancreatic cancers.19, 30
More than 90% of pancreatic cancers show loss of CDKN2A/p16 function, which can occur due to homozygous deletions (40%), mutations with loss of the second allele (40%), or epigenetic silencing by promoter hypermethylation (10–15%). Interestingly, loss of nuclear p16 protein expression is already observed in 30% of PanIN-1, in 55% of PanIN-2, and in 71% of PanIN-3 lesions.31
Approximately 30% of homozygous CDKN2A/p16 mutations also include the MTAP gene, which has recently been proposed as potential therapeutic target.32
Deleted in pancreatic carcinoma 4 (DPC4/SMAD4/MADH4) on chromosome 18q21 is inactivated in about 55% of pancreatic cancers.33
This is due to mutations in one allele and loss of the second allele in about 25% of cases and due to homozygous mutations in 30% of cases. Of note, DPC4/SMAD4/MADH4 mutations are very rarely observed in other malignancies.34
Loss of DPC4/SMAD4/MADH4 function results in reduced growth inhibition and increased proliferation through interference with intracellular signaling cascades downstream of cell surface receptors of the TGF-β family (Figure 2)
. Abrogation of DPC4 function appears to be a rather late event in the pathogenesis of pancreatic carcinomas, as it is not observed in the majority of PanIN-3 lesions.35
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While loss of these three (CDKN2A, DPC4 and TP53) genes is found in the majority of pancreatic cancers, other tumor suppressor genes are inactivated in smaller subsets (<10%) of PDAC, eg, LKB1/STK11 on chromosome 19p,36 TGF-βR1 on 9q, TGF-βR2 on 3p, RB1 on 13q,30 and MKK4 on 17p.37 Interestingly, MKK4 seems to be inactivated specifically in metastatic lesions, suggesting that wild-type MKK4 might have the ability to inhibit development of metastases through a yet unknown mechanism.
Caretaker Genes
As opposed to alterations of oncogenes and tumor suppressor genes, which both drive the neoplastic process by increasing tumor cell numbers through increased tumor cell growth or inhibition of cell death and cell cycle arrest, a third class of genes is commonly involved in the development of malignant neoplasias, such that when mutated, they act in a fundamentally different way. Such genes are commonly referred to as caretakers or stability genes.38
Caretaker genes minimize genetic alterations during DNA replication so that loss of their function can lead to accumulation of additional mutations in different other genes.39
The DNA damage repair genes hMLH1 and hMSH2 are inactivated in a small subset of familial pancreatic cancers, but rarely in sporadic cases,40 mostly medullary carcinomas of the pancreas.41 These tumors constitute a separate entity that is important to recognize, since on the one hand they tend to carry a more favorable prognosis than ductal adenocarcinomas and, on the other hand, they may indicate hereditary nonpolyposis colorectal cancer syndrome, in which case patients might benefit from genetic counseling. Medullary carcinomas of the pancreas show a typical medullary histology, which is characterized by poor differentiation, pushing borders, and syncytial growth pattern.41, 42
Moreover, a subgroup of pancreatic cancers carries mutations in genes of the Fanconi’s anemia DNA repair pathway. Mutations affecting the BRCA2 gene have been found in approximately 17% of familial pancreatic cancers,43 and FANCC and FANCG mutations have been described as rare findings in sporadic pancreatic cancers,44 all of which are thought to be part of the Fanconi’s anemia DNA repair pathway. (See Kennedy and D’Andrea 45 and Taniguchi and D’Andrea46 for a recent review and for a schematic overview of the Fanconi’s anemia pathway.)
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Mutations in Mitochondrial DNA |
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Telomere Length Abnormalities |
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Epigenetic Abnormalities |
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Interestingly, promoter hypermethylation, though most common, is not the only epigenetic modification involved in carcinogenesis. More recently it was found that the reverse means of aberrant gene regulation (hypomethylation) is also exploited by pancreatic cancer cells, ie, some genes, including maspin, S100P, mesothelin, prostate stem cell antigen, and claudin-4, can be overexpressed due to promoter hypomethylation.60
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Transcriptomic Changes |
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Interestingly, six genes—keratin 19, retinoic acid-induced 3, secretory leukocyte protease inhibitor, stratifin, tetraspan 1, and transglutaminase 2—were found to be overexpressed by all three techniques (serial analysis of gene expression and oligonucleotide and cDNA microarrays). It has yet to be elucidated whether up-regulation of these genes is only a bystander phenomenon or is mechanistically involved in malignant transformation and might pose a potential target for the development of novel therapeutic strategies. Moreover, differential gene expression might be used to establish new diagnostic tools such as tumor imaging or early detection of pancreatic cancer.
The tight junction protein claudin 4 was found to be overexpressed in PanIN lesions and in fully invasive pancreatic cancer tissue by microarray analysis, and overexpression was confirmed by immunohistochemistry.69 Radiolabeled anti-claudin 4 antibodies have recently been tested successfully in a preclinical setting as imaging tools as well as for therapeutic purposes in murine xenograft models of human pancreatic cancer.70, 71
Mesothelin was originally identified by serial analysis of gene expression as being overexpressed in pancreatic cancer, and validation by immunohistochemistry revealed it is almost exclusively expressed in neoplastic cells but not in neighboring nonmalignant tissue.72 As a result of this initial finding, both an experimental tumor vaccine against mesothelin and a conjugated immunotoxin directed against mesothelin are currently undergoing initial evaluation in clinical trials.73
Prostate stem cell antigen, originally thought to be restricted to prostatic basal cells and prostate carcinomas, was found by serial analysis of gene expression to be expressed in about 60% of pancreatic cancers, but not in normal, non-neoplastic pancreas tissues.61 Following up on these findings, prostate stem cell antigen has thereafter been successfully tested as a potential target for immunotherapy74 as well as for diagnostic imaging in murine xenograft models of human pancreatic cancer.71
Yes-associated protein, the mammalian homologue of Yorkie, the main effector of the Hippo pathway, has recently found to be overexpressed at the RNA and protein level in pancreatic cancer cells, suggesting a possible role of this pathway in pancreatic carcinogenesis,75 likely through interaction with TGF-β signaling.76 Survivin, a major suppressor of apoptosis, is expressed at the RNA and protein level in low- to high-grade PanIN lesions and fully invasive pancreatic ductal adenocarcinomas in increasing levels, but not in neighboring non-neoplastic tissue, and it is thought to be involved in carcinogenesis as well as drug resistance.77, 78 It might therefore be a promising target both as diagnostic marker for early detection as well as for therapeutic intervention.
Moreover, recently aberrant reactivation of the Hedgehog and Notch signaling pathways, and concomitant overexpression of their respective target genes, has been described in the majority of pancreatic cancers.79, 80, 81, 82 Inhibition of Notch-1 lead to growth inhibition and increased apoptosis in pancreatic cancer cell lines in vitro,83, 84 and ligand overexpression has been linked to neovascularization in vivo.85 To our knowledge, studies examining in vivo effects of Notch inhibition, eg, using xenograft model systems of pancreatic cancer, are still lacking at the time of this manuscript’s preparation.
Hedgehog inhibition with the small molecule smoothened inhibitor cyclopamine has been found to increase cytotoxic effects of paclitaxel treatment and radiation on pancreatic cancer cells in vitro86
and to inhibit growth of pancreatic cancer xenografts and metastases in vivo.79, 80, 87
A simplified, schematic overview of the Hedgehog signaling pathway in mammals is given in Figure 3
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Proteomic Abnormalities |
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The past decade has seen great progress in the development of high-throughput techniques addressing protein expression changes, including chip-based arrays that allow determination of a plethora of proteins within a given liquid sample in parallel, or tissue microarrays, enabling examination of expression of selected proteins in a great number of tissue specimens with antibody-based protocols like immunohistochemistry or immunofluorescence in one assay.
It has become evident from proteomic studies that during the multi-stepwise development of pancreatic cancer, changes in the protein expression pattern do not occur in a random manner but can be grouped into early, intermediate, and late changes, which mirror the stepwise accumulation of genomic alterations as discussed previously.35 (See Feldmann et al89 and Singh and Maitra90 for more detailed reviews of molecular abnormalities observed in precursor lesions of PDAC.) This observation might have direct clinical implications, eg, in the quest to identify novel tumor markers for early detection. While a protein like prostate stem cell antigen, which is already secreted by the earliest PanIN-1 lesions, might be an extremely sensitive marker for early detection, it might nevertheless be of limited clinical value due to the common occurrence of low-grade PanINs in pancreata of older individuals. Detection of mesothelin, which is expressed only in late PanIN-3 lesions and fully invasive cancer tissues, from pancreatic juice could on the other hand have much more severe prognostic implications.
Examination of protein expression patterns from pancreatic juice samples using surface-enhanced laser desorption and ionization mass spectrometry-based protein chips has led to the discovery of hepatocarcinoma-intestine-pancreas/ pancreatitis-associated-protein-1 (HIP/PAP-1) overexpression in pancreatic cancers. It has been shown that individuals with high HIP/PAP-1 concentrations >20 µg/ml had a more than 20-fold increased risk of developing pancreatic cancer.91 Surface-enhanced laser desorption and ionization mass spectrometry has recently successfully been tested to predict pancreatic cancer from patient serum samples with 78% sensitivity and a specificity of 97%.92
Another experimental approach to determine altered protein expression from liquid samples exploits liquid chromatography tandem mass spectrometry, which enables identification of proteins based on their individual charge/mass ratios. This technique has recently been used to identify 170 genes expressed in pancreatic juice of patients with pancreatic cancer, including several previously known tumor markers like CEA, MUC1, or HIP/PAP-1.93
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Mouse Models of Pancreatic Cancer |
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Therefore, recent years have seen increasing use of orthotopic xenograft models, which are more tedious to generate but are able to overcome many of these shortcomings. They are particularly useful to study drug effects on tumor microenvironment including neoangiogenesis and metastatic spread.87, 97 Tumor cells are either injected directly into the mouse pancreas, often in the form of concentrated tumor cell suspensions containing Matrigel, or alternatively are surgically implanted into the murine pancreas as chunks of primary tumor tissues or xenografts. While the first variant is faster and allows generation of xenografts from cell lines without the need to first grow subcutaneous xenografts, the second technique is more reliable in preventing intraperitoneal leakage of tumor cells after injection and also allows for the use of primary tissue samples, thus bypassing the need for in vitro established cell lines.
Transgenic Mouse Models
As opposed to subcutaneous or orthotopic xenografts, transgenic mouse models possess the potential to mimic human disease in a syngeneic system. While they can obviously not represent the whole spectrum of genetic aberrations observed in human pancreatic cancers, these models are of tremendous value for translational studies as they also include a syngeneic tumor environment as well as a fully intact immune system. The earliest models, described almost two decades ago, used acinar-specific elastase promoter to target oncogene expression to the murine pancreas, resulting in neoplasms of predominantly acinar histogenesis.98, 99
The first mouse model most closely resembling histopathological features of human ductal adenocarcinoma was described in 2003.100 In this model, expression of oncogenic KrasG12D is suppressed by combination with Lox-STOP-Lox (LSL) constructs. Repression is released on Cre-mediated excision of the LSL cassettes and subsequent recombination. Targeting of transgene expression to the murine pancreas is achieved by expression of Cre recombinase under the control of pancreas-specific promoters Pdx1 or P48. It is commonly assumed that Pdx1-/P48-double positive cells give rise to virtually all mature cells in the pancreas.100, 101, 102 During embryonic development, expression of Pdx1/PF1 starts around E8.5, and P48/PTF1 expression begins slightly later. All of these mice develop ductal lesions resembling human PanIN lesions, which eventually progress into a fully invasive and metastatic adenocarcinoma phenotype in a small percentage (<10%) of animals. The long latency of 6 to 8 months and low frequency suggest the need of additional genetic alterations, likely including the INK4a-Rb or Arf-p53 pathways, whereas the majority of cells expressing oncogenic KrasG12D alone might undergo ras-induced senescence and thus fail to accumulate additional hits required to develop a fully malignant cancer phenotype.103 Similar to these observations, Grippo et al found multifocal acinar cell hyperplasia in Ela-KrasG12D mice 1 to 2 months of age. Interestingly, by the age of 6 to 18 months, some of these lesions underwent a process the authors referred to as acinar-to-ductal metaplasia and presented with a more duct-like phenotype, including expression of CK-19.104
In fact, newer transgenic models have recently been described, in that KrasG12D expression is directed to the pancreas by means of Cre recombinase under the control of a Pdx1 promoter in combination with inhibition of the INK4A/Arf or p53 pathways, respectively: LSL-KrasG12D; INK4a/Arflox/lox;Pdx1-Cre,105 LSL-Kras;p53lox/lox;Pdx1-Cre,106 and LSL-Kras;Trp53R172H;Pdx1-Cre.107 Mice with knockout of the INK4a/Arf locus, resulting in loss of both murine p16 and p19 function, develop poorly differentiated carcinomas very rapidly and start to die before 7 weeks of age,105 whereas inhibition of p53 function, either by genetic knockout106 or by introduction of a dominant negative p53 allele,107 preferentially leads to moderately to well-differentiated adenocarcinomas. Of note, abrogation of either INK4a/Arf or p53 signaling alone in the absence of oncogenic Kras does not lead to the development of pancreatic carcinomas or associated precursor lesions, underscoring the crucial importance of Kras signaling in initiating the cascade of events, eventually culminating in a fully malignant phenotype during pancreatic carcinogenesis.105
The described models, and especially the latter,107 to date also represent those recapitulating most closely the clinicopathological characteristics of human pancreatic adenocarcinomas and thus carry enormous potential for future translational studies in providing an excellent platform for preclinical evaluation of novel drugs and other therapeutic approaches. Several signaling pathways shown to be aberrantly activated in human pancreatic cancers are also found to be turned on in the discussed mouse models, including the Hedgehog and Notch signaling pathways. As these pathways can be targeted by using blocking antibodies or small-molecule inhibitors, for example, it is tempting to speculate whether therapeutic regimens exploiting blockade of these pathways might have an effect on survival in these preclinical models and might moreover eventually be translated into applications in a clinical setting.
Using a mouse model of TGF-
-induced pancreatic cancer previously described by Wagner and colleagues,108
a recent study from the same group found that pancreatic carcinomas occurring in C57BL/6-EL-TGF-alpha;Trp53–/– mice induced a distinct immune response including secretion of proinflammatory cytokines and occurrence of tumor-specific regulatory T lymphocytes in the host. Surprisingly, tumor-derived cell lines did not form xenograft tumors in immunocompetent mice of the same genetic background, a finding that is yet to be fully understood. From these results the authors conclude that spontaneous tumors arising in this mouse model are recognized by the host immune system and that therefore transgenic models might be more suitable than xenografts to evaluate certain immunotherapeutic regimens in a preclinical setting.109
An immunotherapeutic approach using tumor vaccination with tumor/dendritic cell fusion supplemented by injection of superantigen staphylococcal enterotoxin B leads to generation of tumor-specific cytotoxic T lymphocytes and increased survival in a previously described transgenic mouse model of acinar cell-type pancreatic cancer overexpressing MUC1,110, 111 which is based on a model originally described by Tevethia et al, in which pancreatic acinar carcinomas are induced by pancreas-specific expression of a transgene containing the N-terminal amino acids 1–127 of large T-cell antigen under the control of THE elastase-1 promoter.112
In the last few years, several other transgenic mouse models targeting different pathways thought to be involved in pancreatic carcinogenesis, which allow deeper insight in underlying etiological and pathogenetic mechanisms, have been described. Three recent mouse models addressed the role of TGF-β signaling in pancreatic cancer (see Figure 2
for an overview of the TGF-β pathway) by pancreas-specific deletion of either SMAD4113, 114
or TGF-β receptor type II (TGFBR2).115
Interestingly, as observed for interruption of INK4a/Arf and p53 signaling pathways, neither SMAD4 nor TGFBR2 deletion alone is sufficient to induce pancreatic neoplasia. However, when combined with oncogenic KrasG12D, development of fully malignant carcinomas is enhanced with shorter latencies than observed for KrasG12D alone. While mice lacking pancreatic TGFBR2 expression in the presence of KrasG12D all develop well-differentiated adenocarcinomas and die of their disease within 200 days, with a median survival of 59 days,115
loss of SMAD4 in KrasG12D-expressing pancreata leads to development of premalignant precursor lesions of intraductal papillary mucinous neoplasm or mucinous cystic neoplasm type, which can progress into fully malignant carcinomas. For the latter, median survival of 8 months114
and 7 to 12 weeks113
have been described. TGF-β signaling has previously been proposed to mediate epithelial-to-mesenchymal transition,116
and in line with this concept, INK4A/Arf-null;KrasG12D mice with wild-type SMAD4 usually present with poorly differentiated carcinomas, whereas mice that also lack SMAD4 expression, develop mostly well- to moderately differentiated pancreatic adenocarcinomas that express epithelial markers such as E-cadherin or cytokeratin-19.
Studies examining the role of Hedgehog signaling demonstrated that overexpression of the Hedgehog ligand Sonic Hedgehog (SHH) in the pancreas is sufficient to induce formation of PanIN lesions.79 Introduction of a dominant-active form of the activating Hedgehog transcription factor GLI2 (CLEG2) leads to formation of poorly differentiated pancreatic carcinomas that lack CK-19 expression in about 30% of PDX1-Cre;CLEG2 mice, which seem to develop without evidence of PanINs as precursor lesions.117 Of note, combined expression of CLEG2 and KrasG12D in the murine pancreas results in formation of PanIN lesions and pancreatic carcinomas in all studied mice, with shorter latency and dramatically decreased overall survival of only 3 to 8 weeks.
Overexpression of COX-2 in the pancreas under the control of a keratin 5 promoter leads to formation of IPMN- and PanIN-like lesions, enhanced ras signaling, inflammation, and fibrosis in a subset of mice.118 Clerc and colleagues described development of pancreatic carcinomas through acinar-to-ductal transition in three of 20 mice overexpressing CCK2/gastrin receptor in pancreatic acinar cells.119
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Other Promising Translational Studies |
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Multiple immunotherapeutic trials have been performed in a clinical setting at several institutions, including our own, with variable success.123 Overall, immunotherapeutic regimens using monoclonal antibodies have so far been the most successful approaches. However, tumor vaccination protocols for pancreatic cancer are also increasingly translated into clinical therapies, some of which showed extremely encouraging initial results. A phase I study conducted at our own institution using a whole tumor cell vaccine coadministered with granulocyte macrophage–colony-stimulating factor was shown to be safe and potentially effective in patients with early stage disease.124 Follow-up phase II clinical trials are currently ongoing.
Another idea is based on the recent observation that a small subset of PDAC that carry mutations in the Fanconi anemia/BRCA2 pathway is highly sensitive to cross-linking agents such as mitomycin C or cisplatin in vitro and in vivo.44, 125 Although affecting only 5 to 10% of human PDAC, these findings might soon be translated into effective chemotherapeutic treatment regimens for these cases. A phase II clinical trial is presently underway.
Overexpression of the chemokine receptor CXCR4 is thought to be involved in the development of metastases, possibly through attraction of CXCR4-positive tumor cells by SDF-1alpha/CXCL12.126 Moreover, tumor neoangiogenesis and growth of subcutaneous murine xenografts could be inhibited by administration of anti-CXCR4 blocking antibodies.127 Therefore, the SDF-1/CXCR4 signaling axis might be yet another promising therapeutic target for PDAC in the near future.
Using in vitro and in vivo model systems, treatment with tumor necrosis factor-related apoptosis-inducing ligand has been demonstrated to be a valid novel therapeutic strategy in several solid tumors, including pancreatic cancer, especially when combined with other substances sensitizing cancer cells to tumor necrosis factor-related apoptosis-inducing ligand by overcoming resistance to apoptosis.128, 129 This strategy is also most likely soon to undergo initial evaluation in a clinical setting.
Clinical use of several commonly administered cytotoxic chemotherapeutics is often limited by systemic adverse effects. Utilization of nanotechnology carries the potential to minimize these problems, by encapsulating drugs in nanoparticles and via specific delivery to tumor cells by passive (through enhanced permeation and retention effect) or active targeting (nanoparticles coated with antibodies or receptor analogs directed against tumor-specific surface antigens), thereby drastically reducing the total amount of drug needed to achieve a therapeutic response.130 Moreover, encapsulation into nanoparticles can overcome poor water solubility, a common shortcoming of multiple substances being screened as potential drugs. An example is curcumin, a plant extract from Curcuma longa, which has long been known in traditional Indian medicine and has well-described anti-inflammatory and antineoplastic properties in vitro. While promising in vivo results have been achieved in animal models of PDAC in that comparably huge doses of curcumin could be administered,131 as well as in clinical trials in preventing progression of preneoplastic colon adenomas,132 broader application in different tumor types has been hampered by poor water solubility and almost zero resorption from the gastrointestinal tract and systemic bioavailability.133, 134 Nanoencapsulation of curcumin has recently been shown to render the drug readily water soluble while retaining its biological properties in vitro.135, 136 However, the in vivo efficacy of these new formulations has yet to be evaluated.
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Conclusion |
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Acknowledgments |
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Footnotes |
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Supported by National Institutes of Health grants R01CA113669 and R21DK072532, The Sol Goldman Pancreatic Cancer Research Center, and an American Association for Cancer Research-PanCAN award (to A.M.). G.F. was supported by a fellowship grant within the Postdoc-Programme of the German Academic Exchange Service.
Accepted for publication October 19, 2007.
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References |
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Abstract
Introduction
