Abstract
Pancreatic cancer is a lethal malignancy which is refractory to most chemotherapy drugs. Recent landmark studies have shed new light on the complex genetic heterogeneity of pancreatic cancer and provide an opportunity to utilize “precision-based medicines” to target genes based on the genetic profile of an individual’s tumor to increase the efficiency of chemotherapy and decrease tumor growth and metastases. Gene-silencing drugs in the form of short-interfering RNA (siRNA) have the potential to play an important role in precision medicine for pancreatic cancer by silencing the expression of genes including those considered difficult to inhibit (undruggable) using chemical agents. However, before siRNA can reach its clinical potential a delivery vehicle is needed to carry siRNA across the cell membrane and into the cytoplasm of the cell. Herein, we detail the methods required to use star polymer nanoparticles to deliver siRNA to pancreatic tumors in an orthotopic pancreatic cancer mouse model to silence the expression of an “undruggable” gene (βIII-tubulin) that regulates pancreatic cancer growth and chemosensitivity.
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References
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74(11):2913–2921. https://doi.org/10.1158/0008-5472.CAN-14-0155
Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin. https://doi.org/10.3322/caac.21442
McCarroll JA, Naim S, Sharbeen G, Russia N, Lee J, Kavallaris M, Goldstein D, Phillips PA (2014) Role of pancreatic stellate cells in chemoresistance in pancreatic cancer. Front Physiol 5:141. https://doi.org/10.3389/fphys.2014.00141
Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grutzmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM, Australian Pancreatic Cancer Genome Initiative, Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM (2016) Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531(7592):47–52. https://doi.org/10.1038/nature16965
Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Australian Pancreatic Cancer Genome Initiative, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491(7424):399–405. https://doi.org/10.1038/nature11547
Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, Quinn MC, Robertson AJ, Fadlullah MZ, Bruxner TJ, Christ AN, Harliwong I, Idrisoglu S, Manning S, Nourse C, Nourbakhsh E, Wani S, Wilson PJ, Markham E, Cloonan N, Anderson MJ, Fink JL, Holmes O, Kazakoff SH, Leonard C, Newell F, Poudel B, Song S, Taylor D, Waddell N, Wood S, Xu Q, Wu J, Pinese M, Cowley MJ, Lee HC, Jones MD, Nagrial AM, Humphris J, Chantrill LA, Chin V, Steinmann AM, Mawson A, Humphrey ES, Colvin EK, Chou A, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Pettitt JA, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Jamieson NB, Graham JS, Niclou SP, Bjerkvig R, Grutzmann R, Aust D, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Falconi M, Zamboni G, Tortora G, Tempero MA, Australian Pancreatic Cancer Genome Initiative, Gill AJ, Eshleman JR, Pilarsky C, Scarpa A, Musgrove EA, Pearson JV, Biankin AV, Grimmond SM (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518(7540):495–501. https://doi.org/10.1038/nature14169
McCarroll J, Teo J, Boyer C, Goldstein D, Kavallaris M, Phillips PA (2014) Potential applications of nanotechnology for the diagnosis and treatment of pancreatic cancer. Front Physiol 5:2. https://doi.org/10.3389/fphys.2014.00002
Galant NJ, Westermark P, Higaki JN, Chakrabartty A (2017) Transthyretin amyloidosis: an under-recognized neuropathy and cardiomyopathy. Clin Sci (Lond) 131(5):395–409. https://doi.org/10.1042/CS20160413
Phillips P (2012) Pancreatic stellate cells and fibrosis. In: Grippo PJ, Munshi HG (eds) Pancreatic cancer and tumor microenvironment. Transworld Research Network, Trivandrum, India
Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46(12 Pt 1):6387–6392
Teo J, McCarroll JA, Boyer C, Youkhana J, Sagnella SM, Duong HT, Liu J, Sharbeen G, Goldstein D, Davis TP, Kavallaris M, Phillips PA (2016) A rationally optimized nanoparticle system for the delivery of RNA interference therapeutics into pancreatic tumors in vivo. Biomacromolecules 17(7):2337–2351. https://doi.org/10.1021/acs.biomac.6b00185
McCarroll JA, Sharbeen G, Liu J, Youkhana J, Goldstein D, McCarthy N, Limbri LF, Dischl D, Ceyhan GO, Erkan M, Johns AL, Biankin AV, Kavallaris M, Phillips PA (2015) betaIII-tubulin: a novel mediator of chemoresistance and metastases in pancreatic cancer. Oncotarget 6(4):2235–2249. https://doi.org/10.18632/oncotarget.2946
Kato A, Naiki-Ito A, Naitoh I, Hayashi K, Nakazawa T, Shimizu S, Nishi Y, Okumura F, Tadahisa I, Takada H, Kondo H, Yoshida M, Takahashi S, Joh T (2018) The absence of class III beta-tubulin is predictive of a favorable response to nab-paclitaxel and gemcitabine in patients with unresectable pancreatic ductal adenocarcinoma. Hum Pathol. https://doi.org/10.1016/j.humpath.2018.01.009
Lee KM, Cao D, Itami A, Pour PM, Hruban RH, Maitra A, Ouellette MM (2007) Class III beta-tubulin, a marker of resistance to paclitaxel, is overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia. Histopathology 51(4):539–546. https://doi.org/10.1111/j.1365-2559.2007.02792.x
Acknowledgments
This work was supported by grants from the National Health and Medical Research Council (NHMRC; P. A. Phillips, J. McCarroll, M. Kavallaris; APP1024895), Cancer Council New South Wales (P. A. Phillips, J. McCarroll, M. Kavallaris), Cure Cancer Australia Foundation Grant (P. A. Phillips), Cancer Institute NSW Fellowship (J. McCarroll, G. Sharbeen), NHMRC CDF Fellowship (P. A. Phillips, APP1024896). M. Kavallaris is also supported by funding from National Health and Medical Research Council (NHMRC) Program Grant (APP1091261), Cancer Council NSW Program Grant (PG16-01), Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (project number CE140100036) and an NHMRC Principal Research Fellowship (APP1119152). Joshua A. McCarroll and George Sharbeen contributed equally to this work.Conflict of interest disclosure: The authors declare no competing financial interest.
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McCarroll, J.A., Sharbeen, G., Kavallaris, M., Phillips, P.A. (2019). The Use of Star Polymer Nanoparticles for the Delivery of siRNA to Mouse Orthotopic Pancreatic Tumor Models. In: Dinesh Kumar, L. (eds) RNA Interference and Cancer Therapy. Methods in Molecular Biology, vol 1974. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9220-1_23
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DOI: https://doi.org/10.1007/978-1-4939-9220-1_23
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