Abstract
The development and progression of human cancer are multistage processes that involve a variety of genetic mutations, epigenetic alterations, and interactions between tumor cells and their microenvironment. The genetic and epigenetic abnormalities lead to the selective growth of tumor cells that are highly resistant to apoptotic cell death and capable of avoiding immune surveillance. Those aggressive biological characteristics contribute to intrinsic and acquired resistance to cancer therapeutics. Intrinsic drug resistance refers to a poor therapeutic response of tumors to the initial chemotherapy, while acquired resistance is developed during drug treatment through additional genetic changes and dysregulation of signal pathways in tumor cells. Cross talk between cancer cells and tumor-associated stromal cells promotes infiltration and proliferation of tumor-associated fibroblasts and macrophages, accumulation of extracellular matrix (the supporting framework around the tumor cells), and dysfunctional tumor vasculatures, which create physical barriers for efficient delivery of therapeutic and diagnostic agents into tumor cells. Additional biological barriers include the overexpression of drug efflux pumps, upregulation of signal pathways associated with resistance, and the presence of cancer stem cells within the tumor. Targeting proteins that are overexpressed in the tumors such as human epidermal growth factor 2 (HER-2) aids in enhancing the overall efficiency of therapeutic delivery. While early detection of cancer cells is critical to effective treatment, clinically validated biomarkers of presymptomatic and early-stage disease are typically limited to serum or urine biomarker detection. Although conventional contrast-enhanced imaging approaches have been used for cancer detection, it has been difficult to detect small tumors due to their lack of specificity and sensitivity. Moreover, extensive stromal response in early tumors creates a delivery barrier for targeted imaging contrasts to reach tumor cells for production of specific imaging signals. In this chapter, we will focus on the key biological events in tumor development that result in heterogeneous therapeutic responses in cancer patients.
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References
World Cancer Report 2014. International Agency for Research on Cancer, Lyon (2014)
Dunn, G.P., Old, L.J., Schreiber, R.D.: The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004). https://doi.org/10.1146/annurev.immunol.22.012703.104803
Burnet, F.M.: Immunological surveillance in neoplasia. Transplant. Rev. 7, 3–25 (1971)
Burnet, M.: Cancer; a biological approach. I. The processes of control. Br. Med. J. 1(5022), 779–786 (1957)
Hanahan, D., Weinberg, R.A.: The hallmarks of cancer. Cell. 100(1), 57–70 (2000)
Hanahan, D., Weinberg, R.A.: Hallmarks of cancer: the next generation. Cell. 144(5), 646–674 (2011). https://doi.org/10.1016/j.cell.2011.02.013
Steeg, P.S., Clare, S.E., Lawrence, J.A., Zhou, Q.: Molecular analysis of premalignant and carcinoma in situ lesions of the human breast. Am. J. Pathol. 149(3), 733–738 (1996)
Liang, X.J., Chen, C., Zhao, Y., Wang, P.C.: Circumventing tumor resistance to chemotherapy by nanotechnology. Methods Mol. Biol. 596, 467–488 (2010). https://doi.org/10.1007/978-1-60761-416-6_21
Cary, K.C., Cooperberg, M.R.: Biomarkers in prostate cancer surveillance and screening: past, present, and future. Ther. Adv. Urol. 5(6), 318–329 (2013). https://doi.org/10.1177/1756287213495915
Nedaeinia, R., Manian, M., Jazayeri, M.H., Ranjbar, M., Salehi, R., Sharifi, M., Mohaghegh, F., Goli, M., Jahednia, S.H., Avan, A., Ghayour-Mobarhan, M.: Circulating exosomes and exosomal microRNAs as biomarkers in gastrointestinal cancer. Cancer Gene Ther. 24(2), 48–56 (2017). https://doi.org/10.1038/cgt.2016.77
Zhu, A., Lee, D., Shim, H.: Metabolic PET imaging in cancer detection and therapy response. Semin. Oncol. 38(1), 55–69 (2011). https://doi.org/10.1053/j.seminoncol.2010.11.012
Erkan, M., Hausmann, S., Michalski, C.W., Fingerle, A.A., Dobritz, M., Kleeff, J., Friess, H.: The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat. Rev. Gastroenterol. Hepatol. 9(8), 454–467 (2012). https://doi.org/10.1038/nrgastro.2012.115
Cheung-Ong, K., Giaever, G., Nislow, C.: DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem. Biol. 20(5), 648–659 (2013). https://doi.org/10.1016/j.chembiol.2013.04.007
Senese, S., Lo, Y.C., Huang, D., Zangle, T.A., Gholkar, A.A., Robert, L., Homet, B., Ribas, A., Summers, M.K., Teitell, M.A., Damoiseaux, R., Torres, J.Z.: Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development. Cell Death Dis. 5, e1462 (2014). https://doi.org/10.1038/cddis.2014.420
Boussios, S., Pentheroudakis, G., Katsanos, K., Pavlidis, N.: Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management. Ann. Gastroenterol. 25(2), 106–118 (2012)
Paus, R., Haslam, I.S., Sharov, A.A., Botchkarev, V.A.: Pathobiology of chemotherapy-induced hair loss. Lancet Oncol. 14(2), e50–e59 (2013). https://doi.org/10.1016/S1470-2045(12)70553-3
Noble, C.O., Krauze, M.T., Drummond, D.C., Yamashita, Y., Saito, R., Berger, M.S., Kirpotin, D.B., Bankiewicz, K.S., Park, J.W.: Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors: pharmacology and efficacy. Cancer Res. 66(5), 2801–2806 (2006). https://doi.org/10.1158/0008-5472.CAN-05-3535
Dowell, J.A., Sancho, A.R., Anand, D., Wolf, W.: Noninvasive measurements for studying the tumoral pharmacokinetics of platinum anticancer drugs in solid tumors. Adv. Drug Deliv. Rev. 41(1), 111–126 (2000)
Gangloff, A., Hsueh, W.A., Kesner, A.L., Kiesewetter, D.O., Pio, B.S., Pegram, M.D., Beryt, M., Townsend, A., Czernin, J., Phelps, M.E., Silverman, D.H.: Estimation of paclitaxel biodistribution and uptake in human-derived xenografts in vivo with (18)F-fluoropaclitaxel. J. Nucl. Med. 46(11), 1866–1871 (2005)
Teicher, B.A., Chari, R.V.: Antibody conjugate therapeutics: challenges and potential. Clin. Cancer Res. 17(20), 6389–6397 (2011). https://doi.org/10.1158/1078-0432.CCR-11-1417
Ding, H., Wu, F.: Image guided biodistribution and pharmacokinetic studies of theranostics. Theranostics. 2(11), 1040–1053 (2012). https://doi.org/10.7150/thno.4652
Adams, G.P., Schier, R., McCall, A.M., Simmons, H.H., Horak, E.M., Alpaugh, R.K., Marks, J.D., Weiner, L.M.: High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res. 61(12), 4750–4755 (2001)
Peer, D., Karp, J.M., Hong, S., Farokhzad, O.C., Margalit, R., Langer, R.: Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2(12), 751–760 (2007). https://doi.org/10.1038/nnano.2007.387
Maeda, H., Wu, J., Sawa, T., Matsumura, Y., Hori, K.: Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Release. 65(1–2), 271–284 (2000)
Clark, A.J., Wiley, D.T., Zuckerman, J.E., Webster, P., Chao, J., Lin, J., Yen, Y., Davis, M.E.: CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing. Proc. Natl. Acad. Sci. U. S. A. 113(14), 3850–3854 (2016). https://doi.org/10.1073/pnas.1603018113
Gao, N., Bozeman, E.N., Qian, W., Wang, L., Chen, H., Lipowska, M., Staley, C.A., Wang, Y.A., Mao, H., Yang, L.: Tumor penetrating theranostic nanoparticles for enhancement of targeted and image-guided drug delivery into peritoneal tumors following intraperitoneal delivery. Theranostics. 7(6), 1689–1704 (2017)
Prabhakar, U., Maeda, H., Jain, R.K., Sevick-Muraca, E.M., Zamboni, W., Farokhzad, O.C., Barry, S.T., Gabizon, A., Grodzinski, P., Blakey, D.C.: Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res. 73(8), 2412–2417 (2013). https://doi.org/10.1158/0008-5472.CAN-12-4561
Farokhzad, O.C., Langer, R.: Impact of nanotechnology on drug delivery. ACS Nano. 3(1), 16–20 (2009). https://doi.org/10.1021/nn900002m
Aggarwal, P., Hall, J.B., McLeland, C.B., Dobrovolskaia, M.A., McNeil, S.E.: Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv. Drug Deliv. Rev. 61(6), 428–437 (2009). https://doi.org/10.1016/j.addr.2009.03.009
Choi, H.S., Liu, W., Liu, F., Nasr, K., Misra, P., Bawendi, M.G., Frangioni, J.V.: Design considerations for tumour-targeted nanoparticles. Nat. Nanotechnol. 5(1), 42–47 (2010). https://doi.org/10.1038/nnano.2009.314
Kadam, R.S., Bourne, D.W., Kompella, U.B.: Nano-advantage in enhanced drug delivery with biodegradable nanoparticles: contribution of reduced clearance. Drug Metab. Dispos. 40(7), 1380–1388 (2012). https://doi.org/10.1124/dmd.112.044925
Pietras, K., Ostman, A.: Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res. 316(8), 1324–1331 (2010). https://doi.org/10.1016/j.yexcr.2010.02.045
Tlsty, T.D., Coussens, L.M.: Tumor stroma and regulation of cancer development. Annu. Rev. Pathol. 1, 119–150 (2006). https://doi.org/10.1146/annurev.pathol.1.110304.100224
Jain, R.K., Stylianopoulos, T.: Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7(11), 653–664 (2010). https://doi.org/10.1038/nrclinonc.2010.139
Dudley, A.C.: Tumor endothelial cells. Cold Spring Harb. Perspect. Med. 2(3), a006536 (2012). https://doi.org/10.1101/cshperspect.a006536
Bergers, G., Hanahan, D.: Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer. 8(8), 592–603 (2008). https://doi.org/10.1038/nrc2442
Ariffin, A.B., Forde, P.F., Jahangeer, S., Soden, D.M., Hinchion, J.: Releasing pressure in tumors: what do we know so far and where do we go from here? A review. Cancer Res. 74(10), 2655–2662 (2014). https://doi.org/10.1158/0008-5472.CAN-13-3696
Stylianopoulos, T., Martin, J.D., Chauhan, V.P., Jain, S.R., Diop-Frimpong, B., Bardeesy, N., Smith, B.L., Ferrone, C.R., Hornicek, F.J., Boucher, Y., Munn, L.L., Jain, R.K.: Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc. Natl. Acad. Sci. U. S. A. 109(38), 15101–15108 (2012). https://doi.org/10.1073/pnas.1213353109
Bareford, L.M., Swaan, P.W.: Endocytic mechanisms for targeted drug delivery. Adv. Drug Deliv. Rev. 59(8), 748–758 (2007). https://doi.org/10.1016/j.addr.2007.06.008
Jain, R.K.: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 307(5706), 58–62 (2005). https://doi.org/10.1126/science.1104819
Franklin, R.A., Liao, W., Sarkar, A., Kim, M.V., Bivona, M.R., Liu, K., Pamer, E.G., Li, M.O.: The cellular and molecular origin of tumor-associated macrophages. Science. 344(6186), 921–925 (2014). https://doi.org/10.1126/science.1252510
Mielgo, A., Schmid, M.C.: Impact of tumour associated macrophages in pancreatic cancer. BMB Rep. 46(3), 131–138 (2013)
Yuan, Z.Y., Luo, R.Z., Peng, R.J., Wang, S.S., Xue, C.: High infiltration of tumor-associated macrophages in triple-negative breast cancer is associated with a higher risk of distant metastasis. Onco Targets Ther. 7, 1475–1480 (2014). https://doi.org/10.2147/OTT.S61838
Jokerst, J.V., Lobovkina, T., Zare, R.N., Gambhir, S.S.: Nanoparticle PEGylation for imaging and therapy. Nanomedicine (Lond.). 6(4), 715–728 (2011). https://doi.org/10.2217/nnm.11.19
Li, Y., Lin, R., Wang, L., Huang, J., Wu, H., Cheng, G., Zhou, Z., MacDonald, T., Yang, L., Mao, H.: PEG-b-AGE polymer coated magnetic nanoparticle probes with facile functionalization and anti-fouling properties for reducing non-specific uptake and improving biomarker targeting. J. Mater. Chem. B Mater. Biol. Med. 3(17), 3591–3603 (2015). https://doi.org/10.1039/C4TB01828A
Mills, C.D., Lenz, L.L., Harris, R.A.: A breakthrough: macrophage-directed cancer immunotherapy. Cancer Res. 76(3), 513–516 (2016). https://doi.org/10.1158/0008-5472.CAN-15-1737
Vinogradov, S., Warren, G., Wei, X.: Macrophages associated with tumors as potential targets and therapeutic intermediates. Nanomedicine (Lond.). 9(5), 695–707 (2014). https://doi.org/10.2217/nnm.14.13
Miao, L., Newby, J.M., Lin, C.M., Zhang, L., Xu, F., Kim, W.Y., Forest, M.G., Lai, S.K., Milowsky, M.I., Wobker, S.E., Huang, L.: The binding site barrier elicited by tumor-associated fibroblasts interferes disposition of nanoparticles in stroma-vessel type tumors. ACS Nano. 10, 9243 (2016). https://doi.org/10.1021/acsnano.6b02776
Winograd, R., Byrne, K.T., Evans, R.A., Odorizzi, P.M., Meyer, A.R., Bajor, D.L., Clendenin, C., Stanger, B.Z., Furth, E.E., Wherry, E.J., Vonderheide, R.H.: Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol. Res. 3(4), 399–411 (2015). https://doi.org/10.1158/2326-6066.CIR-14-0215
Topalian, S.L., Drake, C.G., Pardoll, D.M.: Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 24(2), 207–212 (2012). https://doi.org/10.1016/j.coi.2011.12.009
Brahmer, J.R., Tykodi, S.S., Chow, L.Q., Hwu, W.J., Topalian, S.L., Hwu, P., Drake, C.G., Camacho, L.H., Kauh, J., Odunsi, K., Pitot, H.C., Hamid, O., Bhatia, S., Martins, R., Eaton, K., Chen, S., Salay, T.M., Alaparthy, S., Grosso, J.F., Korman, A.J., Parker, S.M., Agrawal, S., Goldberg, S.M., Pardoll, D.M., Gupta, A., Wigginton, J.M.: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366(26), 2455–2465 (2012). https://doi.org/10.1056/NEJMoa1200694
Pardoll, D.M.: The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer. 12(4), 252–264 (2012). https://doi.org/10.1038/nrc3239
Burrell, R.A., McGranahan, N., Bartek, J., Swanton, C.: The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 501(7467), 338–345 (2013). https://doi.org/10.1038/nature12625
Denison, T.A., Bae, Y.H.: Tumor heterogeneity and its implication for drug delivery. J. Control. Release. 164(2), 187–191 (2012). https://doi.org/10.1016/j.jconrel.2012.04.014
Holohan, C., Van Schaeybroeck, S., Longley, D.B., Johnston, P.G.: Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer. 13(10), 714–726 (2013). https://doi.org/10.1038/nrc3599
Choi, C.H.: ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int. 5, 30 (2005). https://doi.org/10.1186/1475-2867-5-30
Goldstein, L.J., Galski, H., Fojo, A., Willingham, M., Lai, S.L., Gazdar, A., Pirker, R., Green, A., Crist, W., Brodeur, G.M., et al.: Expression of a multidrug resistance gene in human cancers. J. Natl. Cancer Inst. 81(2), 116–124 (1989)
Aller, S.G., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., Harrell, P.M., Trinh, Y.T., Zhang, Q., Urbatsch, I.L., Chang, G.: Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 323(5922), 1718–1722 (2009). https://doi.org/10.1126/science.1168750
Dean, M., Fojo, T., Bates, S.: Tumour stem cells and drug resistance. Nat. Rev. Cancer. 5(4), 275–284 (2005). https://doi.org/10.1038/nrc1590
Townsend, D.M., Tew, K.D.: The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 22(47), 7369–7375 (2003). https://doi.org/10.1038/sj.onc.1206940
Rendic, S.: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab. Rev. 34(1–2), 83–448 (2002). https://doi.org/10.1081/DMR-120001392
Raha, D., Wilson, T.R., Peng, J., Peterson, D., Yue, P., Evangelista, M., Wilson, C., Merchant, M., Settleman, J.: The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug-tolerant tumor cell subpopulation. Cancer Res. 74(13), 3579–3590 (2014). https://doi.org/10.1158/0008-5472.CAN-13-3456
Longley, D.B., Harkin, D.P., Johnston, P.G.: 5-fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer. 3(5), 330–338 (2003). https://doi.org/10.1038/nrc1074
Xu, S., Olenyuk, B.Z., Okamoto, C.T., Hamm-Alvarez, S.F.: Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances. Adv. Drug Deliv. Rev. 65(1), 121–138 (2013). https://doi.org/10.1016/j.addr.2012.09.041
Blanco, E., Shen, H., Ferrari, M.: Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33(9), 941–951 (2015). https://doi.org/10.1038/nbt.3330
Yuan, Y.Y., Mao, C.Q., Du, X.J., Du, J.Z., Wang, F., Wang, J.: Surface charge switchable nanoparticles based on zwitterionic polymer for enhanced drug delivery to tumor. Adv. Mater. 24(40), 5476–5480 (2012). https://doi.org/10.1002/adma.201202296
Shim, M.S., Kwon, Y.J.: Stimuli-responsive polymers and nanomaterials for gene delivery and imaging applications. Adv. Drug Deliv. Rev. 64(11), 1046–1059 (2012). https://doi.org/10.1016/j.addr.2012.01.018
Vu, T., Claret, F.X.: Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front. Oncol. 2, 62 (2012). https://doi.org/10.3389/fonc.2012.00062
Koyama, S., Akbay, E.A., Li, Y.Y., Herter-Sprie, G.S., Buczkowski, K.A., Richards, W.G., Gandhi, L., Redig, A.J., Rodig, S.J., Asahina, H., Jones, R.E., Kulkarni, M.M., Kuraguchi, M., Palakurthi, S., Fecci, P.E., Johnson, B.E., Janne, P.A., Engelman, J.A., Gangadharan, S.P., Costa, D.B., Freeman, G.J., Bueno, R., Hodi, F.S., Dranoff, G., Wong, K.K., Hammerman, P.S.: Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun. 7, 10501 (2016). https://doi.org/10.1038/ncomms10501
Sharma, P., Hu-Lieskovan, S., Wargo, J.A., Ribas, A.: Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 168(4), 707–723 (2017). https://doi.org/10.1016/j.cell.2017.01.017
Zaretsky, J.M., Garcia-Diaz, A., Shin, D.S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D.Y., Abril-Rodriguez, G., Sandoval, S., Barthly, L., Saco, J., Homet Moreno, B., Mezzadra, R., Chmielowski, B., Ruchalski, K., Shintaku, I.P., Sanchez, P.J., Puig-Saus, C., Cherry, G., Seja, E., Kong, X., Pang, J., Berent-Maoz, B., Comin-Anduix, B., Graeber, T.G., Tumeh, P.C., Schumacher, T.N., Lo, R.S., Ribas, A.: Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375(9), 819–829 (2016). https://doi.org/10.1056/NEJMoa1604958
McCormick, F.: KRAS as a therapeutic target. Clin. Cancer Res. 21(8), 1797–1801 (2015). https://doi.org/10.1158/1078-0432.CCR-14-2662
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Bozeman, E.N., Yang, L. (2019). Biological Events and Barriers to Effective Delivery of Cancer Therapeutics. In: Rai, P., Morris, S.A. (eds) Nanotheranostics for Cancer Applications. Bioanalysis, vol 5. Springer, Cham. https://doi.org/10.1007/978-3-030-01775-0_2
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