Animal Models of Brain Tumor Surgery

Animal Models of Brain Tumor Surgery

C H A P T E R 9 Animal Models of Brain Tumor Surgery Montserrat Lara-Velazquez1,2, Stephanie Jeanneret1,3, Paula Schiapparelli1, Hugo Guerrero-Cazare...

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C H A P T E R

9 Animal Models of Brain Tumor Surgery Montserrat Lara-Velazquez1,2, Stephanie Jeanneret1,3, Paula Schiapparelli1, Hugo Guerrero-Cazares1 1

Department of Neurosurgery, Mayo Clinic Florida, Jacksonville, FL, United States; Universidad Nacional Aut onoma de Mexico (UNAM), Facultad de Medicina, Plan de Estudios Combinados en Medicina (PECEM), Ciudad de Mexico, Mexico; 3Department of Psychology, The University of Texas at Austin, Austin, TX, United States 2

INTRODUCTION: GLIOBLASTOMA Glioblastoma (GBM) is the most common, proliferative, and aggressive primary brain tumor in adults. Despite current therapeutic strategies that combine surgery, radiotherapy, and chemotherapy, GBM has a devastating average survival expectancy of 14 months (Lara-Velazquez et al., 2017; Stupp et al., 2005). The high invasive capacity of GBM makes total surgical resection almost impossible, resulting in an extremely high recurrence rate of almost 100%. In the United States, the death toll due to GBM is 15,000 per year and 26,000 new cases are detected annually (Stupp et al., 2005) with an estimated economic burden exceeding $300 million (Messali, Villacorta, & Hay, 2014). The tumorigenic capacity of GBM resides in a specific cellular subpopulation which possesses selfrenewing and pluripotent capacities, the cancer stem cells (CSCs) (Guerrero-Cazares et al., 2012), which are major factors contributing to GBM aggressive, chemo-resistant, and recurrent nature. According to the World Health

Comprehensive Overview of Modern Surgical Approaches to Intrinsic Brain Tumors https://doi.org/10.1016/B978-0-12-811783-5.00009-4

Organization (WHO), GBM is a grade IV glioma characterized by necrosis, anaplasia, angiogenesis, and a high proliferative cellular rate and is classified as isocitrate dehydrogenase (IDH)mutant, IDH-wildtype, or NOS (not otherwise specified) (Louis et al., 2016). Cancer preclinical testing is an invaluable tool for the understanding of pathological processes involved in human brain tumors. Therefore, animal models that recapitulate the natural history of human cancer have been created so as to improve strategies to overcome the barriers of in vitro cancer study. Intratumor genetic variability, response to treatment, and postsurgical changes also demonstrate the need for a personalized approach to be implemented in every patient with GBM. To eradicate cancer cells, it has thus become clear today that both the genetic events and molecular mechanisms involved in tumorigenesis need to be considered. These models have made possible the study of the origins and development of cancer, as well as the advancement of various surgical approaches

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9. ANIMAL MODELS OF BRAIN TUMOR SURGERY

and alternative routes for drug delivery that bypass the bloodebrain barrier (BBB). This chapter is focused on the animal models currently available for brain tumor surgery. We will briefly introduce the different animal tumor models and then discuss the surgical approaches that induce brain tumors. In addition, we will describe a surgical approach we have developed to resect a brain mass and the imaging techniques available for the study of brain cancer progression. Finally, we will discuss local therapy strategies developed for the interstitial treatment of glioma.

ANIMALS USED FOR CANCER TREATMENT AND SURGERY MODELS The use of brain tumor intracranial modeling in animals (e.g., rabbits, guinea pigs, and rodents) pioneered in 1945 with the work of Greene and Arnold (1945) who transplanted fragments from adult, embryonic, and cancer tissue in the anterior chamber of the eye, resulting in tumor growth. Soon thereafter, research dedicated to creating a reliable animal model capable of mimicking both the micro- and macroenvironments of brain cancer surfaced and were refined by several groups (Table 9.1). Preclinical cancer models should display the following characteristics: a standardized growth rate to allow reproducibility of the cancer itself; the use of small and nonexpensive species to ensure a high number of subjects in each experimental condition; a short tumor latency to start TABLE 9.1

experimental testing; the allowance of survival time after tumor induction; and the reproducibility of the histological findings from the studied human tumor (invasiveness, necrosis, hypercellularity, and angiogenesis, in the case of GBM) (Huszthy et al., 2012). Three important techniques used to develop intracranial tumor modeling in animals include the administration of carcinogenic agents, genetic modification of animals, and xenotransplantation of human tissue. The main goal of the aforementioned approaches is not only to produce a tumor but also to importantly mimic the tumor interactions with the brain parenchyma environment, as appears in human cancer. Nevertheless, the application of each technique is dependent upon the specific purpose of the research at hand since, as we will show throughout this review, apparent advantages and disadvantages limit their applicability in specific cases (Table 9.2).

CHEMICALLY INDUCED, GENETICALLY ENGINEERED, AND XENOGRAFT MICE MODELS Chemically Induced Models Carcinogens have negative implications on the brain with regard to the significant physiological effects they produce. It is therefore worth investigating the properties of carcinogens and their effects in the brain. The earliest evidence of a successful experiment for brain tumor initiation into mice was demonstrated by Seligman

Timeline of Animal Cancer Modeling

Authors

Model

Year

Greene HS (1)

Transplant of human cancer tissue into the guinea pig eye chamber

1945

Greene HS (2)

Transplant of human neural tumors into animal’s brain

1951

Druckrey H (3)

First rat glioma cell line using MNU

1965

Flanagan SP (4)

Development of the athymic nude mouse model

1966

Ponten J (5)

Development of stabilized long-term cultures from human GBMs

1968

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CHEMICALLY INDUCED, GENETICALLY ENGINEERED, AND XENOGRAFT MICE MODELS

TABLE 9.1

171

Timeline of Animal Cancer Modelingdcont'd

Authors

Model

Year

Fraser H (6)

Description of the first spontaneous glioma in the SMA-560 mouse

1971

Greenspan HP (7)

Description of a model for spheroids tumor growth

1972

Festing MF (8)

Characterization of the athymic nude rat

1977

Kaye AH (9)

Development of a xenograft mouse glioma model

1986

Danks RA (10)

Development of transgenic mice from glioma models using glial celledirected expression of the SV40-T antigen

1995

Holland EC (11)

First transgenic mouse models of astrocytomas based on oncogene overexpression

1998

Engebraaten O (12)

Infiltrative brain tumor model in nude rats based on human biopsy spheroids

1999

Reilly KM (13)

First mouse astrocytoma model generated through tumor suppressor loss

2000

Ikawa M (14)

Use of lentiviral vectors for the generation of transgenic mice

2003

Lee J (15)

Establishment of an animal xenograft model based on GBM stem cells enrichment

2006

Kienast Y (16)

Real-time imaging window technique for the study of brain cancer metastasis

2010

Platt RJ (17,18)

CRISP-CAS9 system for gene editing and cancer modeling

2014

1. Greene, H. S., & Arnold, H. L., Jr. (1945). The homologous and heterologous transplantation of brain and brain tumors. Journal of Neurosurgery, 2(4), 315e331. 2. Greene, H. S. (1952). The significance of the heterologous transplantability of human cancer. Cancer, 5(1), 24e44. 3. Druckrey, H., Ivankovic, S., & Preussmann, R. (1965). Selective induction of malignant tumors in the brain and spinal cord of rats by N-methylN-nitrosourea. Zeitschrift Fur Krebsforschung, 66, 389e408. 4. Flanagan, S. P. (1966). ‘Nude’, a new hairless gene with pleiotropic effects in the mouse. Genetical Research, 8(3), 295e309. 5. Ponten, J., & Macintyre, E. H. (1968). Long term culture of normal and neoplastic human glia. Acta Pathologica Et Microbiologica Scandinavica, 74(4), 465e486. 6. Fraser, H. (1971). Astrocytomas in an inbred mouse strain. Journal of Pathology, 103(4), 266e270. 7. Greenspan, H. P. (1972). Models for the growth of a solid tumour by diffusion. Studies in Applied Mathematics, 52, 317e340. 8. Festing, M. F, May, D., Connors, T. A., Lovell, D., & Sparrow, S. (1978). An athymic nude mutation in the rat. Nature, 274(5669), 365e366. Kaye, A. H., Morstyn, G., Gardner, I., & Pyke, K. (1986). Development of a xenograft glioma model in mouse brain. Cancer Research, 46(3), 1367e1373. 9. Kaye, A. H., Morstyn, G., Gardner, I., & Pyke, K. (1986). Development of a xenograft glioma model in mouse brain. Cancer Research, 46(3), 1367e1373. 10. Danks, R. A., Orian, J. M., Gonzales, M. F., et al. (1995). Transformation of astrocytes in transgenic mice expressing SV40T antigen under the transcriptional control of the glial fibrillary acidic protein promoter. Cancer Research, 55(19), 4302e4310. 11. Holland, E. C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R. E., & Fuller, G. N. (2000). Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genetics, 25(1), 55e57. 12. Engebraaten, O., Hjortland, G. O., Hirschberg, H., & Fodstad, O. (1999). Growth of precultured human glioma specimens in nude rat brain. Journal of Neurosurgery, 90(1), 125e132. 13. Reilly, K. M., Loisel, D. A., Bronson, R. T., McLaughlin, M. E., & Jacks, T. (2000). Nf1; Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nature Genetics, 26(1), 109e113. 14. Ikawa, M., Tanaka, N., Kao, W. W., & Verma, I. M. (2003). Generation of transgenic mice using lentiviral vectors: a novel preclinical assessment of lentiviral vectors for gene therapy. Molecular Therapy, 8(4), 666e673. 15. Lee, J., Kotliarova, S., Kotliarov, Y., et al. (2006). Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell, 9(5), 391e403. 16. Kienast, Y., von Baumgarten, L., Fuhrmann, M., Klinkert, W. E., Goldbrunner, R., Herms, J., et al. (2010). Real-time imaging reveals the single steps of brain metastasis formation. Nature Medicine, 16(1), 116e122. 17. Platt, R. J., Chen, S., Zhou, Y., Yim, M. J., Swiech, L., Kempton, H. R., et al. (2014). CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell, 159(2), 440e455. 18. Huszthy, P. C., Daphu, I., Niclou, S. P., Stieber, D., Nigro, J. M., Sakariassen, P. O., & Bjerkvig, R. (2012). In vivo models of primary brain tumors: pitfalls and perspectives. Neuro-Oncology, 14(8), 979e993. https://doi.org/10.1093/neuonc/nos135. GBM, glioblastoma, MNU, methylnitrosourea.

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172 TABLE 9.2

9. ANIMAL MODELS OF BRAIN TUMOR SURGERY

Advantages and Disadvantages of the Different Approaches of Brain Tumor Modeling

Models

Advantages

Disadvantages

Chemically induced models (1,2,3)

1. Allow the inference of the effect of some carcinogens in the brain 2. Competency of the recipient immune system

1. Tumor formation depends on dose and route of administration 2. Lack of resemblance of cell infiltration and microvascular abnormalities of human glioma tumors

Xenograft models (1,2,3,8)

1. Trackable 2. Controlled and facilitated administration 3. Excellent to predict drug response in human tissue 4. Replicable 5. Personalized approach

1. Tumor location affects cellular behavior 2. Immunocompromised status of the animal does not allow the study of the role of immune cells in cancer 3. Is not possible to study immunotargeting therapies used for neurooncology 4. Homogeneous or oligoclonal populations of cells 5. Difficult establishment of low-grade gliomas

Genetic models (4,5,6,8)

1. Heterogeneous and polyclonal populations of 1. Contain oncogenic drivers irrelevant to the human tumor in question cells 2. Resemblance of cancer-predisposing 2. Mutations can be controlled temporally and syndromes spatially 3. Mouse tumors do not often predict human 3. Competency of the recipient immune system tumors behavior 4. Tumor progression can be studied over time 5. Allowance of study of different therapeutical strategies in various stages of tumor formation

1. Huszthy, P. C., Daphu, I., Niclou, S. P., Stieber, D., Nigro, J. M., Sakariassen, P. O., & Bjerkvig, R. (2012). In vivo models of primary brain tumors: pitfalls and perspectives. Neuro-Oncology, 14(8), 979e993. https://doi.org/10.1093/neuonc/nos1353. 2. Miyai, M., Tomita, H., Soeda, A., Yano, H., Iwama, T., & Hara, A. (2017). Current trends in mouse models of glioblastoma. Journal of Neurooncology, 135(3), 423e432. 3. Peterson, D. L., Sheridan, P. J., & Brown, W. E., Jr. (1994). Animal models for brain tumors: Historical perspectives and future directions. Journal of Neurosurgrey, 80(5), 865e876. https://doi.org/10.3171/jns.1994.80.5.0865. 4. Hesselager, G., & Holland, E. C. (2003). Using mice to decipher the molecular genetics of brain tumors. Neurosurgery, 53(3), 685e694; discussion 95. 5. Holland, E. C. (2004). Mouse models of human cancer as tools in drug development. Cancer Cell, 6(3), 197e198. Kersten, K., de Visser, K. E., van Miltenburg, M. H., & Jonkers, J. (2017). Genetically engineered mouse models in oncology research and cancer medicine. EMBO Molecular Medicine, 9(2), 137e153. 6. Apps, J. R., & Martinez-Barbera, J. P. (2017). Genetically engineered mouse models of craniopharyngioma: an opportunity for therapy development and understanding of tumor biology. Brain Pathology, 27(3), 364e369. https://doi.org/10.1111/bpa.12501. 7. Cekanova, M., & Rathore, K. (2014). Animal models and therapeutic molecular targets of cancer: utility and limitations. Drug Design, Development and Therapy, 8, 1911e1921. https://doi.org/10.2147/DDDT.S49584. 8. Becher, O. J., & Holland, E. C. (2006). Genetically engineered models have advantages over xenografts for preclinical studies. Cancer Research, 66(7), 3355e3358; discussion 3358e3359. https://doi.org/10.1158/0008-5472.CAN-05-3827.

and Shear in 1939. Following intracranial injections of the methylcholanthrene (MCA), the animals formed gliomas, meningiomas, and fibrosarcomas (A & M, 1939). Since then, chemically induced cancer animal models have been developed by exposing animals to local, oral, intravenous, or transplacental carcinogen agents (Peterson, Sheridan, & Brown, 1994). Several

compounds have been tested, including N-ethyl-N-nitrosourea (ENU) (Russell et al., 1979), N-butyl-N-(4-hydroxybutyl) nitrosamine (Ogawa et al., 1999; Zupancic, Kreft, & Romih, 2014), 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone (Schuller & Cekanova, 2005), MCA (A & M, 1939), urethane (Cekanova & Rathore, 2014), azoxymethane (Tanaka et al., 2003), and

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benzopyrene (Denissenko, Pao, Tang, & Pfeifer, 1996) and once injected into the brain the tumor formation is demonstrated. The most common compound used for brain tumor induction is found in the nitrosourea class (Stylli, Luwor, Ware, Tan, & Kaye, 2015). N-nitrosourea and its derivatives are alkylating agents that cause DNA damage. Their carcinogenic effect occurs through DNA mispairs and point mutations due to the nonrandom alkylation of bases (Stylli et al., 2015). In 1979, Wechsler et al. demonstrated the formation of brain and nerve tumors in rats treated with ENU. Interestingly, they also revealed that the oncogenic effects of nitrosoureas were dependent upon biological variants such as age and animal wellness, as well as drug-related variables (i.e., administration route and dosage). Further experiments performed by Schmidek and Koestner separately confirmed the neurocarcinogenic effect of Nnitrosourea in rats (Stoica, Koestner, & Capen, 1983; Wechsler, Ramadan, & Pfeiffer, 1979). Importantly, several cell lines derived from chemically induced tumors have been used for in vitro experiments, such as C6, 9L, T9, GL261, and CNS-1. Multiple injections of methylnitrosourea into adult rats gave rise to C6, 9L, and T9 glioma cell lines (Barth & Kaur, 2009). The 9L and T9 cell lines have been classified as TABLE 9.3

gliosarcomas and have significant implications for therapy studies as they activate the immune systems in genetically identical hosts. In contrast, the CNS-1 cell line presents weak immunogenicity, thus allowing the tumor to integrate wholly into the host (Barth & Kaur, 2009). As a result of the distant similarities shared with human cancer biology, animal cancer models developed by chemical agents present an intricate platform for drug screening and translation into clinical models. Although these cell lines do have the ability to illustrate the invasiveness of tumors as occurs in humans, they fail to recapitulate the genetic diversity of gliomas. From here it is evident that a need for a replication of not only the tumor but also of its diverse genetic events is critical.

Genetically Engineered Mouse Models Over the past 20 years, molecular alterations involved in brain cancer have been reviewed, resulting in the development of several animal models that form in situ, and thus can more reliably illustrate the molecular evolution and diverse genetic events of brain tumors (Table 9.3). The genetically engineered mouse models (GEMMs) can sustain the genetic heterogeneity

Genetic Rodent Models of Glioma and Medulloblastoma

Tumor

Gene

Mechanism

Glioma

Nf1þ/; p53þ/ (1)

Conventional and conditional KO (GFAP-Cre)

Nf1þ/; p53þ/; Pten/ (2)

Conventional and conditional KO (GFAP-Cre)

GFAP

Nf1þ/

CKO (3)

Conditional KO (GFAP-Cre) in Nf1þ/ mice

GFAPT121 (4)

TG

GFAPT121; Pten/ (5)

TG; conditional KO (MSCV-Cre)

GFAP-V12Ras (6)

TG

GFAP-V12Ras; EGFRvIII (7)

TG; adenovirus

S100-v-erbB (8)

TG (Continued)

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174 TABLE 9.3 Tumor

9. ANIMAL MODELS OF BRAIN TUMOR SURGERY

Genetic Rodent Models of Glioma and Medulloblastomadcont'd Gene

Mechanism

S100-v-erbB; p53þ/ (8)

TG; conventional KO

PDGF-B (9) Ink4a/Arf/; Pten/

RCAS; conventional KO; conditional KO (RCAS-Cre)

FIG-ROS; Ink4a/Arf/ (10)

Conditional TG (Adeno-Cre); conventional KO

kRas; Akt (11)

RCAS

p21eRAS (11)

TG

(T2)

(12,13) Nes-CreER Idh1fl(R132H)/þ

Conditional KO

Cdkn2a KO (14)

Kras and AKT (RCAS virus)

Trp53 KO (15,16)

HRASV12 and AKT

Cdkn2a, PTENF/F (15,16)

Ad-Cre virus (EGFRvIII)

1. Zhu, Y., Guignard, F., Zhao, D., Liu, L., Burns, D. K., Mason, R. P., . Parada, L. F. (2005). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell, 8(2), 119e130. https://doi.org/10.1016/j.ccr.2005.07.004. 2. Zhu, Y., Guignard, F., Zhao, D., Liu, L., Burns, D., Mason, R. P., et al. (2005). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell, 8, 119e130. 3. Bajenaru, M. L., Hernandez, M. R., Perry, A., Zhu, Y., Parada, L. F., Garbow, J. R., & Gutmann, D. H. (2003). Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Research, 63, 8573e8577. 4. Xiao, A., Wu, H., Pandolfi, P. P., Louis, D. N., & Van Dyke, T. (2002). Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell, 1(2), 157e168. 5. Xiao, A., Yin, C., Yang, C., Di Cristofano, A., Pandolfi, P. P., & Van Dyke, T. (2005). Somatic induction of pten loss in a preclinical astrocytoma model reveals major roles in disease progression and avenues for target discovery and validation. Cancer Research, 65, 5172e5180. 6. Zhu, Y., Guignard, F., Zhao, D., Liu, L., Burns, D. K., Mason, R. P., . Parada, L. F. (2005). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell, 8(2), 119e130. https://doi.org/10.1016/j.ccr.2005.07.004. 7. Ding, H., Shannon, P., Lau, N., Wu, X., Roncari, L., Baldwin, R. L., . Guha, A. (2003). Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model. Cancer Research, 63(5), 1106e1113. 8. Weiss, W. A., Burns, M. J., Hackett, C., Aldape, K., Hill, J. R., Kuriyama, H., . Israel, M. A. (2003). Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Research, 63(7), 1589e1595. 9. Dai, C., Celestino, J. C., Okada, Y., Louis, D. N., Fuller, G. N., & Holland, E. C. (2001). PDGF autocrine stimulation dedifferentiates cultured nastrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes & Development, 15(15), 1913e1925. https://doi.org/10.1101/gad.903001. 10. Charest, A., Wilker, E. W., McLaughlin, M. E., Lane, K., Gowda, R., Coven, S., et al. (2006). ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice. Cancer Research, 66, 7473e7481. 11. Holland, E. C., Varmus, H. E. (1998). Basic fibroblast growth factor induces cell migration and proliferation after glia-specific gene transfer in mice. Proceedings of the National Academy of Sciences of the United States of America, 95, 1218e1223. 12. Bardella, C., Al-Dalahmah, O., Krell, D., Brazauskas, P., Al-Qahtani, K., Tomkova, M., . Tomlinson, I. (2016). Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis. Cancer Cell, 30(4), 578e594. https://doi.org/10. 1016/j.ccell.2016.08.017. 13. Weissenberger, J., Steinbach, J. P., Malin, G., Spada, S., Rulicke, T., & Aguzzi, A. (1997). Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice. Oncogene, 14(17), 2005e2013. https://doi.org/10.1038/sj.onc.1201168. 14. Yuan, W., Jiong, Y., Huarui, Z., Gerald, J. T., Peng, Z., Paul, E. Mc., . Yuan, Z. Expression of Mutant p53 Proteins Implicates a Lineage Relationship between Neural Stem Cells and Malignant Astrocytic Glioma in a Murine Model. Cancer Cell, 15(6), 514e526. 15. Ohgaki, H., & Kleihues, P. (2013). The definition of primary and secondary glioblastoma. Clinical Cancer Research, 19(4), 764e772. https://doi. org/10.1158/1078-0432.CCR-12-3002. 16. Huse, J. T., & Holland, E. C. (2009). Genetically engineered mouse models of brain cancer and the promise of preclinical testing. Brain Pathology, 19(1), 132e143. https://doi.org/10.1111/j.1750-3639.2008.00234.x. KO, knockout; TG, transgenic.

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CHEMICALLY INDUCED, GENETICALLY ENGINEERED, AND XENOGRAFT MICE MODELS

exhibited by gliomas (Sottoriva et al., 2013). Genetically modified mice with alterations in one or several genes involved in carcinogenesis have thus allowed for the study of the role of single genes and their mutated counterparts present during tumor initiation. Current evidence illustrates the presence of intratumor heterogeneity at the genotypic and phenotypic level mediated by differential responses to kinases, growth factors, and cytokines deriving from the same GBM. Therefore, GBM heterogeneity may clearly reflect on the variability of tumor prognosis. The most common gene mutations that have led to favorable prognosis have been via O6-methylguanine transferase (MGMT) promoter methylation (36% of primary and 75% of secondary tumors) and IDH mutation (5% of primary and 75% of secondary tumors) (Hegi et al., 2005). On the other hand, the markers mentioned in Table 9.4 are importantly associated with poor prognosis if mutated in GBM (Labussiere et al., 2014). Some of these detrimental mutations include INK4A and ARF (50% of high-grade astrocytomas and 8%e10% of secondary tumors), the PI3K/ AKT/mTOR pathway (85% of GBM), and the epidermal growth factor receptor (EGFR) (40%e60% of primary GBM and 8% of secondary tumors). Consequently, multiple GEMM models of human brain cancer have been developed to mimic some of the clinically relevant mutations (Apps & Martinez-Barbera, 2017; Ben-David et al., 2016; Braiden et al., 1998; Deneka et al., 2017; Ma & Saiyin, 2017). The first transgenic mouse model for brain cancer was described in 1984 by Brinster et al. After transfecting embryonic cells with a mutation in the SV40 gene, they observed tumor formation in the choroid plexus of the affected animals (Brinster et al., 1984). Further experiments that investigated the overexpression of different oncogenes in glioma include mutations such as Nf 1, p53, PTEN, PDGFb, EGFR and the knockdown of INK4A and ARF, Rb and p53 (Adams et al., 1985; Hanahan, 1989; Stewart,

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Pattengale, & Leder, 1984). Additionally, conditional strategies may be applied to control gene expression in a specific temporal location via chemically inducible transcription factors or by the Cre- or Flp-system (Becher & Holland, 2006). To establish a reliable GEMM model, the following criteria must be met: (1) the animal must be a carrier of the same mutation than the one in human tumors; (2) the mutations must be introduced within the endogenous locus; (3) the mutated genes must not affect embryogenesis and early postnatal stages of the animal; and (4) the mutations must be present in a limited number of the selected cell types (Gopinathan & Tuveson, 2008; Richmond & Su, 2008). By consequence, it is expected that GEMMs faithfully recapitulate the anatomopathological features of the human cancer type to be studied (Richmond & Su, 2008). Specifically, the physiological relevance of these systems as compared to human counterparts provides a great advantage for their use; as in native tumors, they can mimic tumorestroma interactions and harbor cellular subpopulations in the way CSCs do (Huse & Holland, 2009). Moreover, these models present targeted and sophisticated approaches paving the way for the study of specific oncogenes and their influence on cellular proliferation, differentiation, and tumor progression. However, not all mouse models will recapitulate the changing genetic events alongside the tumor’s progression.

Xenograft Models The transplantation of cells from one foreign species to another is a technique known as xenografting. Although records of murine-to-man transplantations have existed as early as 1905 (Reemtsma, 1995), animals models appear to pose barriers in replicating human biological processes (Quinones-Hinojosa et al., 2006; Sanai et al., 2004); our group elucidates the significance of extending the laboratory to the operating room. To study cells sharing characteristics

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176 TABLE 9.4

9. ANIMAL MODELS OF BRAIN TUMOR SURGERY

Common Markers Associated With Poor and Good Prognosis in Glioblastoma (GBM)

Mutation

Component

Percentage Present in GBM

Associated with poor prognosis

Tp53(1e3) (1,2,3)

28% of primary GBM and 65% of secondary tumors

Retinoblastoma (1,3,4)

10%e25% of high-grade astrocytomas

Neurofibromatosis 1 (1,3)

e

INK4A and ARF (1e3,5)

50% of high grade astrocytomas and 8%e10% of secondary tumors

PI3K/AKT/mTOR pathway (3,6)

85% of GBM

RAS/MAPK pathway (3, 7)

e

Epidermal growth factor receptor (1,8)

40%e60% of primary GBM and 8% of secondary tumors

Platelet-derived growth factor receptor (10,13)

13% of GBM

Phosphatase and hensin homologs (3,9)

25% of primary and 4% secondary tumors

TERT promoter mutations (10)

80% of isocitrate dehydrogenase (IDH)-wild type GBM

Homozygous deletion of CDKN2A/CDKN2B (5,11)

60% of IDH-wild type GBM

Alpha thalassemia/mental retardation syndrome, X linked (ATRX) (12)

e

BRAF (12)

85% of low-grade gliomas

O6-methylguanine transferase promoter methylation (13)

36% of primary and 75% of secondary tumors

IDH mutation (12)

5% of primary and 75% of secondary tumors

Associated with good prognosis

1. The Cancer Genome Atlas Research Network. (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 455, 1061e1068. 2. Louis, D. N. (1994). The p53 gene and protein in human brain tumors. Journal of Neuropathology & Experimental Neurology, 53, 11e21. 3. Parsons, D. W., Jones, S., Zhang, X., Lin, J. C. -H., Leary, R. J., Angenendt, P., et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science, 321, 1807e1812. 4. Henson, J. W., Schnitker, B. L., Correa, K. M., von Deimling, A., Fassbender, F., Xu, H. J., et al. (1994) The retinoblastoma gene is involved in the malignant progression of astrocytomas. Annals of Neurology, 36, 714e721. 5. Cairncross, J. G., Ueki, K., Zlatescu, M. C., Lisle, D. K., Finkelstein, D. M., Silver, R. R. H., et al. (1998). Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. Journal of the National Cancer Institute, 90, 1473e1479. 6. Wong, A. J., Ruppert, J. M., Bigner, S. H., Grzeschik, C. H., Humphrey, P. A., Bigner, D. S., & Vogelstein, B. (1992). Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proceedings of the National Academy of Sciences of the United States of America, 89, 2965e2969. 7. Guha, A., Feldkamp, M. M., Lau, N., Boss, G., & Pawson, A. (1997). Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene, 15, 2755e2765. 8. Di Rocco, F., Carroll, R. S., Zhang, J., & Black, P. M. (1998). Platelet-derived growth factor and its receptor expression in human oligodendrogliomas. Neurosurgery, 42, 341e346. 9. James, C. D., Carlblom, E., Dumanski, J. P., Hansen, M., Nordenskjold, M., Collins, V. P., & Cavenee, W. K. (1988). Clonal genomic alterations in glioma malignancy stages. Cancer Research, 48, 5546e5551. 10. Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., et al. (2009). IDH1 and IDH2 mutations in gliomas. The New England Journal of Medicine, 360(8), 765e773. 11. Ueki, K., Ono, Y., Henson, J. W., von Deimling, A., & Louis, D. N. (1996). CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Research, 56, 150e153. 12. Szopa, W., Burley, T. A., Kramer-Marek, G., & Kaspera, W. (2017). Diagnostic and therapeutic biomarkers in glioblastoma: Current status and future perspectives. Biomed Research International, 2017, 8013575. 13. Hegi, M. E., Diserens, A. C., Gorlia, T., Hamou, M. F., de Tribolet, N., Weller, M., . Stupp, R. (2005). MGMT gene silencing and benefit from temozolomide in glioblastoma. New England Journal of Medicine, 352(10), 997e1003. https://doi.org/10.1056/NEJMoa043331.

CHEMICALLY INDUCED, GENETICALLY ENGINEERED, AND XENOGRAFT MICE MODELS

with CSCs, the neural stem cells, the use of intraoperative human tissue was useful to perform both in vivo and in vitro experiments (Chaichana et al., 2009; Guerrero-Cazares, Chaichana, & Quinones-Hinojosa, 2009). Nowadays, xenograft models are commonly used to reveal tumor response to treatment as well as early stages of gliomagenesis. The cancerous tissue or glioma cell lines can be transplanted ectopically (i.e., subcutaneously) or into the orthotopic site (the native organ where the transplanted cells originally came from) (Huszthy et al., 2012). To recreate human cancer in an animal model and to avoid rejection of the transplanted cells, the immune system of the recipient must be compromised. Current immunocompromised rodent models include athymic nude mice (deficient in T cell function), severely compromised immunodeficient mice (deficient in T and C cell function), beige mice (deficient in NK cells), or other immunocompromised rodents (i.e., a combination of different deficiencies) (Huszthy et al., 2012). For larger animals, their immunosuppression must be chemically induced with cyclosporine as there are no genetic immunosuppressed strains (Archer et al., 2014). In addition to the recipient’s immunological state, the number and histological grade of the transplanted cells influence the rate of tumor formation. Evidently, the patient-specific xenograft model with the implantation of intraoperative human tissue into an animal brain is a personalized approach for cancer. Drug testing and surgery techniques can be further evaluated with this model, allowing the translation of the obtained knowledge into improved treatments (Huszthy et al., 2012).

Orthotopic Implantation of Brain Cancer Stem Cells CSCs have the ability to initiate, propagate, and sustain the growth of tumors that closely

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resemble human pathology (Achanta, Sedora Roman, & Quinones-Hinojosa, 2010; Chaichana et al., 2009; Chesler, Berger, & QuinonesHinojosa, 2012; Guerrero-Cazares, Attenello, Noiman, & Quinones-Hinojosa, 2012; Hsu, Mohyeldin, Shah, Gokaslan, & QuinonesHinojosa, 2012; Singh et al., 2004; Tilghman et al., 2014). These self-renewal and pluripotent cells, firstly isolated from hematological malignancies almost 60 years ago (Bruce & Van Der Gaag, 1963), have also been described in other cancer types, including brain cancer (Chiba, Kamiya, Yokosuka, & Iwama, 2009; GuerreroCazares et al., 2012; Guo, Lasky, & Wu, 2006; Lee, Castilho, Ma, & Ng, 2009; Yi & Nan, 2008). CSCs are located near the core and intermediate areas of the tumor (Maugeri-Sacca et al., 2014) and are known to promote angiogenesis and to avoid the effect of chemotherapeutic agents via multidrug resistance transporters (MaugeriSacca et al., 2014). In addition, these cells present an improper activation of molecular pathways that direct DNA damage repair (p53 and ATR/ Chk1/Chk2 pathways), apoptosis, and survival (Bcl-2, Mcl-1 and PI3K/AKT/mTOR), justifying their resistance to the toxic effects of eradicative treatments (i.e., radiation and drugs) (Kim, Jeon, & Kim, 2015). CSCs can be identified by the expression of protein markers such as CD133, CD90, CD15, musashi, nestin, and olig2, and by testing the activity of ABC-G2 channels and aldehyde dehydrogenase (Emery et al., 2017; Guerrero-Cazares et al., 2012; Kim & Ryu, 2017; Medema, 2013; Wu & Wu, 2009). Functional assays can also be performed on CSCs in vitro by analyzing sphere formation with further differentiation into glia and neurons, as well as tumor initiation when transplanted into animals’ brains (Guerrero-Cazares et al., 2009) (Fig. 9.1) In cancer research, transplantation of human CSCs isolated from intraoperative samples (Chaichana et al., 2009) is a common approach for preclinical cancer testing.

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FIGURE 9.1 Isolation and characterization of human cancer stem cells (CSCs) from glioblastoma patients. (A) Intraoperative samples of the resected tumor are processed for in vitro and in vivo experimentation in the laboratory. (B) After single cells are obtained, CSCs are isolated by both their capacity to form neurospheres in complete base media enriched with growth factors (e.g., EGF, FGF) and their differentiation capacity into neurons and glia after deprivation of the growth factors. (C) The CSCs are injected via a stereotactic approach in the rodent’s brain. (D) The brain is extracted and tumor formation is histologically evaluated.

Upon stereotactic injection, GBM CSCs can indeed integrate into the host brain parenchyma giving rise to tumor formation (Chaichana et al., 2009; Gonzalez-Perez, Guerrero-Cazares, & Quinones-Hinojosa, 2010). The implanted cells can be previously transduced to express GFP and luciferase, thereby monitoring tumor growth in vivo. Other approaches have described tumor intravital imaging through a cranial window in the skull of the animal by using an optical microscope (Sweeney et al., 2014) or by monitoring the implanted cells via imaging techniques such as magnetic resonance (Bianco et al., 2017). In the following paragraphs, we describe the resection technique developed by our group and some available options for adjuvant local therapies against GBM.

Resection Technique for Orthotopic Brain Tumors Surgery is the primary standard treatment for high-grade gliomas (Chaichana et al., 2014). Surgical options for GBM include stereotactic approaches for biopsy or resection, as well as

awake or standard craniotomies (Young, Jamshidi, Davis, & Sherman, 2015). High-grade gliomas cannot be cured with surgery alone; however, the extent of resection is a determining factor for a patient’s overall survival. Evidence shows that maximal safety surgical resection is associated with better survival: a resection of 70% of the total mass with 5% of residual volume led to better outcomes in patients with newly diagnosed GBM (for each 5% resection increment, the risk of death decreased by 5.2%) (Chaichana et al., 2014). As described in humans, the percentage of tumor resection has a substantial impact on survival for animals (Sweeney et al., 2014). As other groups (Baumann, Dorsey, Benci, Joh, & Kao, 2012; Cozzens et al., 2017; Sweeney et al., 2014) have done, we have developed an orthotopic GBM model that allows us to refine resection techniques and to evaluate postsurgery tumor recurrence. Our approach utilizes a surgical drill to perform a 3 mm2 cranial window in the same location where the transduced GBM cells were previously injected. The surface of resection is then marked with a 3.0 mm biopsy punch (Bianco et al., 2017), and tumor debulking is

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performed thereafter using microscissors (approximately 1.8 mm in depth). As a result, the resection area is circular, making the tumor easy to remove entirely (Fig. 9.2). Another device used for tumor resection is a suction device called a water-jet dissector, which consists of a pencil-like handpiece with a nozzle (120 m diameter) that can be preset with different pressures (Keiner et al., 2016). Intraoperative mapping systems have been developed to precisely delimit the tumor’s location and increase the precision and extent of resection. Fluorescence-guided surgery, which is used in humans (Cozzens et al., 2017) and

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animals, is based on the fluorescent signal emitted by the GBM celledriven conversion of 5-aminolevulinic acid (5-ALA) to fluorescent porphyrins. GFP-guided surgery has been shown to produce accurate resection of GBM with over 95% tumor removal, as Hingtgen et al. (2013), illustrated with a xenograft GBM model of U87GFP-FLuc cells (Hingtgen et al., 2013). Finally, the use of an endomicroscope imaging system has been adapted for identifying gliomas in murine models using a variety of fluorophores. This system described by Martirosyan et al. (2014) provides real-time histological information of the tumor.

FIGURE 9.2 Xenograft transplantation of human glioblastoma cancer stem cells into immunocompromised mice. (A) Animal’s head is opened for a clear view of the skull and identification of the sutures. After bregma is located, the X, Y, Z coordinates are fixed at the desired location. (B) A 3.0 mm biopsy punch is used to delimit the surgical area. (C) A cranioplasty is made with a drill, and tumor debulking is then performed with microscissors at a depth of 1.8 mm, allowing whole tumor resection. (D) The cranial defect is repaired using a thin layer of methacrylate fixed to the skull with glue.

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Once the tumor is removed, the skull defect is repaired by placing a methacrylate membrane at the resection site fixed with glue (approximately 0.5e1 mm thick), and finally the skin is closed with glue. Our modified cranioplasty approach allows us to avoid the exposure of the surgical field by covering the resection site (unpublished data). Moreover, any local therapy applied in the resection cavity may be readily maintained. Different approaches for cranioplasties have been described, including a circular glass microscope coverslip that allows for real-time followup of the tumor (Sweeney et al., 2014), the use of impermeable sheets of titanium (Akbar et al., 2009), and the use of a polyester urethane net (Neuro-Patch) (Bianco et al., 2017). The animal can then be subjected to postoperative imaging to evaluate the resected cavity.

EVALUATION OF TUMOR FORMATION AND PROGRESSION Imaging plays a fundamental role in the treatment of cancer. The standard of care for patients with GBM includes a routine follow-up with magnetic resonance imaging (MRI) (Mathur, Jain, Kesavadas, Thomas, & Kapilamoorthy, 2015). MRI has drastically improved the identification of tumor remnants after surgery as well as changes in the tumor’s microenvironment, such as angiogenesis, necrosis, and calcifications (Mathur et al., 2015). MRI is based on the use of strong magnetic fields and radio waves to generate images of the brain; it has also been used in animal models to accurately identify their tumors (Bianco et al., 2017). Since the mouse brain volume is only 0.5e0.6 mL, the voxel size required for an MRI of a rodent’s brain is only 0.1% of the volume required for human imaging (Driehuys et al., 2008). Thus, MRI allows effective in vivo monitoring of not only the surgical approach performed but also the response to treatment.

Besides MRI, in cancer research, functional methods such as bioluminescence imaging (BLI) have enhanced the promise of preclinical testing in brain tumors (Table 9.5). BLI is based on the detection of photons emitted by light from genetically engineered

TABLE 9.5 Advantages and Disadvantages of Bioluminescence Imaging (BLI) and Magnetic Resonance Imaging (MRI) for the Study of Brain Tumors in Small Animals Advantages

Disadvantages

BLI (1,2,3,5) 1. Quantitative data 1. Luminescent source 2. Absence of needed background 2. Overexposure can signal reflect inaccurate 3. Partially results noninvasive 3. Only viable cells contribute to the tumor size data 4. 2D nature MRI (3,4,5,6)

1. No cellular label is needed 2. Noninvasive 3. 3D nature 4. High resolution

1. Time-consuming 2. Inexact with peritumoral edema 3. Noise that can contaminate the image 4. High cost

1. Genevois, C., Loiseau, H., & Couillaud, F. (2016). In vivo follow-up of brain tumor growth via bioluminescence imaging and fluorescence tomography. International Journal of Molecular Science, 17(11). 2. Yahyanejad, S., Granton, P. V., Lieuwes, N. G., Gilmour, L., Dubois, L., Theys, J., et al. (2014). Complementary use of bioluminescence imaging and contrast-enhanced micro-computed tomography in an orthotopic brain tumor model. Molecular Imaging, 13. 3. Folaron, M., & Seshadri, M. (2016). Bioluminescence and MR imaging of the safety and efficacy of vascular disruption in gliomas. Molecular Imaging and Biology, 18(6), 860e9. 4. Denic, A., Macura, S. I., Mishra, P., Gamez, J. D., Rodriguez, M., & Pirko, I. (2011). MRI in rodent models of brain disorders. Neurotherapeutics, 8(1), 3e18. 5. Jost, S. C., Collins, L., Travers, S., Piwnica-Worms, D., & Garbow, J. R. (2009). Measuring brain tumor growth: combined bioluminescence imaging-magnetic resonance imaging strategy. Molecular Imaging, 8(5), 245e253. 6. Koutcher, J. A., Hu, X., Xu, S., Gade, T. P., Leeds, N., Zhou, X. J., et al. (2002). MRI of mouse models for gliomas shows similarities to humans and can be used to identify mice for preclinical trials. Neoplasia, 4(6), 480e485.

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cells expressing a reporter enzyme that will be treated with the enzyme’s substrate (McKinnon, Moore, Dixit, Zhu, & Broome, 2017). Luciferase genes from firefly or Renilla are widely used in experimental biology. Once the luciferaseexpressing cells are implanted into the animal model, the luciferin substrate is systemically injected to identify the manipulated cells in a live organism (Close, Xu, Sayler, & Ripp, 2011). BLI offers the ability to visualize the tumor without sacrificing the animal, as well as the emission of signals that arise solely from the transduced cells due to the lack of endogenous BLI from normal cells (Close et al., 2011). This technique has been successfully applied to monitor the effects of tumor progression, evaluate metastasis, and quantify the volume of the tumor resected in glioma animal models (Martinez-Aranda, Hernandez, Picon, Modolell, & Sierra, 2013; Yahyanejad et al., 2014) (Fig. 9.3). Behavioral changes in animals also predict the rate of tumor progression. As the tumor grows, cytokines and proinflammatory substances are released and affect pain fibers locally or secondary to compression of surrounding nerves (Pacharinsak & Beitz, 2008). Several scales that evaluate the animal’s quality of life allow for early intervention to improve experimental outcomes while reducing animal suffering (Villalobos, 2006). The HHHHHMM (Hurt, Hunger, Hydration, Hygiene, Happiness, Mobility, and More Good Days than Bad Days) scale assesses outcomes such as lethargy, failure to ambulate, hunched posture, and anorexia (Foltz & Ullman-Cullere, 1999). The Basso, Beattie, Bresnahan locomotor rating scale is another tool that measures the motor activity of the animal including weight-supported plantar stepping, coordination of extremities, consistent position of the paw during stepping, and maintenance of the axis (Basso et al., 2006; Sarabia-Estrada et al., 2013, 2017). Two common tests used in rodents to evaluate pain due to tumor growth are the heat paw-withdrawal test (Hargreaves, Dubner, Brown, Flores, & Joris, 1988) and the

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von Frey test (Sarabia-Estrada et al., 2017; Tyner et al., 2007), techniques based on the evaluation of thermal sensitivity caused by a hot stimulus or by filaments of various thicknesses, respectively. Many of the characteristics observed in these animal models are also present in patients with cancer. Thus, the use of these scales aids researchers in deciding when to start adjuvant therapy or when to terminate the experiment (Pacharinsak & Beitz, 2008).

Local Therapies for Gliomas Drug penetration into the brain remains an unsolved challenge. The BBB is a selective system that regulates the passage of different compounds into the brain. In addition, 90% of glioma recurrences occur within 2 cm of initial tumor locations (Hochberg & Pruitt, 1980). Therefore, intensive local drug administration and release are needed to treat gliomas. Various delivery techniques for local application to treat brain cancer have been developed (i.e., drug-loaded polymer implant/wafers, implantable cannulas/catheters, engineered cells, and hydrogels). These regional approaches exhibit several advantages over conventional therapies as they avoid the systemic side effects associated with treatment by penetrating deep into the brain’s parenchyma. Being a local application also serves as an advantage by avoiding the filtration controlled by the BBB. Several chemotherapeutic agents successfully administered via different approaches in clinical and preclinical scenarios investigating glioma will be briefly described (Table 9.6). Impregnated polymers are composed of a matrix and active drugs that degrade and incorporate into the brain parenchyma (Chaichana, Pinheiro, & Brem, 2015). The first attempt for local therapy to treat newly diagnosed and recurrent glioblastoma was the carmustine wafer, Gliadel. This FDA-approved polymeric implant is composed of carmustine, a chemotherapeutic agent (Bota, Desjardins, Quinn,

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FIGURE 9.3 Imaging techniques for glioma. Real-time analysis of tumor formation and progression can be recorded through the use of imaging modalities such as bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). (A) BLI illustrates the signal emitted by the transduced glioblastoma (GBM) cells. (B) MRI shows a well demarked tumor. (C) Histological evaluation of the tumor depicting the high proliferative rate characteristic of GBM.

Affronti, & Friedman, 2007). Additionally, the most adverse effects associated with Gliadel are intracranial infections, edema, wound healing abnormalities, seizures, hydrocephalus, and cerebrospinal fluid leaks (Chowdhary, Ryken, & Newton, 2015). Yet, whether this option is beneficial for glioma patients due to described low penetrance into the brain parenchyma and quick release proves controversial. A recent metaanalysis showed that Gliadel implantation into the resection cavity right after surgery improved the 1-year overall survival (OS) in patients with

newly diagnosed high-grade gliomas 67%, versus 48% OS in patients without the wafer; whereas for recurrent high-grade gliomas the OS was 37% with Gliadel versus 34% without it (Chowdhary et al., 2015). To improve penetration and prolong survival, multiple efforts using carmustine have been investigated in animals. Zhu et al. (2014) described a prolonged survival in mice bearing gliomas treated with wafers fabricated with carmustine and poly (D,L-lactide-co-glycolide) when compared with the nontreated group, secondary

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TABLE 9.6

Local Delivery Strategies Against Glioblastoma in Preclinical Stages

Administration System

Drug

Wafers (1,2,3,4)

Carmustine Mitoxantrone Carboplatin Minocycline Riluzole þ memantine

Liposomes (5)

Doxorubicin

Polymer beads (6)

Rapamycin

Microassemblies implants (7)

Paclitaxel Doxorubicin

Nanoparticles (8)

Camptothecin

Nanocapsules (9)

Lauroyl-gemcitabine

Hydrogels (10)

Paclitaxel Camptothecin Cytarabine

Intratumoral cavity catheters clench to a reservoir (11,12,13,17)

Mitoxantrone,131I-Mab (antitenascin), bleomycin, anti-EGFR Mab þ lymphocytes, HSVTK þ ganciclovir

Convection-enhanced delivery (14,15,16,18)

IL-13/pseudotoxin, paclitaxel, oligonucleotides, TGF-a/pseudotoxin, topotecan

1. Brem, H., Mahaley, M. S., Jr., Vick, N. A., et al. (1991). Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. Journal of Neurosurgery, 74(3), 441e446. 2. Brem, H., Piantadosi, S., Burger, P. C., et al. (1995). Placebocontrolled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet, 345(8956), 1008e1012. 3. Olivi, A., Ewend, M. G., Utsuki, T., et al. (1996). Interstitial delivery of carboplatin via biodegradable polymers is effective against experimental glioma in the rat. Cancer Chemotheraphy and Pharmacology, 39(1e2), 90e96. 4. Weingart, J. D., Sipos, E. P., Brem, H. (April 1995). The role of minocycline in the treatment of intracranial 9L glioma. Journal of Neurosurgery, 82(4), 635e640. 5. Gabizon, A., Isacson, R., Libson, E., et al. (1994). Clinical studies of liposome-encapsulated doxorubicin. Acta Oncology, 33(7), 779e786. 6. Tyler, B., et al. (July 2011). Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats. Neuro-Oncology, 13(7), 700e709. https://doi.org/10.1093/neuonc/ nor050. 7. Zhou, T., Zhu, B., Chen, F., Liu, Y., Ren, N., Tang, J., . Zhu, X.

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(February 10, 2017). Micro-/nanofibers prepared via co-assembly of paclitaxel and dextran. Carbohydrate Polymers, 157, 613e619. https:// doi.org/10.1016/j.carbpol.2016.10.028. Epub 2016 Oct 14. 8. Anxun Wang & Su Li. (2008). Hydroxycamptothecin-loaded nanoparticles enhance target drug delivery and anticancer effect. BMC Biotechnology, 8, 46. Published online 2008 May 4. https://doi. org/10.1186/1472-6750-8-46. 9. Bastiancich, C., Vanvarenberg, K., Ucakar, B., Pitorre, M., Bastiat, G., Lagarce, F., . Danhier, F. (10 March 2016). Lauroyl-gemcitabineloaded lipid nanocapsule hydrogel for the treatment of glioblastoma. Journal of Controlled Release, 225, 283e293. https://doi.org/10.1016/j. jconrel.2016.01.054. Epub 2016 Jan 30. 10. Liang, Y., Dong, C., Zhang, J., Deng, L., & Dong A. (June 2017). A reconstituted thermosensitive hydrogel system based on paclitaxelloaded amphiphilic copolymer nanoparticles and antitumor efficacy. Drug Development and Industrial Pharmacy, 43(6), 972e979. https:// doi.org/10.1080/03639045.2017.1287718. Epub 2017 Feb 14. 11. Nakagawa, K., Kamezaki, T., Shibata, Y., Tsunoda, T., Meguro, K., Nose, T. (1995). Effect of lymphokine-activated killer cells with or without radiation therapy against malignant brain tumors. Neurologia Medico Chirurgica (Tokyo), 35(1), 22e27. 12. Boiardi, A., Salmaggi, A., Pozzi, A., Broggi, G., Silvani, A. (1996). Interstitial chemotherapy with mitoxantrone in recurrent malignant glioma: preliminary data. Journal of Neurooncology, 27(2), 157e162. 13. Quattrocchi, K. B., Miller, C. H., Cush, S., et al. (1999). Pilot study of local autologous tumor infiltrating lymphocytes for the treatment of recurrent malignant gliomas. Journal of Neurooncology, 45(2), 141e157. 14. Tanner, P. G., Holtmannspotter, M., Tonn, J. C., Goldbrunner, R. (2007). Effects of drug efflux on convection-enhanced paclitaxel delivery to malignant gliomas: technical note. Neurosurgery, 61(4), E880eE882. Discussion E882. 15. Kunwar, S., Chang, S., Westphal, M., et al. (2010). Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncology, 12(8), 871e881. 16. Bogdahn, U., Hau, P., Stockhammer, G., et al. Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncology, 13(1), 132e142. 17. Jiangbing, Zhou, Kofi-Buaku Atsina, B. S., Benjamin, T., Himes, B. A., Garth, W., Strohbehn, B. S., Mark Saltzman, W. (JanuaryeFebruary 2012). Novel delivery strategies for glioblastoma. The Cancer Journal, 18(1). 18. Chaichana, K. L., Pinheiro, L., Brem, H. (2015). Delivery of local therapeutics to the brain: working toward advancing treatment for malignant gliomas. Therapeutic Delivery, 6(3), 353e369.

to an inhibitory polymer-mediated effect on tumor growth (Zhu et al., 2014). External devices have also been used for treating gliomas. Soft catheters and/or rigid cannulas placed directly into the resection cavity allow the administration of chemotherapeutic agents into the tumor bed. Detrimental effects associated with the continuous manipulation of the devices

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include hemorrhages, infections, and misplacement of the catheter/cannula (Jahangiri et al., 2017). Ongoing clinical trials test the effect of the cannulas on survival via the administration of drugs, viruses, and recombinant proteins in GBM patients. Preclinical studies using these devices are meant to test the administration of different drugs such as topotecan, gemcitabine, carboplatin, and temozolomide with improved survival in glioma rodents wearing the device (Jahangiri et al., 2017). Cellular therapy is a frontier with great potential in cancer research. Innate tumor-tropism of neural and mesenchymal stem cells has led the development of GBM cellular therapy. Recent advances demonstrate that the use of genetically modified stem cells can produce substances that induce apoptosis of tumoral cells or act as

carriers for the delivery of suicidal compounds. Promising results have been observed after systemic administration of the cells (Altaner & Altanerova, 2012). As described in several preclinical studies, stem cells are able to reach the tumor even after systemic administration and show innate tropism toward the cancer cells, enhanced by inflammatory and angiogenesis factors secreted by the tumor and the peritumoral area. Interestingly, these cells exhibit a lack of immunoreaction after implantation accompanied by a long-lasting therapeutic effect once they reach the tumor site (Namba, Kawaji, & Yamasaki, 2016). The stem cells can be also used as carriers to deliver chemotherapeutic agents which are then converted into an active form in the tumor’s microenvironment. Following the successful results of cellular

FIGURE 9.4 Interstitial therapies for glioma treatment. (A) Local strategies that can be delivered into the resected cavity right after tumor removal. These therapies decrease the risk of toxicity as they allow a localized drug delivery. (B) External devices such as cannulas placed directly into the tumor bed allow the administration of chemotherapeutic agents through minimal invasion. (C) Administration of wafers, engineered cells, and biomaterials such as hydrogels into the postsurgical cavity also enhance the targeted drug delivery.

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REFERENCES

therapy, clinical studies are being developed to optimize the efficacy of this treatment such as the clinical trial developed by Karen Aboody, delivering promising results for GBM patients (Aboody, 2012), or by Zwi N. Berneman who used dendritic cells vaccination plus adjuvant chemotherapy with temozolomide in newly diagnosed-GBM patients (Zwi Berneman & Specenier, 2015). Finally, self-assembling biomaterials used as delivery devices are becoming an important field of study for diverse pathologies such as cancer, stroke, brain and spinal cord injury. For example, hydrogels are degradable and control release rate systems consisting mainly of a pharmacological agent, which is easily cleared from the body. Their high water concentration (90% of water), secondary to their hydrophilic nature, contributes to their elastic and soft properties making it easy to handle in the brain (Hynd, Turner, & Shain, 2007); they also more accurately resemble the characteristics of the extracellular matrix. Materials used for the production of hydrogels include alginate, agarose, collagen, and proteinbased compounds (Aurand, Lampe, & Bjugstad, 2012). Supramolecular agents also have been used in the development of hydrogels; Lock et al. (2017) have constructed a bimodal imaging-compatible biomaterial for therapy and diagnosis, composed of small-molecule peptides and peptide conjugates mixed with FDAapproved chemotherapeutic agents (Lock et al., 2017). A clinical trial using the OncoGel with a formulation of paclitaxel administered into the resection cavity in GBM-recurrent patients was terminated due to the lack of beneficial results (Daugherty, 2007). Thus, further animal studies that show the efficacy of this system need to be performed (Fig. 9.4).

CONCLUSION The study of brain diseases has been made possible by sophisticated preclinical models

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that replicate the biological environments observed in human cancer. Although limitations due to intra- and intertumor heterogeneity must be considered when using animal models, if carefully addressed, preclinical modeling of brain tumors in animals is evidently a valuable resource that serves to expand the understanding of and the therapeutic development of brain cancer.

Acknowledgments MLV was supported by CONACYT. HGC, MLV, PS, and SJ were supported by NIH. We thank Ron Shmueli and Rawan Al-kharboosh for the images provided.

Conflict of Interest Statement None.

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