DESCRIPTION

What are Gliomas?

Gliomas are the most common type of malignant tumor originating in the brain, comprising approximately 80% of all malignant brain tumors and 30% of all central nervous system tumors [1]. They are split into four grades of severity by the World Health Organization (Figure 1) [2] [3]. Compared to other types of cancer, the 5-year relative survival rate of high grade gliomas is much smaller, ranging between 5-15% [4].

Figure 1. Schematic Outlining the Different Characteristics of Tumors in Each Cancer Stage

A widely researched mutation associated with gliomas is in the isocitrate dehydrogenase 1 gene (IDH1). IDH1 mutations alter the function of metabolic enzymes in the tricarboxylic acid (TCA) cycle, causing the abnormal conversion of alpha-ketoglutarate to D-2-hydroxyglutarate (D-2HG). The most frequent variant of the IDH1 mutation changes Arg132 to a histidine (R132H), and is found in over 85% of gliomas [5][6]. Growing evidence indicates that this mutation plays a causal role in gliomagenesis, promoting glioma initiation and progression through epigenetic and metabolic reprogramming [7] [8]. Despite the low survival rate of patients diagnosed with gliomas and the many studies done on their associated pathways and relevant mutations, current treatment methods offer little hope in extending the lifespan of patients [9].

Current Glioma Treatments

The current standard of care for glioma patients is tumor resection surgery, followed by radiation therapy and chemotherapy (Figure 3) [10]. However, surgical resection for high grade gliomas often fails to eliminate cancer, leaving surgery alone as an insufficient treatment option. The addition of radiation therapy after surgery can temporarily control tumor growth. However, this still represents an inadequate solution – mean survival only increases to 12.1 months after radiation therapy in high-grade glioma patients [11] [12]. Further use of chemotherapeutics, such as temozolomide — the most common drug that acts as an agent that delivers a methyl group to purine bases of DNA — represents the last stage of current clinical protocol, but this only increases mean survival to 14.6 months for patients with high-grade tumors [13].

Figure 2: The Current Gold Standard of Glioma Treatment

Despite being the gold standard therapeutic for glioma, temozolomide is still limited in efficacy due to high rates of recurrence and damaging neurological effects [14]. Other candidates, such as alkylating agents carmustine and lomustine, and bevacizumab, a VEGF-A-targeting monoclonal antibody, have also shown potential in glioma treatment, yet studies have also found no additional benefits with increased toxicity [15]. Therefore, the search for more effective and targeted drug candidates as glioma chemotherapeutic agents remains vital for extending patient survival and health.

Lack of Accurate Models for Glioma Drug Screening

Current model systems for drug screening can be grouped into two categories: in vitro utilizing models, or patient-derived cell lines, and in vivo utilizing animal models [16]. However, both systems fail to address the complex features of the brain and are unsuccessful in reflecting conditions [17].

Even the most established in vitro cell lines are controversial due to key differences when compared to in situ gliomas [18]. Furthermore, establishing model cell lines for gliomas with specific mutations, like IDH1, is especially difficult [19]. To address the limitations of traditional in vivo systems, transgenic mouse models and patient-derived xenografts (PDX) have been developed. Although transgenic models have been instrumental in helping researchers understand oncogenic mutation mechanisms, they, like in vitro models, fail to fully represent the complex genetic and phenotypic characteristics of glioma and the brain [16]. PDX, while capturing histological markers and tumor invasiveness, also present limitations, as they are expensive and laborious to establish and maintain [20]. Thus, clinical treatments of gliomas are limited by the lack of a scalable, physiologically-relevant model for testing therapeutics [21].

Figure 3: Different Glioma Drug Testing Methods

To address such limitations of in vitro and in vivo glioma models, sophisticated organoid-glioma systems have been recently developed (Figure 3). Organoids have shown promising results in capturing key features of the brain, including cellular morphology and spatial distribution [16]. In addition, such organoids, also known as minibrains, have proven to be increasingly similar to patient derived samples and are capable of accurately modeling patient-specific responses to treatment. It has been shown that co-culturing cancer cells with organoids better captures the tumor microenvironment, and integration of cancer cells into organoid models has been observed [22]. Thus, a co-culture glioma-organoid model may better recapitulate the tumor microenvironment and provide a more accurate representation of patient-specific treatment response to current glioma therapies.

Our Approach

We are developing a novel organoid-dependent drug efficacy system (NODES) as an improved economical and high-throughput method that screens therapeutic drugs before billions of dollars and multiple years are used to evaluate them through animal testing. NODES can be used by basic science researchers to test novel compounds, pharmaceutical companies to verify the impacts of therapeutics before committing them to clinical trials, and as a personalized medicine platform for patient-specific therapy. By recapitulating the brain microenvironment, NODES has the potential to accurately characterize drug responses, offering new hope to patients in their fight against this lethal disease.

References

  1. Goodenberger, M. L., & Jenkins, R. B. (2012). Genetics of adult glioma. Cancer genetics, 205(12), 613–621. https://doi.org/10.1016/j.cancergen.2012.10.009
  2. Urbańska, K., Sokołowska, J., Szmidt, M., & Sysa, P. (2014). Glioblastoma multiforme - an overview. Contemporary oncology (Poznan, Poland), 18(5), 307–312. https://doi.org/10.5114/wo.2014.40559
  3. Gladson, C. L., Prayson, R. A., & Liu, W. M. (2010). The pathobiology of glioma tumors. Annual review of pathology, 5, 33–50. https://doi.org/10.1146/annurev-pathol-121808-102109
  4. Khan, A. M., Dawe, M., Shahnawaz, W., Saleem, M. W., & Ahmed, Z. (2020). A High-Grade Glioma of Temporal Lobe in a Child: A Case Report and Literature Review. Cureus, 12(11), e11802. https://doi.org/10.7759/cureus.11802
  5. Sporikova, Z., Slavkovsky, R., Tuckova, L., Kalita, O., Megova Houdova, M., Ehrmann, J., Hajduch, M., Hrabalek, L., & Vaverka, M. (2021). IDH1/2 mutations in patients with DIFFUSE GLIOMAS: A single centre retrospective massively parallel sequencing analysis. Applied Immunohistochemistry & Molecular Morphology, 30(3), 178–183. https://doi.org/10.1097/pai.0000000000000997
  6. Myung, J. K., Cho, H. J., Park, C. K., Kim, S. K., Phi, J. H., & Park, S. H. (2012). IDH1 mutation of gliomas with long-term survival analysis. Oncology reports, 28(5), 1639–1644. https://doi.org/10.3892/or.2012.1994
  7. Cohen, A. L., Holmen, S. L., & Colman, H. (2013). IDH1 and IDH2 mutations in gliomas. Current neurology and neuroscience reports, 13(5), 345. https://doi.org/10.1007/s11910-013-0345-4
  8. Huang L. E. (2019). Friend or foe-IDH1 mutations in glioma 10 years on. Carcinogenesis, 40(11), 1299–1307. https://doi.org/10.1093/carcin/bgz134
  9. Alexander, B. M., & Cloughesy, T. F. (2017). Adult Glioblastoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 35(21), 2402–2409. https://doi.org/10.1200/JCO.2017.73.0119
  10. Minniti, G., Muni, R., Lanzetta, G., Marchetti, P., & Enrici, R. M. (2009). Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents. Anticancer research, 29(12), 5171–5184. https://ar.iiarjournals.org/content/29/12/5171.long
  11. Wilson, T. A., Karajannis, M. A., & Harter, D. H. (2014). Glioblastoma multiforme: State of the art and future therapeutics. Surgical neurology international, 5, 64. https://doi.org/10.4103/2152-7806.132138
  12. Mason, W. P., & Cairncross, J. G. (2008). Invited article: the expanding impact of molecular biology on the diagnosis and treatment of gliomas. Neurology, 71(5), 365–373. https://doi.org/10.1212/01.wnl.0000319721.98502.1b
  13. Zhang, J., Stevens, M. F., & Bradshaw, T. D. (2012). Temozolomide: mechanisms of action, repair and resistance. Current molecular pharmacology, 5(1), 102–114. https://doi.org/10.2174/1874467211205010102
  14. Kim, S. S., Harford, J. B., Pirollo, K. F., & Chang, E. H. (2015). Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine. Biochemical and biophysical research communications, 468(3), 485–489. https://doi.org/10.1016/j.bbrc.2015.06.137
  15. Rahman, R., Hempfling, K., Norden, A. D., Reardon, D. A., Nayak, L., Rinne, M. L., Beroukhim, R., Doherty, L., Ruland, S., Rai, A., Rifenburg, J., LaFrankie, D., Alexander, B. M., Huang, R. Y., Wen, P. Y., & Lee, E. Q. (2014). Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab. Neuro-oncology, 16(11), 1523–1529. https://doi.org/10.1093/neuonc/nou118
  16. Rybin, M. J., Ivan, M. E., Ayad, N. G., & Zeier, Z. (2021). Organoid Models of Glioblastoma and Their Role in Drug Discovery. Frontiers in cellular neuroscience, 15, 605255. https://doi.org/10.3389/fncel.2021.605255
  17. Majc, B., Novak, M., Kopitar-Jerala, N., Jewett, A., & Breznik, B. (2021). Immunotherapy of Glioblastoma: Current Strategies and Challenges in Tumor Model Development. Cells, 10(2), 265. https://doi.org/10.3390/cells10020265
  18. Gillet, J. P., Calcagno, A. M., Varma, S., Marino, M., Green, L. J., Vora, M. I., Patel, C., Orina, J. N., Eliseeva, T. A., Singal, V., Padmanabhan, R., Davidson, B., Ganapathi, R., Sood, A. K., Rueda, B. R., Ambudkar, S. V., & Gottesman, M. M. (2011). Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance. Proceedings of the National Academy of Sciences of the United States of America, 108(46), 18708–18713. https://doi.org/10.1073/pnas.1111840108
  19. Luchman, H. A., Stechishin, O. D., Dang, N. H., Blough, M. D., Chesnelong, C., Kelly, J. J., Nguyen, S. A., Chan, J. A., Weljie, A. M., Cairncross, J. G., & Weiss, S. (2012). An in vivo patient-derived model of endogenous IDH1-mutant glioma. Neuro-oncology, 14(2), 184–191. https://doi.org/10.1093/neuonc/nor207
  20. Wang, Q., Hu, B., Hu, X., Kim, H., Squatrito, M., Scarpace, L., deCarvalho, A. C., Lyu, S., Li, P., Li, Y., Barthel, F., Cho, H. J., Lin, Y. H., Satani, N., Martinez-Ledesma, E., Zheng, S., Chang, E., Sauvé, C. G., Olar, A., Lan, Z. D., … Verhaak, R. (2017). Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer cell, 32(1), 42–56.e6. https://doi.org/10.1016/j.ccell.2017.06.003
  21. Pine, A. R., Cirigliano, S. M., Nicholson, J. G., Hu, Y., Linkous, A., Miyaguchi, K., Edwards, L., Singhania, R., Schwartz, T. H., Ramakrishna, R., Pisapia, D. J., Snuderl, M., Elemento, O., & Fine, H. A. (2020). Tumor Microenvironment Is Critical for the Maintenance of Cellular States Found in Primary Glioblastomas. Cancer discovery, 10(7), 964–979. https://doi.org/10.1158/2159-8290.CD-20-0057
  22. Azzarelli, R., Ori, M., Philpott, A., & Simons, B. D. (2021). Three-dimensional model of glioblastoma by co-culturing tumor stem cells with human brain organoids. Biology open, 10(2), bio056416. https://doi.org/10.1242/bio.056416