09 Aug Epigenetic Approach to Pediatric and Adult Brain Tumors

MedicalResearch.com Interview with:

Dr. Sarkar

Sibaji Sarkar, Ph.D.
Division of Biotech, Quincy College
Quincy MA.
Biology/STEM MBC College,
Wellesley MA, Boston MA.

MedicalResearch.com: What is the background for this study? What are the main developmental differences between adult and pediatric tumors?

Response: The treatment of both pediatric and adult types of brain tumors is complex.  The treatment and prognosis depend on their origin, development, progression and location. It is extremely important that the origin, which involves formation of cancer stem/progenitor cells, is investigated to understand growth, drug resistance and relapse of the brain tumors. Pediatric brain tumors often are less metastatic and treatable but chemo leaves adverse effects for longer times. Adult metastatic brain tumors usually have worse prognosis.

To understand and develop better treatments we need to understand the differences in the origin and progression of these different types of brain tumor [1]. One of the important aspects is epigenetic alterations. Epigenetic alterations are reversible and different from mutations in genes, which are usually permanent. In epigenetic alterations, modifications occur on DNA or the protein histones around which the DNA is folded and they regulate whether a gene will express or not (will make a protein or not), that determines a special function.

MedicalResearch.com: Do viruses play a role in any of these tumors?

Response: Though viruses are not known to play a direct role in the development of most brain tumors, infection with Epstein-Barr virus (EBV) may be involved in the central nervous system lymphoma. In addition, cytomegalovirus (CMV) has been observed to be present in some brain tumor tissues [2]. Interestingly, recent studies suggest that EBV alters gene expression by regulating DNA methylation pattern and the levels of cellular H3K27me3, a master epigenetic regulator which we discussed in our article [1, 2].

MedicalResearch.com: What should readers take away from your report?

Response: Development of pediatric brain tumors may have certain differences from adult brain tumors which are often more metastatic in nature. Pediatric brain tumors are more treatable but chemo usually leaves long lasting side effects. Both types of tumors may have similar origin in terms of formation of tumor progenitor cells, which possibly involves epigenetic alterations; more prominent in pediatric brain tumors. Some of these epigenetic alterations could be inheritable. Epigenetic origin of brain tumors with the differences in pediatric and adult types could be exploited to design improved therapy with a better outcome [1].

MedicalResearch.com: What recommendations do you have for future research as a results of this study?

Response: Brain tumor barrier (BTB) is more permeable compared to Brain blood barrier (BBB) and researchers are exploiting this avenue to deliver chemo to the brain in addition to the CNS route. For pediatric brain tumors which are more treatable, effect of chemo results in adverse effects. A combination regimen including epigenetic drugs in low doses possibly will reduce these adverse effects. In both types of tumors, after standard treatments including surgery and radiation, a combination therapy including epigenetic drugs could reduce the drug resistance, will kill tumor progenitor cells and will reduce the occurrence of relapse. How these combinations will be designed will vary from patient to patient. That will be part of a precision-individual medicine [1].

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: Cancer in general is a complex and heterogenous disease. The current paradigm states that sequential mutations promote the development of tumors [3]. The hallmarks of cancer discuss the pathways and mechanisms involved in these processes [4]. We have previously hypothesized that early event in carcinogenesis is the formation of cancer progenitor cells, which is an epigenetic process involving signals from within and outside cells, including stroma [5-11].  These signals change the epigenetic outline of the predisposed cells to push them to form cancer progenitor cells and it is a slow process. Some genes are turned on and some genes are turned off, like a switch. Once formed, they develop with a speed determined by which types mutations they incur or which types of mutations are already present. This phenomenon could be compared with the fate of a car which has a predisposed problem with gas paddle and brake. As long as it is parked, it is fine. The turning on the car is like development of cancer progenitor cells and then it is out of control. We argued that any type of carcinogenesis in terms of developing cancer progenitor cells should have a general mechanism, which involves epigenetic alterations. The local players at the site of the particular organ or tissue may vary [5-11].

By definition, cancer is not malignant if it does not metastases. Metastasis involves dislodging of tumor cells and then landing and growing on a distant organ which needs several types of de-differentiation-differentiation steps which need to reversible and epigenetics satisfies that criterion being a reversible phenomenon [12]. Lastly, standard therapy, does not kill cancer progenitor cells and does not block their formation. Therefore, most cancers result in drug resistant and relapse. We are proposing for some years that a combination therapy including epigenetic drugs could overcome these types of adversary effects, which is also discussed in the current article in the context of brain tumors. Brain tumors have an added difficulty in delivering the drugs as brain possesses blood brain barrier. But around the tumor, the brain tumor barrier is more permeable and is now explored for better delivery of drugs.

But one of the central questions remains valid for brain tumors alike in other types of tumors, they become resistant to chemo. We reasoned if epigenetics plays a significant role in creating cancer progenitor cells and development of drug resistance, a combination therapy developed involving standard therapy including epigenetic drugs should kill cancer progenitor cells, make cancer drug resistance cells susceptible and will reduce relapse [1, 13, 14].

Literature Cited:

1. Sarkar S, Deyoung T, Ressler H, and ChandlerBrain Tumors: Development, Drug Resistance, and Sensitization – An Epigenetic Approach,Epigenetics 2023; 18:1, DOI: 10.1080/15592294.2023.223776
2. Long Leong MM, Ling ML. The Impact of Epstein-Barr Virus Infection on Epigenetic Regulation of Host Cell Gene Expression in Epithelial and Lymphocytic Malignancies. Oncol 2021; 11: article 629780   https://doi.org/10.3389/fonc.2021.629780
3. Tomasetti C, Marchionni L, Nowak M, Parmigiani G, Vogelstein B. Only three driver gene mutations are required for the development of lung and colorectal cancers.  Proc Natl Acad Sci U S A 2015;12(vol 1):118-123. [PMID: 25535351 DOI: 10.1073/pnas.1421839112]
4. Hanahan D, Weinberg R. Hallmarks of Cancer: The Next Generation.  Cell 2011; 144(5):646-74. [PMID: 21376230 DOI: 10.1016/j.cell.2011.02.013]
5. Lapinska K, Faria G, McGonagle S, Macumber KM, Heerboth S, Sarkar S. Cancer Progenitor Cells: The Result of an Epigenetic Event? Anticancer Res 2018; 38:1-6. [PMID: 29277749 DOI: 10.21873/anticanres.12184]
6. Willbanks A, Leary M, Greenshields M, et al. The evolution of epigenetics: From prokaryotes to Humans and its Biological consequences. Genet Epigenet 2016; 8:25-36.  [DOI:10.4137/GEG.S31863. PMID: 27512339]
7. Sarkar S, Horn G, Moulton K, et al. Cancer development, progression, and therapy: an epigenetic overview. Int J Mol Sci 2013;14(10):21087-113. [PMID: 24152442 DOI: 10.3390/ijms141021087]
8. Sarkar S, Goldgar S, Byler S, Rosenthal S, Heerboth S. Demethylation and re-expression of epigenetically silenced tumor suppressor genes: sensitization of cancer cells by combination therapy. Epigenomics 2013; 5(1):87-94. [PMID: 23414323 DOI: 10.2217/epi.12.68]
9. Byler S, Sarkar S. Do epigenetic drug treatments hold the key to killing cancer progenitor cells? Epigenomics 2014;6(2):161-5. [PMID: 24811783 DOI: 10.2217/epi.14.4]
10. Byler S, Goldgar S, Heerboth S, et al. Genetic and epigenetic aspects of breast cancer progression and therapy. Anticancer Res 2014; 34(3):1071-7. [PMID: 24596345
11. Longacre M, Snyder NA, Housman G, Leary M, Lapinska K, Heerboth S, Willbanks A, Sarkar S. A Comparative Analysis of Genetic and Epigenetic Events of Breast and Ovarian Cancer Related to Tumorigenesis. International Journal of Molecular Sciences. 2016; 17(5):759. https://doi.org/10.3390/ijms17050759
12. Heerboth S, Housman G, Leary M, et al. EMT and Tumor Metastasis. Clin Transl Med 2015; 4(1):1-13. [PMID: 25852822 DOI: 10.1186/s40169-015-0048-3]
13. Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers (Basel). 2014; 6(3):1769-92. [PMID: 25198391 DOI: 10.3390/cancers6031769]
14. Leary M, Heerboth S, Lapinska K, Sarkar S. Sensitization of Drug Resistant Cancer Cells: A Matter of Combination Therapy. Cancers 2018; 10(12):483. [PMID: 30518036 DOI: 10.3390/cancers10120483

Citation:

Sibaji Sarkar, Tara Deyoung, Hope Ressler & Whitney Chandler (2023) Brain Tumors: Development, Drug Resistance, and Sensitization – An Epigenetic Approach, Epigenetics, 18:1, DOI: 10.1080/15592294.2023.2237761

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Last Updated on August 9, 2023 by Marie Benz