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Temozolomide resistance in glioblastoma multiforme (GBM) PowerPoint Presentation

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Description : Check out this medical presentation on Brain Tumor, which is titled "Temozolomide resistance in glioblastoma multiforme (GBM) and its application for drug development", to know about brain tumor and glioblastoma multiforme (GBM), Temozolomide (TMZ) and its resistance, and drug development for TMZ resistant GBM.

Tags : Brain Tumor, Temozolomide resistance, glioblastoma multiforme, GBM, application, drug development

Published on : May 10, 2021 | Views : 2337 | Downloads : 1

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Temozolomide resistance in glioblastoma multiforme (GBM) and its application for drug development Sang Y. Lee, Ph.D. Assistant Professor Pennsylvania State University College of Medicine
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Conflict of interest ■ None
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Contents ■ Brain tumor & GBM ■ Temozolomide (TMZ) & its resistance ■ TMZ resistant GBM cell lines (intrinsic, acquired) ■ Drug development for TMZ resistant GBM
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1. Heart disease: 614,348 (23.5% of total deaths) 2. Cancer: 591,699 (22.5% of total deaths) 3. Chronic lower respiratory diseases: 147,101 (5.7% of total deaths) 4. Accidents (unintentional injuries): 136,053 (5.0% of total deaths) 5. Stroke (cerebrovascular diseases): 133,103 (5.0% of total deaths) 6. Alzheimer's disease: 93,541 (3.3% of total deaths) 7. Diabetes: 76,488 (2.9% of total deaths) 8. Influenza and pneumonia: 55,227 (2.2% of total deaths) 9. Kidney disease (Nephritis, nephrotic syndrome, and nephrosis): 48,146 (1.8% of total deaths) 10. Intentional self-harm (suicide): 42,773 (1.6% of total deaths) Top 10 leading causes of death in the US (2014) Centers for Disease Control and Prevention (www.cdc.gov)
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The top 10 cancers in the US (2016) American Cancer Society: Cancer Facts and Figures 2016. Atlanta, Ga: American Cancer Society, 2016. 1 2 3 4 Brain 23,770 (1.4%) 16,050 (2.7%)
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- BTs are the most common cancer among those age 0-19 (leukemia is the second) - BTs are the second leading cause of cancer-related deaths in children (males and females) under age 20 (leukemia is the first) American Brain Tumor Association (www.abta.org) Brain tumor (BT) : statistics (incidence, death)
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BT is an abnormal growth of tissue in the brain or central spine that can disrupt proper brain function BTs may be primary (starting in the brain) or secondary (spreading to the brain from another area of body). Secondary BT (Metastatic BT) is about 5-10 times more common than primary BT Primary BT may be benign or malignant. Benign BT grows slowly, has distinct boundaries, and rarely spreads. Malignant (cancerous) BT grows quickly, has irregular boundaries, and spreads to nearby brain areas BTs are named after the cell type which they grow. There are more than 120 histologically distinct types of primary brain and central nervous system tumors Brain tumor (BT) : general information
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The median age at diagnosis for all primary brain tumors is 59 years old Survival after diagnosis with a primary BT varies significantly by age, histology, molecular markers and tumor behavior. Brain tumor : general information cont’d Central Brain Tumor Registry of the United States (CBTRUS) (1995 – 2010) (www.cancer.org)
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Meningiomas represent 34-36% of all primary brain tumors, making them the most common primary brain tumor. There will be an estimated 24,880 new cases in 2016 Gliomas, a broad term which includes all tumors arising from the gluey or supportive tissue of the brain, represent 27-30% of all brain tumors and 80% of all malignant tumors - Glioblastomas represent 15.1% of all primary brain tumors, and 55.1% of all gliomas Glioblastoma has the highest number of cases of all malignant tumors Astrocytomas, including glioblastoma, represent approximately 75% of all gliomas Brain tumor : statistics (cancer type) American Brain Tumor Association (www.abta.org)
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Brain tumor treatment depends on a number of factors, including the type, location, size, and grade of the tumor, as well as the age and health of the patient. (Image guided) Surgery Radiation therapy (e.g., conventional radiation therapy, stereotactic radiosurgery) Chemotherapy Targeted therapy (e.g., anti-angiogenesis therapy) Alternating electric field therapy (tumor treating fields) for recurrent GBM Brain tumor treatments www.cancer.net
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FDA approved treatments for GBM www.cancer.org
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Stupp R et al. N Engl J Med 2005
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Overall survival according to treatment group (total 573 patients from 85 centers) Stupp R et al. N Engl J Med 2005
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Effect of MGMT promoter methylation status on survival in glioblastoma (n=206) Hegi ME et al. N Engl J Med 2005 EORTC/NCIC Trial 100 80 60 40 20 0 0 6 12 18 24 30 36 42 Mos Probability of OS (%) Methylated MGMT promoter Unmethylated MGMT promoter P < .001 Pts at Risk, n Unmethylated Methylated 11492 100 84 59 64 16 46 7 24 4 7 1 1
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For people with glioblastoma, the latest standard of care is radiation therapy with daily low-dose temozolomide (Temodar), followed by monthly doses of temozolomide after radiation therapy for six months to one year However, the development of TMZ resistance during adjuvant therapy occurs in >30% of patients In addition, it is a challenge in overcoming dose-limiting myelo-suppressive toxicity of TMZ while maintaining its efficacy Standard care for glioblastoma
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Temozolomide (Temodar) Temozolomide (C6H6N6O2, MW 194) is an alkylating agent prodrug MOA: alkylate/methylate DNA, which most often occurs at the N-7 or O-6 positions of guanine residues. The methylation damages the DNA and triggers the death of tumor cells Metabolism: spontaneously hydrolyzed at physiologic pH to the active species, 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) and to temozolomide acid metabolite Usage: Anaplastic astrocytoma (AA), Anaplastic oligodendroglioma (AO), GBM, Melanoma, Metastatic melanoma Side effects: bone marrow suppression, nausea, vomiting, genotoxic
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N3-methyladenine N7-methylguanine O6-methylguanine Cell cycle arrest Alkylpurine-DNA-N-glycosylase (APNG), Base excision repair (BER), DNA mismatch repair (MMR), O6-methylguanine-DNA methyltransferase (MGMT) Nucleic acid TMZ MGMT/APNG/BER Non-cytotoxic (TMZ resistant) MMR MGMT/APNG/BER MMR Mechanism of TMZ and TMZ resistance mG T Cell death (TMZ sensitive) 70%
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Example of intrinsic (pre-existing) TMZ resistant GBM cell lines Lee SY Genes & Diseases 2016 Bold indicates TMZ sensitive/resistant cell lines which reported in the at least two papers
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CCF-STTG1 human GBM cell lines are TMZ resistant Lee SY et al. Int J Cancer 2011 A. Cytotoxicity to TMZ H2O U C U C U C U C U C U C SW1088 U87-MG LN-18 T98G CCF-STTG1 U251 B. MGMT methylation SW1088 U87-MG LN-18 T98G CCF-STTG1 U251 C. MGMT expression
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Effect of MGMT and HFE on TMZ resistance in human glioma cell lines
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HFE (Hemochromatosis protein)  Iron homeostasis gene  Binds to transferrin receptor and reduces its affinity for iron-loaded transferrin  Two major mutation sites : : H63D (histidine  aspartic acid, 1 domain) : C282Y (cysteine  tyrosine, 3 domain)  H63D and C282Y mutant cells have iron overload HFE polymorphisms (H63D and C282Y) are the common genetic variants in Caucasians : Genotype frequency of H63D : 23.6% ~ 26.4% : Genotype frequency of C282Y : 9.6% ~ 11.8% (Hanson EH et al. 2001. Am J Epidemiol; n=6,203) (Adams PC et al. 2005. N Engl J Med; n=44,082) (Allen KJ et al. 2008. N Engl J Med; n=29,676) WT H63D C282Y
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Example of acquired TMZ resistant GBM cell lines Lee SY Genes & Diseases 2016 Bold indicates TMZ sensitive cell lines which reported in the at least two papers 6 fold 10-16 fold ~4 fold 5.6 fold 4.7 fold 40 fold
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Molecular events of intrinsic and acquired TMZ resistant GBM cell lines Lee SY Genes & Diseases 2016 NAMPT: nicotinamide phosphoribosyl transferase
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Treatments to intrinsic (pre-existing) TMZ resistant GBM cell lines Lee SY Genes & Diseases 2016 Bold indicates TMZ resistant cell lines which reported in the at least two papers
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Treatments of acquired TMZ resistant GBM cell lines Lee SY Genes & Diseases 2016 Bold indicates TMZ sensitive cell lines which reported in the at least two papers
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Intrinsic or acquired TMZ resistant xenograft animal models Lee SY Genes & Diseases 2016
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Effects of TMZ on survival on GBM orthotopic xenografts Kitange GJ et al. Neuro Oncol 2009 GBM12 – response well to TMZ GBM14 – response well to TMZ GBM43 – resistant to TMZ (?) GBM44 – resistant to TMZ TMZ is response well to methylated MGMT GBM. Response of TMZ to unmethylated MGMT GBM is diverse MS: 18 d MS: 70 d MS: 41 d MS: 105 d MS: 24 d MS: 48 d MS: 67 d MS: 62 d methylated MGMT low level MGMT unmethylated MGMT higher level of MGMT unmethylated MGMT higher level of MGMT unmethylated MGMT higher level of MGMT Arrow: treatment initiated TMZ: 120 mg/kg/d for 5 days
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Glioblastoma orthotopic xenografts Clarke MJ et al. Mol Cancer Ther 2009 P < 0.001 P < 0.001
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TMZ resistance, MGMT, and HFE mutations in human patient-derived xenograft (PDX) lines Collaboration with Dr. Gasper Kitange & Dr. Jann Sarkaria GS: Gliosarcoma
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Acquired TMZ resistant GBM12 orthotopic xenografts Clarke MJ et al. Mol Cancer Ther 2009 TMZ: 33 mg/kg/d, 5 of 7 d × 2 wk adjuvant TMZ : 66 mg/kg/d, day 1-5, administered in one, two, or three 28-day cycles TMZ : 66 mg/kg/d, day 1-5
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Acquired TMZ resistant GBM22 orthotopic xenografts Clarke MJ et al. Mol Cancer Ther 2009 TMZ; 33 mg/kg/d, 5 of 7 d × 2 wk adjuvant TMZ : 66 mg/kg/d, day 1-5, administered in one, two, or three 28-day cycles TMZ : 66 mg/kg/d, day 1-5
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Testing TMZ in animal models of glioma: 60 papers up to 2013 Hirst TC et al. Br J Cancer 2013 Red line: TMZ resistant Blue line: TMZ sensitive Rat Gliosarcoma Human Glioblastoma Rat Glioma Human Glioblastoma Rat Glioblastoma Human Glioma Rat Glioblastoma Human Glioblastoma Human Glioblastoma Human Glioblastoma Human Glioblastoma
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Hirst TC et al. Br J Cancer 2013 TMZ prolonged survival by a factor of 1.88 (95% CI 1.74-2.03) and reduced tumor volume by 50.4% (41.8-58.9) compared with untreated controls Meta-analysis of TMZ in animal models of glioma: 60 papers up to 2013
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Cytotoxicity of selected compounds in gliomas Cells were treated with 10 µg/ml of compounds for 6 days, followed by SRB assay. Cell viability was compared with DMSO vehicle control group. TMZ sensitive TMZ resistant
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Dose response curve of compounds in CCF-STTG1
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A. B.     Cytotoxicity of CC-I (#19) in GBM and normal cells
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Cytotoxicity of similar structure compounds with CC-I in CCF-STTG1 cells
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Anti-tumor effect of CC-I in s.c. nude mouse brain tumor model i.p. injection (25 mg/kg) of CC-I once a week for 7 weeks SW1088 injected CCF-STTG1 injected Control (n=3)‏ CC-I (n=8)‏ Control (n=3)‏ CC-I (n=7)‏ CC-I treated mice do not loose body weight Lee SY et al. PLOS ONE 2014
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A. Anti-tumor effect of CC-I in intracranial brain tumor model C. B. P<0.0001 Lee SY et al. PLOS ONE 2014
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Anti-tumor effect of CC-I in T4121 glioma stem cell orthotopic BT nude mouse model (1x/w, 20 mg/kg, ip) P=0.03
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■ We need a better understanding for the TMZ resistant (recurrent) GBM ■ There are distinct molecular events between intrinsic TMZ resistant GBM and acquired (recurrent) TMZ resistant GBM. Therefore, we should treat them different way. ■ TMZ resistance is not mediated by a single molecular event but by multiple ones. Therefore, identification of GBM patients based on the patient’s gene/protein profiling data could be beneficial for selecting drugs for their treatment ■ CC-I showed strong anti-tumor effect on GBM in in vivo tumor models Summary
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Acknowledgements Dr. James Connor Ms. Becky Webb Dr. Mohammed Alsaidi Drug Discovery, Development and Delivery Core MRI Imaging Core Facility, Solution Phase NMR Core Facility Dr. Gasper Kitange & Dr. Jann Sarkaria (Mayo Clinic) Penn State Hershey Cancer Institute Experimental Therapeutics Research initiative NIH/NCI R21CA167406 Elsa U. Pardee Foundation Tara Leah Witmer Endowment
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Questions