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Therapeutic potential of survivin in oral cancer Prakash S Bisen, Ph.D., D.Sc. Honorary Emeritus Professor School of Studies in Biotechnology Jiwaji University, Gwalior MP, India
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2 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Oral cancer: a silent killer Oral cancer is a heterogeneous group of cancers arising from different parts of the oral cavity, with different predisposing factors, prevalence, and treatment outcomes. Sixth most common cancer reported globally with an annual incidence of over 300,000 cases, of which 62% arise in developing countries like India. Diagnosed in an estimated 30,000 Americans every year and each year 8,000 people die from oral cancer and its complications, killing roughly 1 person per hour. If the definition is expanded to include cancer of the larynx, the risk factors are the same, the number of cases grow to 41,000 individuals, and 12,500 deaths per year in the US alone.
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3 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Oral Cancer epidemic on the way in India Tobacco use and alcohol are known risk factors for cancers of the oral cavity. The popularity of chewable tobacco, particularly among the young, is a growing concern for doctors in India. They are already reporting a rise in pre-cancerous lesions in the mouth. There is a significant difference in the incidence of oral cancer in different regions of the world. The age-adjusted rates of oral cancer vary from over 20 per 100,000 population in India, to 10 per 100,000 in the U.S., and less than 2 per 100,000 in the Middle East. In India 57% of all men and 11% of women between 15-49 years of age use some form of tobacco. Oral cancer strikes men twice as often as it does women.
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4 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Squamous cell carcinoma (SCC) of head and neck More than 90% oral and pharyngeal cancers arise from squamous epithelial cell. The overall survival rate for oral cancer in the general population is 52%, a survival rate worse than prostate, uterine, breast, bladder, cervical and colon cancers Early Detection Saves Lives: 5-year survival for localized disease is 76% 5-year survival for metastatic disease is 19% Warning Signs: Leukoplakia Erythroplakia Other Possible Warning Signs Lump or thickening of oral soft tissue Soreness or “lump” in throat Difficulty chewing or swallowing Ear pain Difficulty moving jaw or tongue Hoarseness Numbness of tongue or mouth Swelling of the jaw
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5 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Oral squamous cell carcinoma (OSCC): common treatment strategies Radiation Destruction of cells making it impossible for them to grow Chemotherapy Use of chemicals to destroy cancer cells Surgery Oldest form for treating cancer
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6 – Therapeutic potential of survivin in oral cancer - 01/04/2018 OSCC resist conventional cancer therapies In the past decades, chemo-radiotherapy has emerged as the first line of treatment, especially for advanced OSCC patients. Kelland et al. Nat Rev Cancer 2007; 7: 573-84 Veenita et al. J Cancer Res Ther 2005;1:198-203. Development of resistance to these conventional therapeutic agents in tumor cells during sequential treatments is a major obstacle for their clinical application and a primary reason for the failure of head and neck cancer treatments. OSCC patients at early stages of cancer progression give response to chemotherapy of >50%, but patients with recurrent or metastatic disease have a response rate of <30%. Urba et al. J Clin Oncol 2005; 23: 88-95 Raybaud-Diogene et al. J Clin Oncol 1997;15:1030-8 For developing strategies to overcome treatment resistance, it is important to understand the mechanisms that mediate the recurrence, metastasis, and treatment resistance of ONSCC.
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7 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Deregulation of apoptosis malignancy It is considered that defective apoptosis is a feature of malignant development Apoptosis eliminates damaged cells (damage => mutations => cancer) Tumor suppressor p53 controls senescence and apoptosis responses to damage Most cancer cells are defective in apoptotic response (damaged, mutant cells survive) High levels of anti-apoptotic proteins Or Low levels of pro-apoptotic proteins ===> CANCER
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8 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Survivin: an important inhibitor of apoptotic protein Belongs to IAP family of proteins containing single BRIC5 (baculoviral inhibitor of apoptosis repeat-containing 5) domain. 142-Amino Acid, 16.5-kDa BIRC5 gene; 17q25 Highly expressed in embryonic tissues, but absent in terminally differentiated tissues. Survivin is known to be highly-expressed in various carcinomas; and is associated with aggressive tumor behavior. Li et al. Nature 1998; 396 580–3. Ambrosini et al. Nat. Med. 1997; 3: 917–21. Verdicia et al. Nat. Struct. Biol. 2000; 7: 602–8
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9 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Survivin regulates cell cycle Mita et al. Clin Cancer Res 2008;14:5000-5
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10 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Survivin regulates apoptosis Khan et al. BBA Rev Cancer 2013; 1836: 123-145
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11 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Aims of this study To profile survivin gene expression in relation to p53 in oral cancer tissues at various developmental stages. To investigate the role of survivin in conventional therapy resistance of HNSCC. To study the effects of survivin down-regulation on cancer cell proliferation and apoptosis. To design and test combination therapy using survivin-siRNA and conventional therapies for effective killing of cancer cells to improve clinical outcome in head and neck cancer.
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12 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Detection of survivin and p53 in human oral cancer tissues Khan et al. Head and Neck 2009, 1039-48 Wild-type p53 is known to be a negative regulator of survivin in normal tissues, we checked relative expression of survivin and p53 in human OSCC tumors and pre-malignant lesions. Survivin is expressed in about 72% of the OSCC and 44% premalignant cells whereas p53 finds expression in only 59% OSCC and 38% of premalignant cells. However, nearly 50% of these cells show expression of both together. Most of the survivin positive oral cancer tissues were also positive for p53, suggesting survivin is not repressed at least fully by p53 in oral cancer, or p53 may lost their negative control on survivin expression due to mutation. Almost 50% premalignant lesions were positive for survivin, suggesting its role in early stages of OSCC tumorigenesis. Survivin expression in OSCC (29 samples) and premalignant lesions (PL, 16 samples) was significantly higher than in normal oral tissues (OSCC, p < 0.0008; PL < 0.04 Similar expression pattern of these markers were reported at RNA level using RT-PCR. No significant correlation were found between co-expression of survivin and p53 with clinicopathologic parameters such as tumor size (p =1.000), stages (p=0.6513), lymph node metastasis (p=0.3898), and tumor differentiation (p=0.386) Immunohistochemistry
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13 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Targeting survivin in OSCC Cellular models used: Cal27: Tongue carcinoma Cal33: Tongue carcinoma NT8e: Primarily isolated from upper aerodigestive tract carcinoma FaDu: Isolated from Pharyngeal carcinoma 293-cell line: Human epithelial cells (Control) Conventional therapies tested: Paclitaxel Cisplatin Radiation Asanuma et al. Jpn J Cancer Res 2002;93:1057–62. Clinically achievable doses of paclitaxel and cisplatin are greatly limited by toxicity to normal tissues, and ranges from sensory neuropathy and gastrointestinal disturbances to severe myelosuppression. Smith et al. Semin. Oncol. 1995, 22, 41-6. Winer et al. J. Clin. Oncol. 2004, 22, 2061-68. Bauer et al. Int J Radiat Oncol Biol Phys 2007; 69: 106-8. Yamano et al. Int J Cancer 2010; 126: 437-49.
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14 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Is survivin a survival factor for HNSCC cells ? Selected Anti-survivin oligo effectively suppressed expression of survivin Time Course Inhibition of Survivin Expression by antisurvivin Oligonucleotides (100 nM) Western blot analysis Antisurvivin Oligonucleotides Control Oligo Anti-survivin Oligo Khan et al. Curr Cancer Drug Targets 2010, 660-9
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15 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Survivin inhibition reduced HNSCC cell proliferation Effects of survivin-siRNA on HNSCC Cell Growth NT8e: Antisurvivin NT8e: Control Cal27: Antisurvivin Cal27: Control 293T: Antisurvivin Effects of antisurvivin oligonucleotides on HNSCC cell growth. Cells were treated with oligonucleotide (300 nM)-Lipofectin complex for 5h, medium was removed, and cells were cultured in fresh medium for an additional 19h. Dose-dependent Analysis of the Effect of Antisurvivin Oligonucleotides on Cell Viability Dose-response curve of the effect of survivin-siRNA on the growth and viability of NT8e cells. Khan et al. Curr Cancer Drug Targets 2010, 660-9
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16 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Survivin inhibition induced apoptosis in HNSCC cells Khan et al. Curr Cancer Drug Targets 2010, 660-9 Caspase-3 activity assay in NT8e and Cal27 lysate. 300 nM antisurvivin oligonucleotide or control oligonucleotide. Apoptotic analysis by flow cytometry (300nM) TUNEL Assay Percentage of dead cells NT8e Cell death in HNSCC cells after treatment with survivin-siRNA is likely caused by apoptosis signaling pathways.
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17 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Evaluating role of survivin in HNSCC cell response to paclitaxel Khan et al. Curr Cancer Drug Targets 2010, 660-9 HNSCC cells showed dose dependent cytotoxicity to paclitaxel treatment Cytotoxicity was very low (~15%) at physiologically tolerable dose of paclitaxel (0.1 µM) MTT Cytotoxicity Assay Response of HNSCC to paclitaxel is limited at clinically relevant dose. HNSCC cells showed resistance to paclitaxel at low concentration
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18 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Paclitaxel treatment induced survivin expression Khan et al. Curr Cancer Drug Targets 2010, 660-9 Induced expression of survivin in cancer cells at low paclitaxel level may acquire resistance against cell death.
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19 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Survivin is a strong paclitaxel-resistance factor Khan et al. Curr Cancer Drug Targets 2010, 660-9 293-cell line was transfected with a survivin expression vector. Higher expression of survivin is able to turn sensitive 293-cell line (neo-293) to highly resistant (survivin-293) against paclitaxel. There is also reduction in caspase-3 activation in survivin-293 cells.
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20 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Survivin inhibition sensitizes cancer cells to paclitaxel TUNEL Assay qPCR Survivin down-regulation significantly induced apoptotic death of HNSCC cells at low concentration of paclitaxel. Khan et al. Curr Cancer Drug Targets 2010, 660-9
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21 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Survivin inhibition induced radio-sensitization of HNSCC cells Clonogenic assay Inhibition of survivin strongly induced radiation-mediated apoptotic death of HNSCC cells Cal27 Khan et al. Radiother Oncol, 2010, 267-73 NT8e TUNEL assay
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22 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Ectopic survivin expression turns radiation-sensitive cells to radiation-resistance Khan et al. Radiother Oncol, 2010, 267-73 Expression of survivin in normal 293-cell line gives strong survival phenotype against radiation treatment as like cancer cells.
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23 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Survivin-siRNA lentivirus vector We have developed lentivirus vector to deliver survivin specific siRNA into cells and animals for therapeutic purposes. Lentivirus-siSurvivin effectively down-regulate survivin expression. Khan et al. Curr Gene Ther, 2012; 12(6): 444-53 Testing lentivirus vector for survivin silencing 60ng p24 titre/24-well 200ng p24 titre/6-well
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24 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Lentivirus survivin-siRNA therapy inhibits cancer cell proliferation Khan et al. Curr Gene Ther, 2012; 12(6): 444-53 Lenti-siSurvivin therapy significantly inhibits cancer cell proliferation.
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25 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Cell cycle and apoptosis analysis Khan et al. Curr Gene Ther, 2012; 12(6): 444-53 Lenti-siSurvivin therapy caused significant increase of cells in the G0/G1 phase and hypodiploid DNA content, an indicator of apoptotic cell death. Also induced TUNEL positive cells.
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26 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Lenti-siSurvivin induced cisplatin-mediated cytotoxicity Khan et al. Curr Gene Ther, 2012; 12(6): 444-53 Lenti-siSurvivin pre-treated cells give better response to cisplatin treatment.
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27 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Lenti-siSurvivin induce cisplatin-mediated cell death Khan et al. Curr Gene Ther, 2012; 12(6): 444-53 Lenti-siSurvivin therapy induced cisplatin-mediated apoptosis.
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28 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Svv-Lentiviral therapy effectively suppressed tumor growth in mice. Svv-Lent Cont-Lent Cal27 human xenograft tumor n = 6 per group ** Khan et al. Radiother Oncol, 2016, 118(2):359-68. Svv-Lentiviral therapy
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29 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Svv-Lentiviral therapy Survivin knockdown inhibits lung metastasis Khan et al. Radiother Oncol, 2016, 118(2):359-68.
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30 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Svv-Lentiviral therapy Khan et al. Radiother Oncol, 2016, 118(2):359-68. Survivin knockdown inhibits liver metastasis
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31 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Svv-Lentiviral therapy Khan et al. Radiother Oncol, 2016, 118(2):359-68. Svv-Lent treatment improved overall survival of mice bearing Cal27 tumor.
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32 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Combination therapy of Lenti-siSurvivin and cisplatin or radiation Khan et al. Radiother Oncol, 2016, 118(2):359-68. Combined therapy (Lenti-siSurvivin and cisplatin or radiation) worked well with high efficacy and safety. Combination therapy suppressed tumor growth significantly higher than monotherapy.
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33 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Conclusions Survivin and p53, two important apoptotic regulators, are frequently expressed in OSCC and premalignant lesions. Survivin is a key factor for OSCC progression whereby its expression in cancer cells generates resistance to apoptosis. At low dose of chemo-radiotherapeutic treatments, survivin gets up-regulated, which may acquire resistance against cell death Inhibition of survivin using anti-survivin siRNA therapy effectively suppressed proliferation of tumor cells and induced apoptosis. Survivin expression is directly associated with the sensitivity of OSCC cells to conventional therapies, such as paclitaxel, cisplatin and radiation. Down-regulation of survivin increases sensitivity of cancer cells to these conventional drugs. We have also tested combination therapy using Lenti-siSurvivin and cisplatin or radiation on OSCC tumor xenographt in nude mice. We observed high efficacy of combination treatment, and it suppressed tumor growth effectively as compared to monotherapy. Taken together our study demonstrates survivin to be a good target for oral cancer therapy.
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34 – Therapeutic potential of survivin in oral cancer - 01/04/2018 Acknowledgements Dr. Zakir Khan Department of Biomedical Sciences Cedars Sinai Medical Center Los Angeles, USA Dr. GBKS Prasad School of Studies in Biochemistry/Biotechnology Jiwaji University Gwalior, India Dr. IK Patro School of Studies in Neuroscience Jiwaji University Gwalior, India Dr. RP Tiwari Research and Development Centre, Diagnova, RFCL Limited, New Delhi 110020, India Dr. NK Sah Department of Botany/Biotechnology, TNB College, T.M. Bhagalpur University, Bhagalpur-812007, India Collaborators Dr. BR Shrivastava Clinical Oncologist Cancer Hospital & Research Institute Gwalior, India Dr. Rita Mulherkar Department of Genetic Engineering ACTREC, Tata Memorial Centre, Mumbai, India Dr. Ashok K. Varma Structural and Molecular Biology Lab ACTREC, Tata Memorial Centre, Mumbai, India