Abstract

Abstract:
The tumor suppressor gene therapy (TSG therapy) is available for the treatment of lung cancer, especially Non-small cell lung carcinomas (NSCLC), which works on principle of replacement of mutated or deleted tumor suppressor genes such as P53, mostly found inactivated (50%) in lung cancer. Clinical trial phase I and phase II study of TSG therapy has shown improved efficacy and low toxicity compared to conventional treatments available for treatment of lung cancer and can restore sensitivity of tumors to radiation and chemotherapy. Trials on tumor suppressor gene therapy started at the end of 90’s, but due to limitation of gene delivery techniques to transfect only small percentage of tumor cells and having low bystander effect due to this, it requires more time for further improvement and development of new techniques for systemic delivery of genes. According to my opinion, despite this limitation, due to rapid development in gene therapy, these problems will be resolved, and TSG therapy have auspicious future for treatment of lung cancer.

Introduction:
The aim of this opinion paper is to identify and analyze the advantages and disadvantages of tumor suppression gene therapy for treatment of lung cancer based on the literatures and research articles available till current date and to give opinion regarding therapy whether it is fruitful or have any drawbacks and its future aspects in lung cancer treatment.
Lung cancer is the highly diagnosed and the major reason of death due to cancer in both men and women in Canada. The 5-year survival rate is 14% for males and 20% for females in Canada (1). Lung cancer is divided into two major subtypes based on the type of cell involved: 1) Small-cell lung carcinomas (SCLC) and 2) Non-small cell lung carcinomas (NSCLC). NSCLC is subcategorized into three divisions: 1) Squamous-cell carcinoma, 2) Adenocarcinoma, and 3) Large-cell carcinoma and NSCLC is the chief leading cause of the demise in the world (Figure 1) (2). Risk factors for lung cancer includes tobacco-smoking with highest cause and others are air-pollution, fuel burning and organic chemical exposure to environment (3).
The tumor Suppression Genes (TSG) regulate cell cycle progress and apoptosis, inactivation or deletion of both alleles of gene induce formation of the tumor (2). The deletion of both allele known as Loss of Heterozygosity (LOH), found in deletion of TSG (4). The major TSG found to be inactivated in lung cancer are P53, Rb, P16, FHIT, SMAD1, SMAD2, TUSC2/FUS1(TUSC2), PARD3 (Table1) (5). Tumor suppression gene therapy works based on the transfer of single functioning copy of TSG to cancer cells which leads to clampdown of cancerous tumor cells growth by cell-cycle arrest, induction of apoptosis and some trials also shows the existence of bystander effect on neighboring tumor cells (2). Vectors used to transfer the gene includes different viral vectors like adenovirus, retrovirus, adeno-associated virus and non-viral vectors like liposomes, polymers and molecular conjugates (6).

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Search strategy:
The information has retrieved from various sources by using different kind of search strategy. I used Google Scholar https://scholar.google.ca, PubMed Central www.ncbi.nlm.nih.gov/pmc/, Leddy library online resources E-articles http://primo.uwindsor.ca/primo_library, ScienceDirect Journals www.sciencedirect.com, Springer link https://link.springer.com, etc. to explore articles and information to justify my opinion regarding the therapy. During my search by using above mentioned resources, I used different types of titles such as “Tumor suppression gene therapy for lung cancer”, “Future aspects of tumor suppression gene therapy”, “Tumor suppression gene therapy lung cancer review”, “Current approved treatment for lung cancer”, “Types of lung cancer”. In addition, I filtered my search by selecting articles form recent years by using “Since 2017”, “Since 2014” on google scholar, by selecting latest publication date such as 1 year, 5 years on PubMed Central and the same kind of strategy on other resources also to search the latest articles available for therapy.
Discussion:
TSG therapy have advantages in treatment of NSCLC over conventional therapy like chemotherapy, surgery and radiation therapy due to their low survival rate as well as failure of conventional therapy due to resistance of tumor cells with mutated or deleted gene to therapy. It also has low toxicity due to direct intratumor injection to target cells compared to conventional therapy which damage the DNA of replicating tumor cells (7). TSG therapy have some limitations as direct intratumoral injection of viral vectors is usually not achievable in lungs and therapy is used only in local application of lung cancer by using intratumoral injection or inhalation, so not useful in treatment of advanced or metastatic tumors of the lung (8). In addition, by using the currently available vectors, it can transfect only small percentage of tumor cells, having lack of solid bystander effects (6).
Different preclinical and clinical trials of P53 gene replacement therapy in treatment of NSCLC by using retroviral and adenoviral vector showed mediate tumor regression with minimum toxicity. Moreover, overall the results of phase-1 and phase-2 clinical trials for P53 gene therapy in combination with chemotherapy and radiation therapy in NSCLC have shown increased apoptosis of the tumor cells and increased sensitivity of tumor cells to radiation respectively (2). Based on review of current literatures available for treatment of lung cancer by tumor suppression gene therapy, despite some limitation of tumor suppression therapy, it is good choice treatment compared to conventional therapy as it causes low toxicity and more specifically act on the targeted cells without damaging to normal cells by proper selection of vectors for transfer of gene into tumor cells and this therapy works better in combination with conventional therapy to achieve better results of treatment.
The others therapy available for treatment of lung cancer are surgery which is viable option in NSCLC, chemotherapy and radiation therapy. In addition, in past decade, many other drugs approved and are helpful for treatment of NSCLC which includes epidermal growth factor receptor inhibitors like erlotinib, gefitinib, afatinib; anaplastic lymphoma kinase (ALK) inhibitor which includes crizotinib and vascular endothelial growth factor (VEGF) receptor inhibitor monoclonal antibody like bevacizumab; that all are provided improved survival for patients with NSCLC (9).

Future directions:
TSG therapy require phase III and phase Iv clinical trial study after success of phase I/II trial of P53 gene replacement therapy by using adeno virus as vector in NSCLC lung cancer, which will consume extensive time and numbers of patients to establish the effectiveness of treatment. In addition, phase I study of N-1-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammonium chloride (DOTAP):cholesterol nanoparticle encapsulating a TUSC2 expression plasmid vector in stage IV of NSCLC confirms the success of TSG therapy in systematic lung cancer and needs further exploration in that area like new vectors and targeting strategies (2). In addition, future direction will incorporate development of additional efficient vectors and use of novel genes for treatment (7).
Based on results of preclinical, clinical study and progresses that occurred in last few years in gene delivery system and molecular biology of tumorigenesis, TSG therapy will be successful in the future and become first line treatment of lung cancer as a individual treatment or in combination with available conventional therapy because therapy directly attacks the etiology of ailment, but for that it will take a long time for development and commercialization (2).

References:
Canadian Cancer Society’s Advisory Committee on Cancer Statistics. (2017). Canadian Cancer Statistics 2017. Toronto, ON: Canadian Cancer Society.

Lara-Guerra, H., & Roth, J. A. (2016). Gene Therapy for Lung Cancer. Critical Reviews™ in Oncogenesis,21(1-2), 115-124. doi:10.1615/critrevoncog.2016016084
Testa, U., Castelli, G., & Pelosi, E. (2018). Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells. Cancers,10(8), 248. doi:10.3390/cancers10080248
Swisher, S. G., & Roth, J. A. (n.d.). Adenoviral p53 Gene Therapy Strategies in Nonsmall-Cell Lung Cancer. Chemoradiation in Cancer Therapy,349-358. doi:10.1385/1-59259-325-9:349
Kohno, T. (1999). How many tumor suppressor genes are involved in human lung carcinogenesis? Carcinogenesis,20(8), 1403-1410. doi:10.1093/carcin/20.8.1403
Vachani, A., Moon, E., Wakeam, E., Haas, A. R., Sterman, D. H., & Albelda, S. M. (2011). Gene Therapy for Lung Neoplasms. Clinics in Chest Medicine,32(4), 865-885. doi:10.1016/j.ccm.2011.08.006
Lee, J., & Moon, C. (2011). Current status of experimental therapeutics for head and neck cancer. Experimental Biology and Medicine,236(4), 375-389. doi:10.1258/ebm.2010.010354
Chao, C., Lin, M., Fang, C., Chen, P., Chang, D., Shen, C., & Wang, M. (2016). Gene Therapy for Human Lung Adenocarcinoma Using a Suicide Gene Driven by a Lung-Specific Promoter Delivered by JC Virus-Like Particles. Plos One,11(6). doi:10.1371/journal.pone.0157865
Minguet, J., Smith, K. H., & Bramlage, P. (2015). Targeted therapies for treatment of non-small cell lung cancer-Recent advances and future perspectives. International Journal of Cancer,138(11), 2549-2561. doi:10.1002/ijc.29915
Appendix
Figures:

Figure 1: Type of Lung cancer,
Retrieved from: (n.d.). Retrieved from http://blogs.nature.com/ofschemesandmemes/2014/09/11/the-dominant-malignancy-lung-cancer
Tables:
Table 1: List of variations in tumor suppression genes in human lung cancer
Gene name Chromosomal location Mode of Inactivation Frequency
SCLC
p53 17p13.1 LOH + mutation 80-100 50-80
RB 13q14 LOH + mutation 80-90 20-30
p16 9p21 Homozygous deletion (HD), LOH + mutation <10 60
SMAD2 18q21 LOH + mutation <10 <10
SMAD4 18q21 LOH + mutation <10 <10
PTEN 10q23 Homozygous deletion (HD), LOH + mutation 10 <10
FHIT 3p14.2 Homozygous deletion (HD) 75 75
PPP2R1B 11q23 LOH + mutation unknown unknown
TUSC2 3p21.3 Homozygous deletion (HD) unknown unknown
Retrieved from: 1) Kohno, T. (1999). How many tumor suppressor genes are involved in human lung carcinogenesis? Carcinogenesis,20(8), 1403-1410. doi:10.1093/carcin/20.8.1403 and 2) Rimkus, T., Sirkisoon, S., Harrison, A., & Lo, H.-W. (2017). Tumor Suppressor Candidate 2 (TUSC2; FUS-1) and Human Cancers. Discovery Medicine, 23(128), 325–330. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808457/
Tables:
Table 1: List of p53 gene clinical trials
Tumor type Phase Total No.
(#Evaluable) Vector Delivery Best clinical response$
NSCLC I 9 (7) Retroviral p53 Intratumoral (single injection) 3 (33%) with PR
NSCLC I 15 (15) Ad.p53 Intratumoral (single injection) 0 with PR
7 (47%) with SD
NSCLC I 28 (25) Ad.p53 Intratumoral (repeated injection) 2 (7%) with PR
16 (57%) with SD
NSCLC I 24(23) Ad.p53 Intratumoral + cisplatin (upto 6 cycles) 2 (8%) with PR
17 (71%) with SD
NSCLC II 25(25)*Ad.p53 Intratumoral + chemo. (upto 3 cycles) IT injecedlesion: 13 (52%) with PRComparatorlesion:
12 (48%) with PR
NSCLC II 19(17) Ad.p53 Intratumoral (3 injection) + radiation 1 (5%) with CR
11 (58%) with PR
3 (16%) with SD
NSCLC I 15(13) Ad.p53 Intratumoral only, every 28 days (9 pts.)
Intratumoral + cisplatin, every cycle (6 pts.) 1 (7%) with PR
10(66%) with SD
BAC I 29(23) Ad.p53 BAL, multiple instillations 16 (70%) with SD
NSCLC** II 58(58) Ad.p53 Vector only: Intratumoral injection or BAI combo: vector + chemotherapy Vector only:
15 (38%) with PR,
8 (42%) with SD
Combo: 2 (11%) with CR,
7 (37%) with PR,
18 (46%) with SD
Abbreviations: BAL – Bronchoalveolar lavage, Ad- Adenovirus, CR- Complete response, PR- partial response, SD- stable disease, NSCLC – non-small cell lung cancer
*This study included patients that had two similar lesions, allowing for a comparison of the injected lesion to a comparator lesion
**This study involved vector delivery by either by intratumoral injection or bronchial artery instillation (BAI), chemotherapy delivered via BAI
$Best clinical response is noted for injected lesion only, unless otherwise noted.
Retrived from: Vachani, A., Moon, E., Wakeam, E., Haas, A. R., Sterman, D. H., & Albelda, S. M. (2011). Gene Therapy for Lung Neoplasms. Clinics in Chest Medicine,32(4), 865-885. doi:10.1016/j.ccm.2011.08.006