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Tumor Suppressor Gene Therapy for Lung Cancer

Info: 3334 words (13 pages) Essay
Published: 8th Feb 2020 in Biology

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CRITICAL APPRAISAL PAPER

ABSTRACT

         The Tumor Suppressor Gene therapy (TSG therapy) is now available for the treatment of Non-Small Cell Lung Carcinomas (NSCLC), which works on the principle of replacement of mutated or deleted tumor suppressor genes such as p53, mostly found inactivated (50%) in the 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 chemotherapy and radiation therapy. Trials on tumor suppressor gene therapy started at the end of 90’s, but due to the 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 has auspicious future for treatment of lung cancer.

INTRODUCTION

         The aim of this opinion paper is to identify and analyze the advantages and disadvantages of TSG therapy for treatment of lung cancer based on the literature and research articles available till current date and to give an 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 females and males 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 known as SCLC, 2) Non-Small Cell Lung Carcinomas known as NSCLC. There are three subdivisions of NSCLC: 1) Squamous-cell carcinoma, 2) Adenocarcinoma and 3) Large-cell carcinoma and NSCLC is the chief leading cause of the mortality in the world (See Figure 1 Appendices) (2). Risk factors for lung cancer include tobacco-smoking with principal leading cause and others are air-pollution, fuel burning and organic chemical exposure to an environment (3). 

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         The tumor Suppression Genes (TSG) regulate cell cycle progress and apoptosis, inactivation or deletion of both alleles of gene induce the formation of the tumor (2). The deletion of both alleles 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 (See Table 1 Appendices) (5). TSG therapy works based on the transfer of the 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 clinical 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).

SEARCH STRATEGY

          The information has retrieved from various sources by using different kinds 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 search words 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 from 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 has several advantages in the treatment of NSCLC over conventional therapy like chemotherapy, surgery and radiation therapy having their low survival rate as well as the failure of conventional therapy due to the 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 has some limitations as direct viral vector intratumoral injection is usually not achievable in lungs and therapy is useful in metastatic lung cancer as it is available now only for local application in cancer by using inhalation or intratumoral injection (8). In addition, by using the currently available vectors, it can transfect only a small percentage of tumor cells, having a lack of solid bystander effects (6).

             Different preclinical and clinical trials of p53 gene replacement therapy in the 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 the sensitivity of tumor cells to radiation respectively (2) (See Table 2 Appendices). Based on review of current literatures available for treatment of lung cancer by TSG therapy, despite some limitation of tumor suppression therapy, according to my opinion, it is good choice for treatment of lung cancer 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 other therapies approved for treatment of lung cancer are surgery which is a 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 further requires phase III and phase IV clinical trial study after the success of phase I/II trial of p53 gene replacement therapy by using adenovirus as a 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). Moreover, future direction will incorporate the 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, as per my perspective, TSG therapy will be successful in the future and become first-line treatment of lung cancer as an 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

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

2)     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

3)     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

4)     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

5)     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

6)     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

7)     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

8)     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

9)     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

APPENDICES

Figures

Figure 1: Types of Lung cancer

Source: (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 lung cancer”

Name of Gene

Location on Chromosome

Inactivation Mode

Frequency in %

SCLC

NSCLC

p53

17p13.1

Mutation + LOH

80-100

50-80

RB

13q14

Mutation + LOH

80-90

20-30

p16

9p21

Mutation + LOH, Homozygous deletion (HD)

<10

60

SMAD2

18q21

Mutation + LOH

<10

<10

SMAD4

18q21

Mutation + LOH

<10

<10

PTEN

10q23

Mutation + LOH, Homozygous deletion (HD)

10

<10

FHIT

3p14.2

Homozygous deletion (HD)

75

75

PPP2R1B

11q23

Mutation + LOH

unknown

unknown

TUSC2

3p21.3

Homozygous deletion (HD)

unknown

unknown

Abbreviations: RB-Retinoblastoma, PTEN-Phosphatase and Tensin Homolog deleted on chromosome TEN, FHIT- Fragile Histidine Triad, PPP2R1B- Protein Phosphatase 2 Scaffold Subunit Abeta, TUSC2-Tumor Suppressor Candidate 2

Sources:

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 Medicine23(128), 325–330. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808457/

Table 2: “Lists of clinical trials of p53 gene therapy”

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 injectedlesion: 13 (52%) with PR
Comparatorlesion:

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.

Source: 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

 

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