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43801
Gene therapy application for cancer: virotherapy
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Cancer Biology Mapa Mental sobre Gene therapy application for cancer: virotherapy, criado por maisie_oj em 11-04-2013.
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cancer biology
cancer biology
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Gene therapy application for cancer: virotherapy
Concept of gene therapy and virotherapy
What is gene therapy?
A technique of correcting defective genes responsible for disease by introducing genetic material into the patient to treat or cure a disease
Why gene therapy?
Many diseases caused by genetic events (e.g. cancer)
Single gene mutations or abnormal expression
Include; cystic fibrosis, X-linked severe combined immuno deficinecy (SCID), haemophilia, thalassaemia, CML, infectious diseases; AIDS
Neurological; Huntington's, Parkinson's, Alzheimer's(?)
Blindness; Leber congenital amaurosis (LCA)
Rare metabolic syndromes; lipoprotein lipase deficiency (LPLD)
Only disease with an approved virotherapy - Glybera (EU approved, 2012)
Virotherapy with adeno-related virus under clinical trials with promising results
No current drugs available to treat many diseases
Drug-resistance and drug-desensitisation of many cancers
How?
Insert a normal gene in a non-specific location within the genome to substitute for a non-functional one
Insert a normal gene in a specific place to replace a non-functional one
Intorduce new genetic material without inserting it into the patient genome
How can we deliver the genes?
Cells
Viruses
DNA
siRNA
How gene therapy and oncolytic viruses can be used in the treatment of cancer
Vectors
Most common viral vectors; adeno-associated viruses (adenovirus) and vaccinia (replicates and transcribes genes outside of host nucleus)
Using replicating viruses (replication-competent)
Tissue selectivity through;
Mutational complementation (cancer cells feature a mutation that enhances virus uptake/activity)
Only mutated cells are infected/affected by gene
Tissue/tumour specific promter
Viral gene can only be activated in specific tissue/tumour type
Specific receptor targetting
Using replication-defective viruses
Deliver genetic material but lack genes to replicate
Onyx-015 (mutated adenovirus with E1B55K and E1B19K mutations)
Can only replicate in cells lacking p53 and that are immune to apoptosis
Mutational selectivity (complementation)
The first oncolytic adenovirus in clinical trials - for; head/neck, glioblastomas, ovarian, bladder and colorectal cancers
Not efficacious as a single agent - improved activity with cytotoxic drugs
Can carry the genetic material to code for thymidine kinase (TK)
HSV TK is a suicide gene which when inserted into a cancer converts the harmless prodrug ganciclovir into a cytotoxic metabolite
Can carry the genetic material to code for cytosine deaminase (CD)
CD is another suicide gene that converts 5-fluorocytosine (5-FC) into 5-FU within the tumour cell
H101 (first approved replicating viral therapy in China) - for treating head an neck cancers
Like onyx-015 - can only replicate in cells lacking p53 (i.e. cancer cells)
How to manipulate viruses to target cancer cells
Viral biology, life cycle and engineering
Examples
Adenovirus is commonly used for virotherapy
Easy to modify - small genome and life cycle well known
Does not integrate - no risk of cancer
Can enhance anti-tumour immune response
Safe in patients - but only efficacious in combination with drugs
Replication-competent - this can be exploited to make it tumour-selective
Life cycle and proteins well known
Naturally the virus can only replicate in epithelial cells that are replicating
However it can hijack the host cell to force it into S-phase
Viral proteins; E1a (binds and inhibits Rb), E1B55K (inhibits p53)
Therefore deletion of E1a (adenovirus mutant Ad-CR2) requires a cell that has lost Rb function for replication
Therefore deletion of E1B55K (adenovirus mutant Onyx-015) requires a cell that has lost p53 activity for replication
Host cells can detect the presence of the virus and intiate apoptosis
Adenovirus can also hijack this by viral protein E1B19K (inhibits pro-apoptotic proteins Bax-bak)
Therefore to replicate adenovirus mutants lacking E1B19K (Ad-19K) require cells that can self-evade apoptosis
Some viruses are inherently selective for tumours; e.g. Reovirus
Others can be made selective by deletion of certain genes; HSV1, vaccinia, adenovirus
Novel therapeutic developments
Examples
(1990) Using retroviral therapy to insert a gene for adenosine deaminase (ADA) into patient T-cells with ADA-SCID
Number of T cells normalised and so did cell and humoral immune responses
ADA expression in immune cells persisted despite the discontinuing of the treatment - following 2 years of treatment
Proved that gene therapy could be achieved safely
(2010) Human PE65 gene therapy for Leber congenital amaurosis (LCA)
Early visual improvements and no unwanted effects after 1 year
Using adeno-associated virus vector
Of the >1,800 gene therapy trials currently going one a majority are still only at Phase I (~60%)
Most of these are aimed at a therapy for treatment of cancer (~65%)
H101 and onyx-015
Showed promising signs whien used in combination with cytotoxic drugs - however very little activity alone (14% necrotic response)
Needs further work - investigations into the host immune response againstthe virus
How to improve efficacy of viral therapy
In onyx-015
Include immunomodulating proteins?
E3 proteins - inhibit MHC class I molecules and cytotoxic T cell killing; inhibit fas mediated apoptosis
Include tumour specific promoters with prodrug converting enzymes, protein inhibitors, androgen receptor inhibtors etc.
Other viruses
Vaccinia - JX-594 (phase I trial)
Advantages
Can be administred sytemically
Fast and potent lysis
Large genome (+++ cloning capacity)
Infects many cell types - prefers cancer cells
Disadvantages
Large genome - still some unknown functions
Uptake mechanisms uknown
HSV-1 - Oncovex-GMCSF (currently phase III)
Delivers genetic material coding for GMCSF - promotes an immune response
In trial against unresectable late stage melanoma
Colon, prostate and pancreatic cancer
Current treatment is with cytotoxic compounds (and suregery and radiotherapy)
Capecitabine (5-FU prodrug)
5-FU (thymydilate synthase inhibtor - no nucleotide synthesis)
Mitoxantrone (Inhibitor of topoisomerase II - inhibits DNA synthesis/transcription)
Cisplatin/carboplatin (platinum-based - causes direct DNA damage [crosslinking] - apoptosis)
Gemcitabine (nucleoside analogue - replaces cytosine)
Docetaxel (taxane - disrupts microtubules - mitotic spindle, intracellular transport, cell shape and interaction with ECM)
Commonly become drug-resistant - then metastasise
We need new therapies!
Oncolytic viruses - adenovirus (+ chemo drugs + cytotoxic genes), vaccinia etc
Gene therapy approaches to kill cancer cells
Prodrug activation therapy: thymidine kinase (TK), cytosine deaminase (CD), nitroreductase (NR)
Tumour supressor replacement: p53, PTEN
Inhibiton of oncogenes: shRNA, siRNA, ribozyme
Immunomodulation: cytokines, granulocyte macrophage colony stimulatinig factor (GMCSF)
Stromal targetting - antiangiogenesis
Cell therapies and vaccines
Oncolytic biotherapy - the vector as therapy: adenovirus, vaccinia, HSV
Delivery of suicide genes
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