Cancer Gone ViralOncolytic Virotherapy for Cancer Treatment

Madeline GrayBIO 320 SEC 010Genetics and SocietyNovember 7, 2014

What We KnowCancer

Cancer is a genetic disorder due to genomic alterations 2 Properties

Abnormal cell division and growth (proliferation) Ability to spread via blood or lymph (metastasis)

Vary in many factors (age of onset, growth rates, invasiveness, and responsiveness) Requires multiple mutations

Vary in mutations (cell cycle regulation, genomic instability, DNA repair, chromatin modifications)

Cell does not under apoptosis Viruses can contribute to cancer by stimulating cell growth

Retroviruses Human Immunodeficiency Virus (HIV) Human T-Cell Leukemia Virus (HTLV-1) About 15% of human cancers are associated with viruses worldwide (Klug 2012)

(Pfeffer 2006)

What We KnowViruses

Bacteriophages are used as model systems for genetic research Viruses are infectious particles that use a host to reproduce May contain DNA or RNA The protein coating of the virus determines which host it will infect When host cell is infected, it produces proteins encoded by the virus

instead of its own gene products Many types and variants of viruses affecting both bacteria and

prokaryotes as well as eukaryotes 2 Stages

Lysogenic (virus is dormant in infected host cell) Lytic (virus is stimulated, new viruses produced, lysis occurs) (Klug 2012)

(Pfeffer 2006)(Introduction to…)

What We Know Retroviruses are most common among animal viruses

Contain RNA Use reverse transcriptase to integrate virus RNA with host cell’s DNA Integrated viral DNA called provirus Cause cancer in 3 ways:

Proviral DNA may integrate near one of cell’s normal proto-oncogenes Enhancers and promoters of provirus stimulate transcription of proto-oncogene leading to higher

proliferation rates Retrovirus may use a copy of a host proto-oncogene and integrate into its genome

Proto-oncogene may be mutated or abnormally expressed under viral promoters Retrovirus may contain normal viral gene whose product can stimulate cell cycle or regulate

gene expression for both viral and host genetic information Expression of gene can stimulate cell growth or abnormally express cancer-related cellular genes

In humans, most cancer causing viruses contain DNA Viruses in humans are believed to cause cancer by a retrovirus’s normal gene product

affecting cell growth and/or abnormally expressing cancer-related genes

Viruses

(Klug 2012)(Introduction to…)

What We Know…• Cancer cells do not undergo apoptosis• Viruses induce lysis in host cells

What We Need…• A method of targeting and destroying cancer cells, preferably

before they reach metastasis• A method that does not harm other, normal cells in the body

Where We Are Headed: Oncolytic Viruses Oncolysis: destruction of tumor cells Oncolytic Virus: virus that infects and breaks down cancer cells without affecting

normal cells Adenovirus (double-stranded DNA virus with no membrane envelope)

In mutant forms, it can only be replicated by cancerous cells- not normal cells Measles Herpes simplex Reovirus (double-stranded DNA virus, no envelope)

Known to infect Ras-transforming cells Ras gene mutations have been observed in over 30% of all human cancers (Ras gene family encodes signal transduction molecules that regulate cell growth and division)

Myxoma (a rabbit-specific poxvirus, nonpathogenic for all vertebrate species including humans)

Rabies Some oncolytic viruses are known to preferentially infect p-53 or ATM-deficient cells

(tumor suppressing genes) Oncolytic viruses also used to influence the immune system to attack cancerous tumors

(Donnelly 2014)(Fillat 2010)(Bridle 2010)(Kim 2010)(Basu 1998)(NCI 2014)

How It Works: Oncolytic Virotherapy

(Donnelly 2013)

How It Began: Oncolytic Virotherapy In 1904, a woman in Italy was diagnosed with cervical cancer, and

bitten by a dog. After receiving a rabies shot, her “enormous” tumor seemed to have

disappeared…until 1912 In 1910, several other Italian cervical cancer patients also received

the vaccine (live, weakened rabies virus) and reported shrinkage of their tumors as well All patients eventually relapsed

Obstacles for Initial Research: Limited knowledge of viral mechanisms Effects of new viral strains Concept of purposely infecting individuals with pathogens Necessary tools and technology

(Mahoney 2014)

Further Implications and Obstacles Could potentially replace chemotherapy and radiation therapy More precise and accurate method of treatment Need more accurate and safe methods of monitoring virus targeting

Study published in October showed intratumoral viral delivery can effectively be monitored using image-guided injection techniques (Penheiter 2012)

More studies on non-pandemic viruses for oncolytic potential Effect on perspective of vaccinations and their uses Oncolytic viruses are highly immunogenic, limiting use in immune-competent hosts

Implies that oncolytic viruses have a small window to time to be effective Immune competent hosts quickly build an immune response, secondary “vaccinations”

could lose effectiveness Study published in 2010 designed an oncolytic virus to express a tumor-associated antigen

and then use this virus in a host that has been previously vaccinated against this same antigen to boost the response for a second vaccination (Bridle 2010)

Immunotherapy must improve as well

Relevancy Cancer is genetic disorder Viruses genetic “Trojan Horses” Most are affected in some way by cancer In the US, men have slightly less than a 1 in 2 lifetime risk of developing cancer Women in the US have a risk of a little more than 1 in 3

(Estimated New 2014)(Cancer Facts 2014)

References Basu, S. The Adenovirus Family [Internet]. Stanford, CA: Stanford Univ; 1998 [cited 2014 Nov 4].

Available from: http://web.stanford.edu/group/virus/adeno/adeno.html Bridle, B., Stephenson K., Boudreau J., Koshy S., Kazdhan N., Pullenayegum E., Brunellière J., Bramson J.,

Lichty B., and Wan Y. 2010 [cited 2014 Nov 4]. Potentiating Cancer Immunotherapy Using an Oncolytic Virus. Mol Ther [Internet]; 18(8): 1430-1439. Available from: http://www.nature.com/mt/journal/v18/n8/full/mt201098a.html

Cancer Facts & Figures 2014 [Internet]. American Cancer Society (US); 2014 [cited 2014 Nov4]. Available from: http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2014/index

Donnelly, C., Errington-Mais, F., Prestwich, R., Harrington, K., Pandha H., Vile R., and Melcher A. 2014. Recent Clinical Experience with Oncolytic Viruses. C Pharm Bio [Abstract Internet]; 13(9): 1834-1841. Available from: http://www.eurekaselect.com/99693/article

Donnelly, O., Harrington, K., Melcher, A., and Pandha, H. 2013 [cited 2014 Nov 4]. Live viruses to treat cancer. J R Soc Med [Internet]; 106: 310-314. Available from: http://jrs.sagepub.com/content/106/8/310

Estimated New Cancer Cases and Deaths for 2014 Table 1.1 [Internet]. 2014. National Cancer Institute [cited 2014 Nov 4]. Available from: http://seer.cancer.gov/csr/1975_2011/browse_csr.php?sectionSEL=1&pageSEL=sect_01_table.01.html

Fillat, C., José, A., Bofill-De Ros, X., Mato-Berciano, A., Maliandi, M., and Abate-Daga D. 2010 [cited 2014 Nov 2014]. Controlling Adenoviral Replication to Induce Oncolytic Efficacy. J O Gene Ther [Internet]; 3: 15-23. Available from: http://benthamopen.com/togtj/articles/V003/SI0008TOGTJ/15TOGTJ.pdf

Introduction to the Viruses [Internet]. Berkely, CA: Univ of California Museum of Paleontology. Available from: http://www.ucmp.berkeley.edu/alllife/virus.html

References Kim, M., Williamson, C. T., Prudhomme, J., Bebb, D. G., Riabowol, K., Lee, P. K., Lees-Miller, S., Mori, Y.,

Rahman, M., McFadden, G., and Johnston, R. N. 2010 [cited 2014 Nov 4]. The viral tropism of two distinct oncolytic viruses, reovirus and myxoma virus, is modulated by cellular tumor suppressor gene status. Oncogene [Internet]; 29(27): 3990-3996. Available from: http://ezproxy.reinhardt.edu:2278/ehost/detail/detail?sid=d2d6515a-b91a-4ef3-9601-d7f724771b74%40sessionmgr4001&vid=0&hid=4113&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=syh&AN=51990009

Klug, W., Cummings M., Spencer C., Palladino M. Concepts of Genetics. 10th ed. San Francisco (CA): PB Cummings; 2012. p. 474-487.

Mahoney, D. J., Stojdl, D. F., and Laird, G. 2014 [cited 2014 Nov 4]. VIRUS THERAPY FOR CANCER. Sci Amer [Internet]; 311(5): 54-59. Available from: http://ezproxy.reinhardt.edu:2278/ehost/detail/detail?sid=c7393f6a-94b5-4ee9-b505-a62526ee9ad5%40sessionmgr4003&vid=1&hid=4113&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=syh&AN=98969991

NCI Dictionary of Cancer Terms [Internet]. National Cancer Institute (US); 2014 [cited 2014 Nov 4]. Available from: http://www.cancer.gov/dictionary?cdrid=615577

Penheiter, A., Dingli, D., Bender, C., Russell, S., and Carlson, S. 2012 [cited 2014 Nov 4]. Monitoring the initial delivery of an oncolytic measles virus encoding the human sodium iodide symporter to solid tumors using contrast-enhanced computed tomography. J Gene Med [Internet]; 14(9-10): 590-597. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930067/.

Pfeffer, S., and Voinnet, O. 2006 [cited 2014 Nov 4]. Viruses, microRNAs and cancer. Oncogene [Internet]; 25(46): 6211-6219. Available from: http://ezproxy.reinhardt.edu:2278/ehost/detail/detail?sid=9be68b3a-2be4-4320-9872-be584d1dcb94%40sessionmgr4002&vid=0&hid=4113&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=syh&AN=22633219