Posted by: Akseli Hemminki | April 27, 2010

Cancer cells resistant to conventional therapeutics can be killed by oncolytic viruses

Most conventional cancer therapeutics have more activity on rapidly dividing cells in comparison to non-replicating cells. Since most cells in adult normal tissues do not replicate much, while many cancer cells do, chemotherapy and radiation therapy have some selectivity for tumor cells. However, side effects are frequently seen from normal tissues that rely on constant cell division for maintenance, including the bone marrow where blood cells are made, mucous membranes, intestinal lining, hair follicles, among others. Also, the normal tissue DNA damage caused by these treatments increases the risk of new cancers.

In contrast, oncolytic viruses can be engineered to take advantage of specific tumor associated molecular changes. One example is Rb/p16 pathway selective oncolytic adenoviruses, which replicate preferentially in tumor cells defective in this central growth control circuit. Since Rb/p16 deficiency is one of the hallmarks of cancer, and probably a requirement for tumor formation, this pathway is abnormal in basically all tumors. However, in normal tissues with intact Rb/p16, little virus replication is seen. Similar approaches have been used to render oncolytic vaccinia viruses dependant on excess nucleotides (DNA building blocks) as found in tumors, and overactivity of the EGFR pathway, another classic tumor associated feature.

A useful feature of normal tissues is the cellular interferon response, which can protect against many types of viruses. Defective interferon signaling is another hallmark of cancer and this yields additional selectivity to many oncolytic viruses. The difference in interferon responses has even allowed use of some unmodified naturally occurring  viruses for experimental cancer treatment. Chemotherapy and radiation therapy kill tumor cells by inducing DNA damage, which is then recognized by cellular quality control circuits. Some damage may be repaired but as it accumulates the cell is eventually instructed to self-destruct (apoptosis).

However, advanced tumors are able to develop resistance to apoptosis, which restricts the efficacy of these therapeutics. And in contrast, such tumors are not resistant to oncolytic viruses. Oncolytic viruses are similar to other targeted drugs, such as small molecular inhibitors and monoclonal antibodies, in that their selectivity if dependant on tumor associated molecular features.

A major difference is that molecular inhibitors only inhibit cells, they do not kill them. Thus, while the “red light” is on, tumors are under pressure to develop resistance mechanisms, which allow them to continue growth. In contrast, oncolytic viruses only the need the “green light” from the molecular defect and then they will proceed with killing the cell without allowing it to develop resistance.

Advanced tumors are experts in self-protection. They often express high levels of special ion channels which can pump out toxic molecules such as chemotherapeutics and also small molecular inhibitors. However, this feature does not protect them from oncolytic viruses.

In summary: while advanced tumors have several means they can employ to develop resistance to conventional therapeutics, these features do not confer resistance to oncolytic viruses.

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