Herpes Simplex Virus (HSV I) as Cancer Targeting Agent

Created by Eva Klinman and Jackie Goldstein

Brief Project Overview

We will attempt to target the Herpes virus against specific cancer cells, using a modified form of Herpes which will do one of two things:

• Only infect cells exhibiting certain cell-surface proteins (cancer-specific proteins)
• Only replicate in cells with certain expressed proteins (cancer-specific)

Background Info

Two Herpes Virus Particles, prepared for TEM

The Herpes virus naturally attacks and kills quickly dividing cells, such as the ones present around the mouth, which results in cold sores. Currently, Herpes is being used to target fast growing cancers in areas of little cell growth, such as the brain. However, researchers and doctors have no guarantees of success with this treatment method, and no assurance that the virus will stop after it has destroyed the cancer, and instead turn on the normal human body cells.

Function of Herpes in nature

1. Find natural function of Herpes (cold sores, what they do)
2. Reproductive cycle
3. How Herpes inserts itself into living cells (host)
4. Promoter/activator sequence in Herpes

Signaling of Cancer

1. How quickly the cancer divides
2. Cell-surface signal proteins presented by cancer cell
3. Most common location of cancer

Papers

1. Ebright MI et al. Replication-competent herpes virus NV1020 as direct treatment of pleural cancer in a rat model. J Thorac Cardiovasc Surg 2002;124:123-129.
   • Showed that a specific herpes virus is effective at killing a human lung cancer line both in vitro and in vivo (in mice)
2. Stojdl DR et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell. 2003 Oct;4(4):263-75.
   • Demonstrated how an oncolytic virus is capable of killing human ovarian cancer (in vitro) metastatic colon cancer (in vivo- mice)

Statement of Research Problem

Anti-cancer drugs are not specific enough, and cause long-term harm in humans who undergo cancer treatment.

The Herpes virus provides a way of selectively targeting cancer cells in vivo. Herpes has already been used to kill fast-growing cancers in areas of minimal normal cell growth, such as in the brain.

We plan to alter the Herpes recognition and duplication cycle such that it bind to specific cell surface proteins presented by cancer cells. This way, the Herpes virus should invade and kill the cancer cells, but leave the surrounding cells untouched, even after the cancer is destroyed.

Research Goals

1. Identify internal and external proteins exhibited by the cancer of choice, that are not present in nearby cells.
2. Find a promoter or operator sequence within the Herpes virus which will allow us to selectively turn it on and off (either its invasion or replication/division orders).
3. Modify the controlling sequence, such that Herpes is inactive unless it is in the presence of the chosen protein.
4. Test the Herpes in three conditions:
   1. Will it kill the chosen cancer if injected into the tumor
   2. Will it selectively kill the cancer if placed in the tumor growing on normal tissue
   3. Will it deactivate when the cancer is gone/if no cancer is present

Ultimately, if our research goal is met, we plan to make Herpes which target many types of cancer, and is financially affordable.

Predicted Outcomes

There are two possible outcomes:

1. The modified virus works
2. The modified virus fails

Herpes effectively targets cancer cells

• • The cancer cells will die, having been selectively targeted by the modified Herpes virus
  • Remaining Herpes would remain in the bloodstream and body for a short period of time, and then die, or lie quiet (not infect normal cells)
• If this occurs, we would continue research:
  • Publish.
  • Apply for the ability to test the Herpes in actual cancer patients in a clinical trial
  • Attempt to target other types of cancer (expand the research)

Herpes does no effectively target cancer cells

• • The virus was not selective enough (was toxic to human cells as well)
  • The virus did not function (its ability to destroy cells was demolished)
  • The virus remained active even after the cancer was gone
• If any of the above occurs, we would change our experiment, and propose a new method of approach, perhaps including:
  • Returning to using Herpes virus to kill cancer only in regions of slow normal cell growth
  • Testing other viruses for ease of modification
  • Looking for different possible sites of mutation/regulation within Herpes.