Discovering a Drug that Kills Cancer Cells in the Laboratory

Principal Investigator: Rebecca Riggins, PhD

A newly discovered drug stops the transformation of a healthy tumor suppressor gene into a rogue one that triggers breast and brain cancer.

P53 is a gene that, when healthy, functions to suppress tumors. But when that function is lost or mutated, p53 galvanizes the development and spread of many cancers, including breast and brain tumors.

GUMC researchers discovered a new drug that in the laboratory kills p53-mutant breast and brain tumor cells -- but spares normal, non-tumor cells. The drug, acyl hydrazone GW4716, is known as GW4716 for short.

When treated with GW4716, cancer cells with mutations in or loss of p53 die rapidly, resulting in breaks in both DNA strands. Other genes or proteins that are known targets of GW4716 do not kill the p53-mutant tumor cells. We will test whether novel molecular targets of GW4716 are responsible for its ability to kill p53-mutant breast and brain tumor cells.

Ours is an innovative, multidisciplinary approach that combines sophisticated molecular biology techniques with high-level mathematics. This approach will allow us to develop a ‘systems view’ of how the drug targets cancer cells with missing or defective p53. This comprehensive picture is essential not only for understanding how GW4716 kills cells at the molecular level, but especially for future clinical trials to ensure that patients receiving therapy have tumors that express the target of this drug.

Two experiments, or Specific Aims, will be used to investigate our hypothesis:

Specific Aim 1: Determine whether GW4716 is able to slow or prevent the growth of p53-mutant human breast and brain tumor cells implanted into mice. This vital step is required for all new or re-purposed drugs to determine whether they can treat cancers in a patient as effectively as they can kill tumor cells in the laboratory.

Specific Aim 2: Identify the molecular targets of GW4716 by finding out how it changes gene function in p53-mutant tumor cells. First, we measure changes in messenger RNAs – molecules that carry protein-coding information - after GW4716 treatment. Then, we analyze the data using three different algorithms, each of which will predict how GW4716 reprograms a p53-mutant tumor cell to die. Finally, we test the accuracy of these predictions by measuring expression of GW4716’s predicted gene/protein targets in p53-mutant tumor cells with and without treatment.

Together with our existing data, the important new information gained by the proposed studies has exciting clinical implications for breast, brain, and other types of tumors where loss or mutation of p53 results in poor survival. While great efforts have been made to restore normal p53 gene function in these cancers, successful translation of these approaches from the laboratory to the clinic has been slow and challenging. Our approach is unique, impactful, and significant because it spares normal cells while exploiting an inherent weakness in these tumor cells.