Selective Lung Cancer Treatment with Small Conditional RNAs

Institution:
Investigator(s):	Niles Pierce, D.Phil.
Award Cycle:		Grant #: 20XT-0143	Award: $0
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Abstracts

Initial Award Abstract

Smoking is the dominant risk factor for lung cancer. Over the last half-century, five-year survival rates for lung cancer have remained low, and the age-adjusted US death rate due to lung cancer has risen dramatically. Lung cancer now accounts for more US deaths than any other type of cancer. There is an urgent societal need for fundamentally new approaches to lung cancer treatment.

To block replication of rapidly dividing cancer cells, conventional chemotherapies systemically disrupt cell division, causing diverse and often severe side effects as a result of collateral damage to normal cells. To overcome this shortcoming, we pursue therapeutic regulation that is conditional, activating selectively in cancer cells.

Our approach is based on small conditional RNAs (scRNAs) that change shape to activate a cell death pathway if and only if a particular cancer mutation is detected within a cell. In lab-grown human brain, prostate, and bone cancer cells, scRNAs mediate cell death with striking effectiveness and selectivity: a single dose yields a 20- to 100-fold reduction in population for cells containing a targeted cancer mutation, and no measurable reduction for cells lacking the mutation. These results suggest the potential for engineering chemotherapies that are conditional, activating selectively in cancer cells while leaving normal cells untouched. Moreover, the sequences of the scRNAs can be designed to recognize different cancer mutations, suggesting the potential for treating cancers caused by diverse mutations.

Here, our objective is to design and validate scRNAs for selective killing of lung cancer cells in mice. This is a critical step toward our goal of creating conditional chemotherapies that selectively kill lung cancer cells in humans, leaving normal cells untouched.