Disrupting Cancer’s Circuitry – an Electrician’s View of Oncology

In many ways, cancer can be viewed like an integrated circuit. On-off switches and back up switches constitute the controls. When one of these switches stops working and a cell “short circuits,” cancer is the result. As we become more sophisticated in our understanding of cancer biology, we begin to create drugs that specifically target these short circuits.

On April 3, 2011, I will be reporting our most recent findings on novel compounds that target two parallel circuits in cancer cells. These compounds, or small molecules, disrupt the signal that drives cancer cell survival and proliferation. While the profiles of each drug alone are of interest, the profiles of the drugs in combination are better still. The phenomenon of cross talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When we as therapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies. This is what we have observed with these duel inhibitor combinations.

What is interesting is the fact that the activities cut across tumor types. Melanomas, colon cancers and lung cancers seem to have similar propensities to drive along these paths. Once again, we find that cancer biology is non-linear. Moreover, cancers share pathways across tumor types, pathways that might not intuitively seem related. This is the beauty of our platform — for it allows us to explore drugs and combinations that most people wouldn’t think of. It is these counterintuitive explorations that will likely lead to meaningful advances.

Horizontal and Vertical Signal Pathway Inhibition

The importance of signal pathway inhibition in human tumor primary culture microspheroids.

Signal transduction pathways are important targets in cancer therapy. Small molecule inhibitors for the tyrosine kinase and serine threonine kinase pathways are already available for clinical therapy. Additionally, compounds targeting the PI3K, AKT and MEK pathways will be available in the coming years. To explore the interaction of these parallel survival pathways, we compared activity and combined these inhibitors in human tissues — the results were instructive.

Our findings include favorable interactions between EGFr tyrosine kinase inhibitors and compounds that block the PI3K pathways. The most active combinations were those that inhibited the cross-talk between pathways (horizontal inhibition) over drug combinations that targeted the same pathway at different downstream points (vertical inhibition). Similar observations have been made combining PI3k inhibitors and MEK inhibitors. One such report in PNAS (May 10, 2010) closely paralleled the work conducted in our laboratory, Rational Therapeutics, that we reported at the AACR.

Noteworthy, a series of studies utilizing these combinations, indicate that certain tumors respond to their drug exposure by undergoing autophagic death, not necrotic or apoptotic. This distinction is possible, as the Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) platform has the capacity to measure all forms of cell death – apoptotic and non-apoptotic.

We continue these studies in numerous solid tumors to explore those diseases that will be the best candidates for these types of combination therapies. Please leave a comment below if you would like more information on these studies.