ISSCR final day – Not just one hit… finding combinations in cancer

Author: David Kent, 07/18/16
Institute for Research in Immunology and Cancer, Universite de Montreal

Guy Sauvageau, Institute for Research in Immunology and Cancer, Universite de Montreal

During the morning plenary session on the final day of ISSCR, we were treated to a delightful mix of basic and translational science as well as a riveting public policy lecture from Alta Charo. The session was all about disease modeling and stem cells and the highlight talk for me was from Guy Sauvageau, who is based at the Université de Montreal’s Institute for Research in Immunology & Cancer, and has co-founded a clinical stage biotech company that expands HSCs to treat cancer. Dr. Sauvageau’s talk stood out because it emphasized the importance of thinking about cancer (specifically leukemia) as a multi-component disease, unlikely to be solved by a single magic pill.

Dr. Sauvageau was giving the Ernest McCulloch Memorial Lecture, which must have been humbling considering that Dr. McCulloch is his “scientific great-grandfather” (Dr. Sauvageau trained with Keith Humphries, who trained with Connie Eaves, who trained with Ernest McCulloch). But humility aside, this talk was a real tour de force on the power of high throughput screens to identify key regulators of leukemic stem cell biology.

He started by reminding the audience that mutated genes are not easy to target since mutations often occur in genes that are quite important in normal cells, so one needs to spare the normal while targeting the abnormal. Next Dr. Sauvageau bemoaned the field’s tendency to neglect the highly complex clonal architecture of cancers: understanding this patchwork, its origins and predicting its future evolution are essential to curbing disease outgrowth. I was nodding along, especially considering our recent work that showed that the order of mutation acquisition was another important (and neglected) variable in this complicated journey from a single cell to an overt leukemia.

But these are manageable issues, right? Well, not so easy claimed Dr. Sauvageau, because we are currently unable to keep actual leukemia stem cells alive in their immature state outside the body. This makes them incredibly difficult to use in large-scale drug screens. The need for cell-based assays with defined functional outcomes, however, is an absolutely essential tool for understanding which drugs might work on which cells from which patients, so a solution had to be found.

Recent work, published by the Sauvageau lab, highlighted one such tool to keep leukemic stem cells happy in cell culture assays – something I’ve touched on before on Signals. The small molecule UM-171 is able to keep the majority of leukemic stem cells in a state where they can be assayed and this set the stage for much of the scientific work that Dr. Sauvageau presented in the remainder of the talk.

First, he walked through recent work from Caroline Pabst who showed that a protein, GPR56, specifically marked leukemic stem cells in vitro as demonstrated by successful animal xenotransplantation experiments of GPR56 positive (leukemic) compared to GPR56 (non-leukemic) negative cells. This is an important tool because it now allows powerful in vitro screening of potential drugs to be undertaken (e.g., look for the specific destruction of the leukemic cells).

This is where the talk got especially interesting, because it became very obvious in the Sauvageau lab work that Acute Myelogenous Leukemia patients (they studied more than 400) were a highly heterogeneous set of diseases with an equally heterogeneous response to individual drugs. Through a complicated series of pathway interaction studies, however, the common cell signaling pathways that regulate leukemias started to drop out and which ones work in tandem became more clear.

The reason this is so important is that we now must think of each leukemia observed in a patient as an individual disease with its own set of target cell populations, but the drugs most likely to work in combination can be inferred from these large scale studies, although these cell-based assays are still in their infancy.

Interestingly, this reminded me of Austin Smith’s talk on Day 1 where mouse embryonic stem cells also required a collection of pathway inhibitors to remain in the immature state. Leukemic stem cells cultured outside of the body seem to require a similar sort of braking mechanism to avoid maturation and exhaustion. In the case of leukemia patients, however, this would be a good thing and has already proven to be incredibly successful in the case of acute promyelocytic leukemia where treatment with all-trans retinoic acid (ATRA) makes the leukemia exhaust itself in a highly specific manner.

Fingers crossed more such clever therapies are on the way off the back of chemical inhibitor screens!

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David Kent

David Kent

Principal Investigator at University of Cambridge
Dr. David Kent is a Principal Investigator at the University of Cambridge in the Cambridge Stem Cell Institute (http://www.stemcells.cam.ac.uk/research/pis/kent). His laboratory's research focuses on fate choice in single blood stem cells and how changes in their regulation lead to cancers. David is currently the Stem Cell Institute’s Public Engagement Champion and has a long history of public engagement and outreach including the creation of The Black Hole in 2009. He has been writing for Signals since 2010.
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