AACR 2016

Repopulation of cancer stem cells in therapeutic resistance

Prof Keith Chan - Baylor College of Medicine, Houston, USA

I presented in an educational session on stem cells in cancer. So our work is primarily focussed on cancer stem cells and therapeutic options that you can exploit by targeting cancer stem cells. Particularly, actually, we look at cancer stem cells in the context in response to chemotherapy.

What is so unique about cancer stem cells?

Cancer stem cells are these unique cells that have intrinsic properties, that are intrinsically resistant to conventional therapy. But our study actually shows another dimension of cancer stem cells, so they actually are similar to normal stem cells, they have this wound response mechanism and they respond to tissue induced damage. So what we found is that chemotherapy actually induces some sort of induced damage, effectively targeting downstream differentiated cells but these differentiated cells actually induce signals that recruit these cancer stem cells to expand. So it’s like a wound response that are utilised by cancer stem cells to repopulate residual tumours and because chemotherapies are treated in multiple cycles with a gap in between, the intention is for the normal stem cells to recover during these gap periods but cancer stem cells also repopulate during these gap periods and therefore the tumour becomes progressively more and more unresponsive to chemotherapy.

Are there currently any trials or treatments that you can report on?

What is intriguing is we found that when the differentiated die, when they are undergoing programmed cell death, they actually release a factor, prostaglandin E2, which induces the residual cancer stem cells to repopulate. We were able to use neutralising antibodies to normalise this effect and actually there’s an FDA approved drug, celecoxib, that can actually target the upstream enzyme that metabolises arachidonic acid to upstream prostaglandins. We’ve found there’s significant effect to enhance chemotherapeutic response of a patient derived xenograft from the original patient that they do not respond to chemotherapy. So actually we are trying to plan a phase I clinical trial with our colleagues, clinical colleagues, at Baylor College of Medicine to try move it forward and test this hypothesis.

Are you able to target cancer stem cells before they reach the population phase in chemotherapy gaps?

It would be more ideal to actually directly target and deplete the stem cells. So that’s work in progress for us in the lab that we’re designing a drug screen, trying to directly target and kill them, it means blocking them from repopulating.

What is the next course of action?

There are multiple approaches, you mentioned some of which. If we can identify antigens specific to these cancer stem cells then we can use immunotherapy like CAR T cells or maybe a more general immunotherapy. Actually my previous mentor is using a molecule called CD47 as a target. It’s expressed highly in the cancer stem cells but also at a certain level in the differentiated cells, at least in some solid tumours. So those are both good approaches. Actually there are also other companies using targeted therapies to specifically target molecules that are unique to these cancer stem cells that are in early trials in.

What hopes do you have for treatment in the near future?

In immunotherapy I think there’s a lot of promise right now but I think these therapies actually have to be tested in each cancer tissue type to demonstrate their efficacy. So it’s hard to generalise a specific therapy across tumour types, especially even within tumour types there are actually multiple subtypes within a cancer type. So that’s what the so-called precision medicine type of therapy is trying to find - a common target within a particular group of patients in combination with immunotherapy, hopefully to more effectively target these certain patient groups. I think the key is how do you find them early in advanced; we know these patients fit into this group and can we have anything that predicts a response. For example, immunotherapy does not work in every patient and there is no prognostic, or a better term would be predictive marker, for response. So can we just target the patients that we will know have response to immunotherapy and then leave those that do not respond for other types of therapy.