I had heard about this talk earlier this week, but had decided to skip it, seeing as it sounded unrelated to my own work, however, a last minute email from a colleague suggested I might want to go, so I stopped to read the abstract. There was a great line in the abstract that grabbed my attention:
The widespread intra-tumoral heterogeneity across space and time demonstrated highly suggests that targeted therapies will need to be developed and used in specific clinical scenarios. Use of targeted therapies developed through study of primary untreated tumors with subsequent use at clinical trials on recurrent metastatic disease is likely doomed to failure.
Since that sums up my opinion on cancer, these days, I thought it might be worth attending, after all.
In any case, the start of the presentation is delayed, due to a “catastrophic” computer failure, presumably the one hosting the powerpoint, so we’ll get underway shortly.
In the meantime, A bit of the background:
Title: Clinical Implications of Medulloblastoma Inter and Intra-tumoral Heterogeneity Through Space and Time”
Presented by: Michael D. Taylor MD PhD,
Associate Professor, University of Toronto,
Scientist, Program in Developmental Biology,
Neurosurgeon, The Hospital for Sick Children
Ok, and now it seems we’re ready to go!
Intra and intertumoral Hererogeneity in Medulloblastoma.
Interest in pediatric tumours, speciflcally, small blue cell tumours, such as medulloblastoma. Brain tumours are the most common cause of non-accidental dealth in Canadian children.
Targetted therapy would be a huge step forward in the treatment of medulloblastoma (MB). There are many subtypes of MB, but so far no one has manged to separate these into cohrerent sub-groups, mainly because of small tumour size. However, Sick Kids has managed to get up to 100 tumours, and were able to show that there are 4 different diseases. Not actually sub-groups, but different diseases. Driven by different genetic events.
There are different genes with different expression. (WNT- because of Wint signalling, SHH- hedgehog signalling, Group C and Group D). Group C and D are most similar of the group.
Tool: mesirov: NMF: (Missed the name, but different type of clustering from unsupervised heirarchical, which was used to generate 4 groups originally.) Also showed the same 4 types, which are entirely different.
Also interesting is that the different types of tumours affect different age groups, and have different phenotypes and outcomes. However, even more interesting, there’s a significant difference in the demographics by gender. WNT is 3x more common in girls than boys, and WNT survival is practically 100%.
Metastasis occurence is also dramatically different in 4 different subgroups. The group C tumours have MUCH higher incidence. (33%)
There are also subgroup specific mutations. Great heat map classification of MB subtypes, it shows clearly all of the different subgoups. However, Clinicians DO NOT want Affymetrix technology. However, 4 genes can be used to differentiate the same categories – and clinicians LOVE antibody based technology. 4 antibodies can then be used to subgroup tumours.
Went to the lab and tested this out on 300 tumours. 98% of the time only one antibody was observed to bind, and same results were found using microarray. Thus, this technology appears to be working as advertised.
Survival curve: suvival for WNT is nearly 100%, Group C is nearly 0% at 96 months. Group D is 50% by 144 months, SHH is about 80% at 216 months. Once you account for subgroup, metastasis is not a useful indicator of your survival – thus, we should clearly use a molecular approach for selecting treatment options.
The Myth of Medulloblastoma – there is no single medulloblastoma – there are indeed 4 different cancers.
The next question is if there are subtypes within the subgroups. The answer is yes, there does appear to be subtypes within the subgroups – 2 in WNT, 4 in SHH, etc.
There are now drugs for SHH that bind smoothin (?) and block the hedgehog signalling. Unfortunately, response is transient, and eventually cancer recurrs. However, SHH tumours have Chr9q, causing a loss of another key gene.
Looked at SHH group specifically, trying to subtype, even further – and yes, again they have phenotypes again – and they classify according to age, as well. SHH affects 4 month olds differently to adults.
So, where to next?
The antibodies work, but they’re polyclonal, so there is variability. As well, there are also different ways to embed/prepare cancer samples. Thus, a better technology is needed.
nanoString assay used instead, uses a probe set instead with PCR. The test is $50, 48 hour turn around – and gives the same results as the array – and now using new tumour sets to test them on. Can even be used on parafilm samples up to 5 years old. (Quality degrades rapidly on older samples). Also tested at other locations around the world.
[Ok, Starting to feel like I’m in a commercial for a new medical product, despite the fact that I’m enjoying the data tremendously.]
Currently looking at CNV and SNVs for medulloblastoma, and have identified a lot of new oncogenes. [Probably putative oncogenes, really, but not specified.]
All the data above was for the primary medulloblastoma. What about metastasis? It’s not the primary tumour that kills kids – it’s less well studied.
Assumption in the field that the primary is identical in the metastasis, but was never really tested.
Retroviruses as insertional mutagenesis. Use as tool to insert a transposon into random genes. “Sleeping Beauty” system, which only moves when the correct enzyme is present. Restricting the transposase allows you to target the cell of origin.
targetting the system to the putative cell of origin gave no results.
However, if you use Ptch mutant mice, you get a VERY high incidence of SHH medulloblastoma, and it’s metastatic.
Another experiment was to study Common insertion genes (overlap of genes). In fact, this led to looking at the metabolism in primary and metastatic tumours. Although they were the same tumour, the markers show that sometimes the primary tumours lose events, gain events or completely modify their characteristics.
Conclusions: Metatstatic tumours are seeded from the primary tumour. [Missed the second one… too fast.]
SHH alone: low metastasis event occurance. SHH + oncogene (eg, AKT), you get a significant increase in metastasis.
This model appears to apply to humans as well: Primary tumours frequently respond, but the metastatic does not – or vice versa. Thus, it’s pretty likely we’re seeing the same thing happening.
Using a small number of paired primary/metastatic tumours – primary clusters with metastisis, but the metastasis cluster more closely together than they do with the primary.
Take home message: don’t assume the metastatic tumours are identical to the primary tumour. They may be – but may also NOT be.
Next question: Is recurrent cancer the same as the primary? NO! They are genetically distinct from their primary tumour. Most of the tumour dies when therapy is given but clonal tumours resurge at some point.
Medulloblastoma has 4 subgroups, with each subgroup having subtypes. Each subtype can be further divided into a primary type and one or more metastatic types, and recurrent types are different again.
Future work: using Next Gen sequencing here at the GSC to study 1000 RNA-Seq samples!
[Overall, a neat talk and Dr. Taylor is an excellent speaker. The story is great, and the case is presented very well. I’m entirely convinced by the data here, and it fits nicely with my own work. There are probably subtypes in each tumour type, depending on the molecular biology, and those should be more predictive than the classical methods – and that the only way to approach proper treatment will be to understand the cancer types individually. Glad I came to the talk!]