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RCC - The sneaky disease

Texas_wedge's picture
Texas_wedge
Posts: 2807
Joined: Nov 2011

It's no wonder that the problems in dealing with RCC seem so intractable, when you read information like that in the article I've copied below. However, it serves to show the immense effort being made world-wide and the rapid and solid progress now being made. (Another example is the sterling efforts at developing a universal cancer vaccine currently going on in Israel.)

The BBC's Horizon science programme had an episode screened last night entitled "Defeating Cancer". It showed treatment of 3 patients at one of the UK's most notable hospitals for cancer research and pioneering treatment (The Royal Marsden). All three were doing well, one after Cyberknife radiotherapy, one after da Vinci robotic surgery and one on a new targeted therapy (Vemurafenib, marketed as Zelboraf) for advanced metastatic melanoma (the other cases were prostate cancer).

I've been following up on some info emerging from the Horizon programme and it has led me to some interesting material, such as that below. The seeming intransigence of kidney cancer when attacked with the latest cleverly 3D-designed drugs, is explained to a great degree by the following:

Cancer genes differ in different parts of a tumour

15 March 2012

Taking a sample from just one part of a tumour may not give a full picture of its ‘genetic landscape’, according to a landmark study published in the New England Journal of Medicine this month.

The findings could help explain why attempts at using single biopsies to identify biomarkers to which personalised cancer treatments can be targeted have not been more successful. They also point to a way forward.

Cancer Research UK scientists carried out the first ever genome-wide analysis of the genetic variation between different regions of the same tumour using kidney cancer samples. They found that around two-thirds of gene faults were not shared across other biopsies from the same tumour.

The tumour samples analysed in this study were donated by patients with advanced kidney cancer treated at The Royal Marsden under the supervision of Dr James Larkin.

Dr Larkin said: “The idea of personalised medicine is to tailor treatments to suit individual patients. This study in kidney cancer has shown significant molecular changes between different parts of the same tumour. We have also seen differences between primary kidney tumours and cancer cells that have spread to other organs. This may be relevant to how we treat kidney cancer with drugs because the molecular changes that drive the growth of the cancer once it has spread may be different from those that drive the growth of the primary tumour.”

Professor Charles Swanton, based at Cancer Research UK’s London Research Institute and the UCL Cancer Institute, said: “We’ve known for some time that tumours are a ‘patchwork’ of faults but this is the first time we’ve been able to use cutting-edge genome sequencing technology to map out the genetic landscape of a tumour in such exquisite detail.

“This has revealed an extraordinary amount of diversity, with more differences between biopsies from the same tumour at the genetic level than there are similarities. The next step will be to understand what's driving this diversity in different cancers and identify key driver mutations that are common throughout all parts of a tumour."

The researchers compared the genetic faults in samples taken from different parts of four separate kidney tumours, and also from sites where the cancer had spread to other organs.

This allowed them to identify 118 different mutations.

40 of these were ‘ubiquitous mutations’ found in all biopsies.
53 were ‘shared mutations’ that were present in most but not all biopsies.
25 were ‘private mutations’ that were only detected in a single biopsy.
By analysing the location of shared mutations in relation to the whole tumour, the researchers were able to trace the origins of particular subtypes of cancer cells back to key driver mutations. This allowed the scientists to create a ‘map’ of how the pattern of faults within the tumour might have evolved over time.

Professor Swanton added: “For the first time we’ve been able to use the pattern of genetic faults in a tumour to trace the origins of certain populations of cancers cells, much in the same way as Darwin used his ‘tree of life’ theory to show how different species are related.

“This underscores the importance of targeting common mutations found in the ‘trunk’ of the tree as opposed to those found in the ‘branches’, which may only be present in a relatively small number of cells. It may also explain why surgery to remove the primary kidney tumour can improve survival, by decreasing the likelihood that resistant cells will be present that could go on to re-grow the tumour after treatment.”

alice124's picture
alice124
Posts: 860
Joined: Mar 2012

Let me ask what probably is a dumb question, but it's what I thought about in reading this. Would this explain why cancer treatments such as HDIL2 sometimes result in a mixed response -- shrinking some tumors while others continue to grow? Also do you know if the Horizon program is aired in the states?

Texas_wedge's picture
Texas_wedge
Posts: 2807
Joined: Nov 2011

Alice, please let me know if this does it for you. If not I'll try other ways to put you on to Horizon.

http://www.bbc.co.uk/i/b01g7lhb/

Not a dumb question at all and an entirely plausible conjecture. It could also explain the differential results of different agents across patients. Moreover, it sheds further light on the issue of the molecular differences between primary and secondary tumours of the same cancer form. The latter may even mean wholly different modalities might be optimal as between primaries and secondaries. So far still a bit of not even knowing which haystack might contain a needle but progress is being made apace.

Texas_wedge's picture
Texas_wedge
Posts: 2807
Joined: Nov 2011

Alice, unless I've got it wrong, there can be delayed benefit from HD IL2, appearing only months later. If so, don't assume that John got nothing from his tough regimen of treatment. It may have cleared the way for benefit from subsequent treatments.

The theme of this thread is that RCC is unimaginably complex and we're only just starting to scratch the surface. The information above looks at one aspect. Another is explained in a piece that's just appeared in Nature Medicine, entitled "A delicate balance: tweaking IL-2 immunotherapy" which casts interesting new light on the variability of response across individuals. The key insights are summarised in these few sentences:

"These papers highlight that as we understand more about immune processes we can better exploit them to potentially reinvent the role of a disease-modifying agent. It is revealing and perhaps ironic that earlier clinical studies attempted not to administer but to block IL-2 in GVHD5. The immune system seems to exist in a dynamic state of tension between suppression and activation, with the same cytokines capable of exerting effects in either of these paradigms, and to some degree simultaneously. Modulating the immune response in disease represents perhaps the greatest hurdle of individualized medicine. Age, genetic factors and prior and present immune experiences throughout life constantly modulate the immune signature of an individual, markedly altering the effects of the same immunomodulatory therapeutic in different individuals or even within the same individual over time. ..... All these factors make one also better appreciate the complexity of attempting systemic immune modulation. Stay tuned, as it is likely that as we understand more, we may be in for more surprises that challenge earlier dictums."

PS I believe it is possible to get BBC progs like Horizon in the USA. Did you enjoy success?

alice124's picture
alice124
Posts: 860
Joined: Mar 2012

TW,

I am able to get to the BBC website and can find mention of "Defeating Cancer" and it shows still clips, but--for some reason--probably my own deficiency, I cannot get it to play. Rather than continuing to try and get it to play, I finally went into my own TV DVR system and programmed it to look for and record when it is aired again (if, of course, it is on a program in the U.S.). One time when I tried to play from my office, it came back telling me it wasn't available outside of the UK.

You're probably right I shouldn't give up on a delayed good response, and I have read your sneaky disease post multiple times (because it takes more than once for me to absorb it all), but a delayed response to the HDIL2 has never been mentioned by John's doctor. And I find that a little odd if he thinks there's a chance it will happen. I guess--that combined with John's lack of progress has deteriorated my optimism. But you're absolutely right, I shouldn't write off a delayed response possibility. The complexities mean there is much still to be learned. Thanks for the reminder.

Texas_wedge's picture
Texas_wedge
Posts: 2807
Joined: Nov 2011

Another good summary of the magnitude of the problems facing researchers in this domain is a piece from the NY TImes last year concerning genomic signatures and biostatistics

http://www.nytimes.com/2011/07/19/health/19gene.html?pagewanted=all

It's entitled "Add Patience to a Leap of Faith to Discover Cancer Signatures" and the last sentence of a well-written piece says

“What it means, as I suppose everybody is beginning to know, is that cancer is a very complicated thing,” Dr. Berry said.

Ain't that the truth!?

Alice, it might be worth asking John's doctor over what time period benefits from IL2 could accrue. I'm sorry John isn't making the progress you'd hoped for but all is not lost and a lot is happening that holds early promise.

Texas_wedge's picture
Texas_wedge
Posts: 2807
Joined: Nov 2011

More recent research revelations that underline the complexities!!

http://www.sciencedaily.com/releases/2012/05/120507210137.htm?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+sciencedaily%2Ftop_news%2Ftop_health+%28ScienceDaily%3A+Top+News+--+Top+Health%29

"Not All Tumor Cells Are Equal: Huge Genetic Diversity Found in Cells Shed by Tumors

ScienceDaily (May 7, 2012) — The cells that slough off from a cancerous tumor into the bloodstream are a genetically diverse bunch, Stanford University School of Medicine researchers have found. Some have genes turned on that give them the potential to lodge themselves in new places, helping a cancer spread between organs. Others have completely different patterns of gene expression and might be more benign, or less likely to survive in a new tissue. Some cells may even express genes that could predict their response to a specific therapy. Even within one patient, the tumor cells that make it into circulating blood vary drastically.

The finding underscores how multiple types of treatment may be required to cure what appears outwardly as a single type of cancer, the researchers say."

I guess it bears out my speculation on another thread two days ago (on "Just found out I have Kidney cancer") where I said

"There are at least a couple of hundred different cancers and it's maybe an open question whether kidney cancer is one disease or many. Even if it's only one, it's very complicated and next to nothing is known for sure about it - there's a vast amount of information but that represents only a tiny fraction of what remains to be learnt and there are huge advances of knowledge going on on a daily basis."

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