This would be quite an interesting paradigm shift from what I understood was the prime reason for therapy drug resistance. It is commonly assumed, in CLL/SLL, that clones are born with different degrees of resistance to drugs and lay in hiding only to emerge after therapy or a time lapse. Speculation has it that there might exist a competition of sorts between clones that often keeps a numerically indolent clone dominating until a frontline chemo based therapy wipes it out, allowing the drug resistant clone(s) to rise to dominance.
This research, using breast cancer, suggests that members of the dominant cancer cell population, having been exposed to chemotherapy, react to chemo stress by creating cancer stem cells from its own ranks with differing phenotypic characteristics.
Quote: "...our study emphasizes cancer cell plasticity as greatly important to the sub-clonal heterogeneity of tumors. Therapy can exacerbate this plasticity, forcing cells into new phenotypic states. I think classifying cancer cells into hierarchical arrangements may need to be dissolved in models of adaptive resistance to chemotherapy"
The research involves breast cancer and the resistance is referred to as from "chemotherapy" so I wonder if the finding of resistance would be applicable to all therapies i.e. immunotherapies (CD20 mAbs like Rituxan, Ofatumumab, Obinutuzumab etc), Kinase inhibitors i.e. (Ibruinib, Idelalisib, Imatinib), deacetylase inhibitors etc.? In CML the chosen therapy of Imatinib aka Gleevec still produces resistant cancer. Curiously to both "mammary carcinoma" and Imatinib relapsed CML patients, Dasatinib, a Src tyrosine kinase inhibitor, has shown efficacy. Dasatinib has been used experimentally in lysing senescent cells in conjunction with Quercetin in mouse studies. Recently posted.
Bottom line: Correctly timed combination of phenotype targeting drugs may be needed to cure our cancers.
WWW
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interesting, thanks for jiggling the greys WWW, good to muse every now and then.
Nice word "quiescent" to describe harder to reach cells able to avoid chemo,
"Tumors are composed of genetic and phenotypic diversity in which their distinct phenotypes are in constant flux, and dynamic equilibrium, as a consequence of inherent phenotypic plasticity. I believe that, in the context of drug resistance, classifying cells into a hierarchy is somewhat impeding. It seems more rational, based on our evidences, to visualize them on a continuum in which dynamism exists in a back-and-forth direction depending on what specific features are requisite for survival."
It is our cells ability to evolve that has makes humans the success we are, and age and developed CLL reduces the bodies ability to police this to remove the mistakes.
My musings often take me to wondering when available novel technologies will be trialed early in the CLL pathway when there are fewest number of tumor cells and mutations and the chaos that developing CLL causes. Improved prognostics at diagnosis such as telomere evaluation and a quick one two combination punch early on could one day test the need for watch & wait.
logic suggests that novel therapies now coming available if used in early CLL in combination could be the route to true management or a cure. Is it ethics that is preventing trialing this group or that drugs are not target specific enough yet?,
I was just reading some related material - again based on the study of breast cancer, that argues that there's a small percentage of Cancer Stem Cells (CSCs) that have different markers than the bulk of the tumour. If (as happened by chance with some breast cancer chemo treatments), the chemo also happens to target these CSCs, then the likelihood of the cancer recurring is reduced. Likewise, a patient can have a very good response to chemo treatment (i.e. an impressive reduction in tumour size), but not have good long term survival, if the chemo selectively melts away the bulk of the tumour but leaves the CSCs to regrow the tumour.
How this relates to CLL? That I would like to know.
Neil
Hmm' I have to wonder how my current chemo treatment for ovarian cancer is eventually going to affect my CLL. I was told it would most probably knock the CLL back a bit, now I wonder at what cost long term.
I will be rereading the article as it is quite a bit to take in on first read through.
I read somewhere, wish I could remember where, that a drug in the US is in trial that treats both ovarian cancer and CLL.
Not knowing your situation for specifics regarding your ability to access a research facility, I would urge you to contact a CLL specialist where the facility is actively doing deep NGS (next gen sequencing) to see if they would take you as a "project". One thing is very clear from this article and other research is that phenotypically unique markers for our cancers cells exist and are varied, offering more targets for therapies that may already exist and are in use in other cancers.
We all need individualized "maps" illuminating as many marker data points as possible to put cancers down for good.
CLL is paving the way as one of the conditions being first studied in a partnership between the The UK CLL Trials Biobank and Genomics England
the 100,000 Genomes Project, an initiative led by Genomics England (GEL) who are a company wholly owned by the Department of Health (website genomicsengland.co.uk ). This project aims to sequence a total of 100,000 whole genomes from NHS patients and will develop a resource for researchers. Its main objective is to work towards more rapid diagnosis and possibly new treatments for individuals affected by rare disease, cancer and infections.
There is a target to involve 1000 UK CLL patients within a short timescale and the results will be available very quickly. Researchers, including CLL researchers, will submit applications for access to the results in the near future. The UK Clinical Community are taking this project very seriously and looking to identify breakthroughs in predictive markers, improved response to therapy through personalised medicine and ultimately a cure. It is a very exciting time in the development of research into our CLL and we are fortunate that the existing UK CLL Biobank has given us a lead in this field.
If you have any queries about how the UK CLL Biobank/GEL partnership will affect you or your trial then you should talk to your doctor or trial nurse.
This is very good news as many drugs that CLLers could potentially use are already in existence but may be used in other cancers where markers have been discovered that are yet unrecognized in some CLL patients.
I have wondered about the possibility for some of us to get comprehensively sequenced and getting a search engine app to do a crowd-sourced effort of research?
Somatic evolution would seem to be the result in any case. Cells that are not so specialized can evolve more quickly. Heavy Chain mutation status may be a surrogate for overall development status - and thus also for the ability to evolve quickly.
I wonder, how heterogenous are CLL cells of the major varieties (del 17p, 11q, 13q, trisomy 12), irrespective of Heavy Chain status? I'm sure I've read things like this, but this article casts a new light on it.
In the case of CLL where cause or causes are unknown, the instability of a progenitor cell could go back to a hematopoietic stem cell defect or be "created" just before entering or passing through a germinal center. I guess I don't understand why the monoclonality of CLL would matter to the hypothesis of the speculation that "chemotherapy" used in the article is not the agent of CSC creation using non stem cells? The question is whether therapy drugs and what type of therapy drugs may act to create resistance simply by clearing the landscape of clones easy to kill thus allowing the already existent resistant subclone(s) to flourish or does the therapy drug take an active role in changing some of the soldiers of the clone into progenitor leukemic stem cells of new more aggressive clones? This may be an adaptive vs speciation difference but worthy of study to validate or refute.
Given the latency of CLL and the impotence of CLL cells in the peripheral blood it is open to speculate on all the conditions that spur proliferation and resistance. The monoclonality of CLL should be an advantage in testing the hypothesis of CSC creation by chemo.
Why would this exclude the possibility of RT (Richter's Transformation) occurring?
The potential for benefit of kinase inhibitor drugs may be to lessen this path to that type of clonal evolution/proliferation if the hypothesis proves true.
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Ibrutinib Slow but steady foreward movement.
Richter syndrome - Resonance result of the breast
