tag:blogger.com,1999:blog-4826023149139426251.post5703011873750053917..comments2024-03-28T09:33:06.715+00:00Comments on AntiCancer: The Wrong Models of Cancer - Part 1Unknownnoreply@blogger.comBlogger3125tag:blogger.com,1999:blog-4826023149139426251.post-80751455268588800932012-03-17T18:16:47.528+00:002012-03-17T18:16:47.528+00:00Pan
Thanks for asking. "Some" reference...Pan<br /><br />Thanks for asking. "Some" references.<br /><br />Clinical application of functional profiling in advanced NSCLC and colorectal cancers ASCO Meeting Abstracts 26: 13547 R. A. Nagourney, J. Blitzer, D. McConnell, R. Shuman, S. Grant, K. Azaren, I. Shbeeb, T. Ascuito, B. Sommers, and M. Paulsen <br /><br />Functional profiling in stage IV colorectal cancer: A phase II trial of individualized therapy ASCO Meeting Abstracts 27: e15124. J. B. Blitzer, I. Shbeeb, A. Neoman, K. Azaren, M. Paulsen, S. Evans, and R. Nagourney <br /><br />Functional profiling in stage IV NSCLC: A phase II trial of individualized therapy ASCO Meeting Abstracts 27: e19079. R. A. Nagourney, J. Blitzer, E. Deo, R. Nandan, R. Schuman, T. Asciuto, D. Mc Connell, M. Paulsen, and S. Evans<br /><br />It's a theoretical but overrated problem. The same problem applies to ER, Her2, EGFR mutations, KRAS, OncotypeDx. Even worse for trying to do studies on individual cells, e.g. as from circulating tumor cells. Less of a problem for cell function analysis, since they are sampling a much bigger mass of cells and are homogenizing the mass (actually homogenizing the distribution of microclusters).<br /><br />It's analogous to the Gallup poll. You are projecting the behavior of a national electorate, based on a sample of 1,500 voters, who may or may not be representative of the whole. Rasmussen and Gallup have the same sized sample, but select different people for their polling ("likely voters" vs "all voters"), so their projections often disagree.<br /><br />It is one of the reasons why (1) "resistance" predictions tend to be more accurate than "sensitive" predictions (of the cancer is resistant anywhere, it pretty much doesn't matter), if you use the "resistant" drug, the patient will have progressive disease and (2) the tests are more analogous to using the barometric pressure to predict for rain than they are analogous to a serum sodium level; i.e. the predictions are useful (assay "sensitive" drugs being seven times more likely to work than assay "resistant" drugs), but they aren't perfect (i.e. 100%), no diagnostic test in medicine is.<br /><br />GregGreg Pawelskihttps://www.blogger.com/profile/13881517358316630729noreply@blogger.comtag:blogger.com,1999:blog-4826023149139426251.post-49352688366832646402012-03-17T14:23:12.795+00:002012-03-17T14:23:12.795+00:00Greg, thanks for the comment. Do you have some ref...Greg, thanks for the comment. Do you have some references to recent work on the type of functional profiling platform you mention?<br /><br />Thanks.<br /><br />PanPan Pantziarkahttps://www.blogger.com/profile/06402257217928470486noreply@blogger.comtag:blogger.com,1999:blog-4826023149139426251.post-7456941007499404172012-03-16T19:51:27.040+00:002012-03-16T19:51:27.040+00:00I couldn't agree more on your commentary in re...I couldn't agree more on your commentary in regards to studying cell-lines, cell-growth assays, and genetic analysis. All used for "theoretical" work on cancer. A better model for cancer is provided by "fresh" living tissue. In real cancer, tumors emerge in tissues surrounded by a bed of non-cancerous cells (stroma), with blood and lymphatic vessels, immune cells and the like (the microenvironment).<br /><br />That's why the functional profiling platform has recognized the interplay between cells, stroma, vascular elements, cytokines, machrophages, lymphocytes and other environmental factors. This has lead the focus on the human tumor primary culture microspheroid (microclusters), which contains all of these elements. The functional profiling platform studies cancer response to drugs within this microenvironment, enabling it to provide clinically relevant predictions to cancer patients.<br /><br />The "intratumor heterogeneity issue is not a new revelation to cell function analysis. Searching for genetic predispositions is like searching for a needle in a haystack. One can chase all the mutations they want, because if you miss just one, it may be the one that get through. Or you can look for the drugs that are "sensitive" (cooperative) to killing all of your cancer cells, not theoretical candidates.<br /><br />Contrary to anlayte-based genomic and proteomic methodologies that yield static measures of gene or protein expression, functional profiling provides a window on the complexity of cellular biology in real-time, gauging tumor cell response to chemotherapies in a laboratory platform. By examining drug induced cell death, functional analyses measure the cumulative result of all of a cell's mechanisms of resistance and response acting in concert. Thus, functional profiling most closely approximates the cancer phenotype.<br /><br />Testing of one sample of the tumor may well not render an accurate environment, unless you are recognizing the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. The human tumor primary culture microspheroid contains all of these elements. Studying cancer response to drugs within this microenvironment would provide clinically relevant predictions to cancer patients. It is the capacity to study human tumor microenvironments that distinguishes it from other platforms in the field.<br /><br />They have observed some degree of "genetic drift" where mets tend to be somewhat more resistant to drugs than primaries. Over the years, they have often encouraged physicians to provide nodal, pleural or distant site biopsies to give the "best shot" at the "most defended" of the tumor elements when metastatic disease is found.<br /><br />The tumor of origin (as in the NEJM study as well) and the associated mets tend to retain consanguinity. That is, the carcinogenic processes that underlie the two populations are related. This is the reason they do not see "mixed responses" (one place in the body getting better and another place in the body getting worse), but instead, generally see response or non-responses.<br /><br />Heterogeneity likely underlies the recurrences that are seen in almost all patients. This is why they try to re-biopsy and re-evaluate when recurrences are observed. Heterogeneity remains a theoretical issue no matter what platform one uses. Why complicate this fact by using a less biologically relevant method like genomics that only scratches the surface of the tumor biology?Greg Pawelskihttps://www.blogger.com/profile/13881517358316630729noreply@blogger.com