In what appears to be a season of blockbuster conceptual research results in the cancer medical literature, comes a recent study involving leukemia cells but which has implications for the entire spectrum of cutting edge cancer treatment. The general current prevailing thought on the origin of cancer is that a pattern of gene mutations or epigenetic changes emerge – that initiates signaling miscues to the normal orderly growth pathways of a cell – thus launching subsequent rapid and erratic cellular division and growth: cancer.
The present study takes the above as a starting point, but in a heretofore unknown (to this author) minor strain of research over the last few years – asks the questions: are these genetic mutations physically uniform throughout a tumor, and does the mutation profile of the tumor remain uniform over time? Of course, their answers are no and no. They cite research primarily from the last two years, but going back until 2008 demonstrating that there exists genetic diversity within a single tumor – and they indicate that “intraclonal genetic and phenotypic diversity is an inherent feature of [cancer].”
The implications of this concept are large, in that much of the idea of personalized medicine and targeted therapy is aimed at specific genetic patterns. If such a pattern is not uniform throughout a tumor then the results of the therapy may not be effective, or could possibly be ameliorated.
Greaves and colleagues primarily from The Institute of Cancer Research in London E-published the results of their research on November 6th 2013 in the journal Genomics Research that offers an in-depth view of genetic diversity in leukemia cells. In a multi-stage procedure the authors used state-of-the-art technologies to undertake single cell whole genome DNA sequencing, repeated in approximately three hundred cells. This was done for an individual with leukemia, and later for two other leukemia patients. The results showed not merely the expected mutations, but a large range of genetic mutations, and which were seen to be distributed in a manner which suggested sub-clonal populations (as identified by mutation patterns). These data were sorted and placed into a tree-and-branch clonal phylogeny by algorithm which physically demonstrated the relationships and temporal evolution of the DNA mutation patterns. In effect, these results showed that the individual patients did not have “leukemia” but in fact (rather astoundingly) had between two and ten genetically distinct leukemias.
Interestingly, the authors refer to their research process in such terms as “interrogating” clonal genetic complexity, in the sense that the DNA profile might perhaps be coaxed (through similar observation) to tell the story of what has happened to the cell over time. The researchers make the point that the beginning of disorderly cell division and growth due to DNA mutations in cancer increases the likelihood of subsequent DNA mutations in the same tumor / cell line. They indicate that leukemia is less likely to be complex in these matters than carcinoma (one might insert here “pancreatic cancer”). Finally, with all of the potential problems that these results confer to the idea of personalized medicine (treatments aimed at a patient’s tumor profile) the authors’ offer some promise in the sense that future doctors on understanding a more complex picture of the underpinnings of a given tumor, may be more likely to treat the “founder lesion” rather than a clonal branch or even a more minor clone – thus conferring more likely success in therapy.
This is large concept work – shown in meticulous, brilliant detail. It is actually rather breathtaking science that reveals again the unexpected at the cutting edge of medicine; plaudits to these researchers.
Dale O’Brien, MD
As alluded to in another recent blog entry, the study of microRNA has been a source of great interest as to the possible development of biomarkers that may screen or aid on the diagnosis of pancreatic cancer (ductal adenocarcinoma of the pancreas). MicroRNAs (or sometimes abbreviated miR) are small (18 to 25 nucleotide) non-coding RNA molecules that are involved in genetic regulation – that were first discovered and better characterized in the decade of the 1990s and since.
A number of microRNAs appear to be overexpressed in pancreatic cancer including miR-10b, miR-21, miR-196a, miR-203, miR-155, miR-210 and miR-221. But at an approximately four-fold increase noted by the authors, in this and earlier research by the researchers in the present study (below) hold that microRNA-10b is one of the most frequently overexpressed microRNAs in pancreatic cancer.
We addressed this area of biomarker research involving miR-27a-3p by Chinese researchers in our June 17 Pancreatica Blog posting. And now comes further interesting research on the subject as published by Korc and colleagues from the University of Indiana as E-published on October 7, 2013 in the journal Oncogene. The authors again verify that miR-10-b is overexpressed in adenocarcinoma of the pancreas, correlate increasing levels of 10-b with increased aggressiveness of cancer activity, and better characterize some of 10-b’s biochemical and growth pathway role and interactions.
Thus interestingly, the authors point to miR-10b’s potential as both a possible biomarker for pancreatic cancer, and as a possible therapeutic target.
This is provocative thoughtful research that represents early work in the promising area.
Dale O’Brien, MD
Acronyms in medicine are often a hoot. We have the four-drug combination called FOLFIRINOX for advanced pancreatic cancer (ductal adenocarcinoma of the pancreas). Recently, here at Pancreatica we reported on a study of a three-drug version of the above termed: OFF. Now comes a review of the regimen of S-1 plus oxaliplatin by Japanese researchers, which combination they term: SOX. In a sense SOX is very similar to OFF, as both regimens essentially involve the coupling of a thymidylate synthase inhibitor (TS-inhibitor) together with oxaliplatin (platinum drug) for advanced pancreatic cancer. Also, essentially both of these drug combinations are each abbreviated forms of the FOLFIRINOX drug regimen.
S-1 is given orally, and is a formulation of the chemo drug tegafur with added modulators: gimeracil and oteracil. S-1 is a TS-inhibitor, and a pro-drug of fluorouracil which functionally becomes 5-FU when metabolized. It has been studied extensively in Japan, and there has been approved for use in treatment of stomach cancer, colorectal cancer, biliary cancer, head and neck cancer, non-small cell lung cancer, metastatic breast cancer, AND pancreatic cancer. S-1 is also under study in the U.S.
Koike and colleagues from the University of Tokyo published the results of their research in the November 2013 issue of the journal Cancer Chemotherapy and Pharmacology which reviewed the results of the SOX regimen given after patients with advanced pancreatic cancer were deemed refractory to initial treatment with gemcitabine. 30 patients with advanced pancreatic cancer were given an S-1 plus oxaliplatin regiment as second line over a two-year period. The median progression-free survival duration was 5.6 months, and the median overall survival duration was found to be 9.1 months. The side effects were adjudged to present a reasonable profile.
The authors conclude that the SOX regimen is a reasonably effective option as second-line treatment for advanced refractory pancreatic cancer.
Dale O’Brien, MD