Understanding Glioblastoma
Noting that accumulating evidence suggests that intratumor heterogeneity most likely is the essential to Discovering Glioblastoma (GB) treatment failure, Andrea Sottoriva, Ph.D., and colleagues in the department of oncology at University of Cambridge produced a surgical multisampling scheme to collect spatially distinct tumor fragments from 11 GB patients.
The authors reported their findings in the March 5, 2013 issue of PNAS. Their integrated genomic analysis, they said, uncovers extensive intratumor heterogeneity, along with many patients displaying various GB subtypes within the very same tumor. They likewise reconstructed the phylogeny of the fragments for each patient, determining copy number alterations in EGFR and CDKN2A/B/p14ARF as early events, and aberrations in PDGFRA and PTEN as later events throughout cancer progression. Their clonal characterization of each tumor fragment at the single-molecule degree detected multiple coexisting cell lineages.
Taken together, the researchers concluded, their outcomes show the genome-wide architecture of intratumor variability in GB across multiple spatial scales and patient-personal designs of cancer evolution, along with consequences for treatment design.
Asked exactly how his findings in MM and those of others along with various tumors may without delay translate in to method for oncologists, Dr. Golub said that the notion of a yes or no answer, that is, whether or not a provided mutation is present in a tumor, is also simplistic, particularly in interpreting clinical trial outcomes testing targeted agents.
“It is unreasonable to anticipate that an entire tumor would certainly respond to a drug if the target of the drug is just present in a minority of the tumor cells,” he explained. “If the mutation, for example, is sub-clonal and the patient doesn’t respond clinically, it would certainly be the wrong conclusion to point out the drug is ineffective.”
He added that exactly what is required is a quantitative approach to understand in exactly what proportion of the tumor the mutation is found.
“For example, if a mutation is just present in a minority of the tumor cells, the drug may not be so great for the patient. However if the mutation were present in 100 percent of the cells, it’s a much better choice,” he said. “Targeted agents that go after the least-heterogeneous aspect of the tumor may be a much better choice.”
The very same goes for clinical trials as you may come to various results, continued Dr. Golub. In the MM study, for example, “we located that in some patients the BRAF mutation was clonal (present in every one of the cells), However in some patients present just in a minority.” If you did a clinical trial of a BRAF inhibitor and you just enrolled sub-clonal patients, you may conclude that BRAF is not a great target in MM, “whereas, if you enroll just patients along with clonal mutations in clinical trials, you may come to a forever various conclusion.”
With respect to drug discovery, Dr. Golub is much more optimistic regarding making drugs that go after the founding mutations that will certainly be present in every one of a tumor’s cells. “Those will certainly make the very best therapeutic targets,” he said. “I am much less optimistic regarding attempting to choose off 5 sub-clones along with a five-drug combination.”
Beverly Mitchell, M.D., director of the Stanford Cancer Institute, David Rubenson, associate director for administration and strategic planning, and Daniel S. Kapp, M.D., professor emeritus of radiation oncology, posed some strong questions regarding the meaning of these findings for cancer therapeutics in the April 11, 2015 edition of The Scientist. These consist of whether intra-tumor heterogeneity implies that a solitary targeted therapeutic, while developing short-term responses, brings us any type of closer to long lasting ailment control. Or, they ask, do we just necessity a better, or a second or third, targeted therapeutic?
While uncertainties remain, they said, there is sufficient data for each serious cancer research and treatment focus to assess exactly how intra-patient heterogeneity will certainly affect research priorities, clinical trial design, and the patient’s choice of treatment.
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