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Genes Are Not The Only Drivers Of Colon Cancer

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    Genes Are Not The Only Drivers Of Colon Cancer

    Genes are not the only drivers of colon cancer. A new study suggests cellular factors play an equally important part, and these not only drive tumor growth, but also affect how well the disease responds to chemotherapy.

    Senior study author John Dick, of the Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, and colleagues, write about their findings in a paper published online in Science on Thursday.

    Using lab-bred mice with poor immune systems to grow human colorectal cancers, they found biological factors and cell behavior, not just genes, drove tumor growth and contributed to treatment failure and relapse.

    Dick, who is also a Professor in the Department of Molecular Genetics at the University of Toronto, says in a press statement that the study represents a "a major conceptual advance in understanding tumor growth and treatment response".

    Not All Cancer Cells are Equal

    For their study, Dick and colleagues found a way to follow single tumor cells as they developed with time.

    They discovered that not all cancer cells are equal. Only some keep the cancer growing, and within this group, there are further differences: for instance some cells drove growth for long periods, up to 500 days, while others stopped after 100 days.

    They also found a class of cancer-driving cells that lies dormant before being activated.

    And they were surprised to discover that the mutated genes were the same for all the different cell behaviors.

    Cells Responded Differently to Chemo

    Dick and colleagues then tested the effect of chemotherapy on the human tumors growing in the immune-deficient mice.

    They found that the treatment generally killed off the longer-term tumor-driving cells.

    But unexpectedly, instead of killing the shorter-term tumor-driving cells, chemotherapy brought them out of their dormant state into an active state, causing tumors to grow again.

    And again, the researchers found the tumor-driving cells that survived had the same mutations as the ones killed off by the treatment.

    They say this proves it was cellular factors and not genetic mutation that was responsible for treatment failure.

    "Paradigm Shift" Challenges Conventional View

    The findings challenge the conventional view that tumor growth and chemotherapy resistance are governed purely by the genetic mutations in the cells of the tumor.

    "The data show that gene sequencing of tumours to find the spectrum of their mutations is definitely not the whole story when it comes to determining which therapies will be most effective," says Dick.

    He says the findings confirm for him that to design effective personalized cancer treatments, cancer doctors will have to look beyond gene mutations.

    "This is a paradigm shift that shows research also needs to focus on the biological properties of cells," explains Dick, who also holds a Canada Research Chair in Stem Cell Biology and is a Senior Scientist at University Health Network's McEwen Centre for Regenerative Medicine and Ontario Cancer Institute, the research arm of the Princess Margaret Cancer Centre.

    "For example, finding a way to put dormant cells into growth cycles could make them more sensitive to chemotherapy treatment. Targeting the biology and growth properties of cancer cells could expand the repertoire of usable therapeutic agents and provide better outcomes for patients," he adds.
    Cancer Research Pioneer

    Dick is a pioneer in cancer stem cell research. He first identified leukemia stem cells in 1994 and in 2006, how stem cells could also be driving colon cancer tumors.

    More recently, in 2011, he and his team revealed how they developed a method to convert normal human blood cells into "human" leukemia stem cells.

    Funds from the Genome Canada through the Ontario Genomics Institute, various Canadian foundations, the Ontario Ministry of Health and Long-Term Care, and The Princess Margaret Cancer Foundation, helped pay for the research behind the study.

    "Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer"; Antonija Kreso, Catherine A. O’Brien, Peter van Galen, Olga Gan, Faiyaz Notta, Andrew M. K. Brown, Karen Ng, Jing Ma, Erno Wienholds, Cyrille Dunant, Aaron Pollett, Steven Gallinger, John McPherson, Charles G. Mullighan, Darryl Shibata, and John E. Dick; Science 1227670 Published online 13 December 2012; DOI:10.1126/science.1227670

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    Catharine Paddock PhD "Genes Are Not The Only Drivers Of Colon Cancer." Medical News Today. MediLexicon, Intl., 15 Dec. 2012
    Gregory D. Pawelski

    Metabolism Is The Principal Driver Of Human Cancer

    Sometimes the genetic signal may not be the driver mutation. Other signaling pathways, like passenger mutations, could be operative.

    Driver mutations are the ones that cause cancer cells to grow, whereas passengers are co-travellers that make no contribution to cancer development. It turns out that most mutations in cancers are passengers.

    However, buried among them are much larger numbers of driver mutations than was previously anticipated. This suggests that many more genes contribute to cancer development than was thought.

    Cells speak to each other and the messaages they send are interpreted via these intracellular pathways. You wouldn't know this using analyte-based genomic and proteomic methodologies. However, functional phenotype analysis provides the window. It can test various cell-death signaling pathways downstream.

    While most scientists use genomic or proteomic platforms to detect mutations in these pathways that might result in response to chemicals, functional cytometric platforms have taken a different tack. By applying functional analysis, to measure the end result of pathway activation or deactivation, they can predict whether patients will actually respond.

    The functional cytometric profiling platform has the capacity to measure genetic and epigenetic events as a functional, real-time adjunct to static genomic and proteomic platforms.

    As virtually every presentation at the 2012 American Association for Cancer Research (AACR) meeting made obligatory reference to genomic analysis, almost every one of them then doubled back to metabolism as the principal driver of human cancer.

    It may be very important to zero in on different genes and proteins. However, when actually taking the "targeted" drugs, do the drugs even enter the cancer cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In other words, will it work for every patient?

    All the validations of this gene or that protein provides us with a variety of sophisticated techniques to provide new insights into the tumorigenic process, but if the "targeted" drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, it just isn't going to work.

    To overcome the problems of heterogeneity in cancer and prevent rapid cellular adaptation, oncologists are able to tailor chemotherapy in individual patients. This can be done by testing "live" tumor cells to see if they are susceptible to particular drugs, before giving them to the patient. DNA microarray work will prove to be highly complementary to the parellel breakthrough efforts in targeted therapy through cell function analysis.

    Gene Mutation vs Chromosomal Theory of Cancer

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    Driver Mutations and Passenger Mutations on the road to cancer

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    Gregory D. Pawelski


      Cancer More Diverse than Its Genetics

      Stephen Baylin, M.D.
      Professor of Oncology
      Johns Hopkins University School of Medicine

      Tumor cells can exhibit different behaviors despite being genetically indistinguishable.

      One reason certain tumors can be hard to eliminate is that they contain a variety of different cells. This inherent heterogeneity was thought to be driven largely by the cells’ high mutation rates, but a report published in Science today, December 13, 2012, adds to growing evidence that non-genetic factors are also responsible.

      “The take home message is, yes, it is important to know what the genetic heterogeneity of cancer is, but heterogeneity among genetically-stable cell lineages is a factor that you also have to consider,” said Stephen Baylin, professor of oncology at The Johns Hopkins University School of Medicine, in Baltimore, who was not involved in the study.

      Cancer cells, by their very nature, tend to be genetically unstable. And it is thought that this instability leads to the generation of tumor cell populations, also known as subclones, that possess different mutations and behaviors. Indeed, genetic differences have been shown to affect the growth rate, metastatic potential, and tumorigenicity of individual subclones, as well as their response to therapy.

      Of all these behaviors, tumorigenicity—the ability to give rise to new tumors— particularly interested John Dick, a cancer biologist at the University of Toronto. “The only cells that are really important in a tumor, are the cells that are able to propagate that tumor for the long-term,” said Dick. Because, he explained, if any such cells are left behind after treatment, they could recreate a new tumor.

      Even among tumorigenic cancer cells, however, behavior is not uniform. A tumorigenicity assay—in which researchers dissociated cells from a human tumor and injected them into mice to form new tumors, then repeated the procedure four more times—revealed considerable variety in the subclones that contributed to the new tumors. Some were detectable in each of the five new tumors, while others dwindled after the first tumor, suggesting they either lost their tumorigenicity, or became dormant. Some subclones were initially undetectable, but became abundant in later tumors, suggesting they had been dormant and then ramped up their proliferation. And others still varied in their contribution from tumor to tumor, appearing to be dormant in some and active in others.

      To test if this heterogeneity reflected genetic differences among the subclones, the team performed whole-exome sequencing and other genetic comparisons. To their surprise, the cells were indistinguishable. “The bottom line was that we saw remarkable genetic stability,” said Dick. ”This wide functional behavior of clones was not reflected in their genetics.”

      Even more surprising to Dick was the fact that the subclones also differed widely in their responses to a common chemotherapy drug, oxaliplatin—specifically, in their abilities to regrow tumors. Interestingly, cells that had previously robustly turned up in every new tumor dwindled in quantity following treatment with oxaliplatin, while subclones that had not appeared early on began to flourish. “The conclusion that we came to was that there must be non-genetic mechanisms that are governing drug resistance,” said Dick. Not only that, the results also suggested that cell dormancy itself was a mechanism of drug-resistance.

      This is important, because it might explain why some cancers recur after treatment, said Dick. “Chemotherapy is mostly targeted to cells that are proliferating,” he explained. Indeed, said Mel Greaves, professor of cell biology at the Institute of Cancer Research in London, “the genetic plus epigenetic or phenotypic diversity of cancer stem cells is probably a major reason for the clinical intransigence of most advanced cancers.”

      “There’s a huge enterprise and belief that if we sequence more tumors and identify more mutations that we are going to be able to effect more cancer cures,” said Dick. While he doesn’t doubt the importance of such endeavors, he suggested studying epigenetic and microenvironmental factors affecting cancer cell heterogeneity is also essential. “We should not be putting our eggs exclusively in the genetics basket,” he said.

      A. Kreso et al., “Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer,” Science, doi: 10.1126/science.1227670, 2012.

      The Scientist, News & Opinion and News
      Gregory D. Pawelski


        Mixed Responses & Intratumor Heterogeneity

        The phenomenon of “mixed responses” is certainly a recognized clinical occurrence. Most patients have responses that are reflected in most areas of the disease. That is, "mixed responses" are somewhat less common.

        Clearly, some tumors progress in what would be described as a clonal evolution. The initiating clone, over time, may acquire new features, some of which could conceivably result in drug resistance.

        While some clonal variation could be anticipated, it cannot possibly be better to "guess" what drug might work as opposed to getting a reasonable approximation of the tumor biology by sampling a portion of the disease.

        Testing 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.

        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.

        The tumor of origin 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.

        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?

        Human beings are demonstrably more than the sum of their genes. Cancer biology and the study of cancer therapy are many things, but simple is not one of them. Complex problems require solutions that incorporate all of their complexities, however uncomfortable this may be for genomic investigators.

        Contrary to analyte-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.

        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

        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

        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
        Gregory D. Pawelski


          Cancer cells hide by going dormant

          In a major breakthrough that will change the way cancer is studied and treated in the future, Toronto scientists have discovered a key reason why many tumours may return after chemotherapy.

          In a new study, researchers at the Princess Margaret Cancer Centre have shown that some of the cells that drive tumour growth hide from common chemotherapy drugs by going “dormant” — reigniting the disease when they awaken after treatments end.

          “That’s where this paper lies is to begin to add more depth (and) complexity to why cancers come back, why they recur,” says renowned stem cell scientist John Dick, whose paper was released Thursday by the journal Science.

          “This will stimulate a lot of activity,” says Dick, the study’s senior author.

          Luba Slatkovska, head of research with Canadian Cancer Society’s Ontario division agrees, saying the discovery represents a paradigm shift for research into the disease.

          “John Dick is one of those researchers who is really changing the way we think about cancer, and this is another example,” Slatkovska says.

          “We think that it’s going to become one of the new hot topics in cancer research,” she says.

          Dick, also a molecular geneticist at the University of Toronto, says the newly-discovered dormant cells have precisely the same genetic mutations as those active ones that drove the original tumour to begin with.

          Cancers occur when genetic mutations to a cell’s DNA cause them to replicate in an out-of-control fashion.

          And it was assumed, Dick says, that cancers returned after chemotherapy because of subsequent genetic mutations that made them resistant to the drugs being used against the original tumours.

          “And that is certainly true in many cases,” he says.

          But the discovery of the genetically-identical dormant cells shows that other forces are at play in cancer recurrence and that these nongenetic forces must now command the attention of the oncology community.

          “We thought that there would have been a different set of (genetic) mutations, a different spectrum of mutations that would have explained why (the recurring) cells were resistant to chemotherapy,” Dick says.

          “And in a sense that’s not what we saw. We saw that they seemed to be quite similar or essentially identical (genetically) and so something else was driving their resistance to therapy.”

          Dick, who last made headlines in 2011 when he led the team that first isolated blood stem cells, says that “something else” could include the micro-environments in which the dormant cells are located within the tumour.

          “Is it that cells are sitting in the tumour in a location that makes them dormant?” he asks.

          Dick says that along with cancer cells, tumours contain a number of normal tissues, including blood vessels and immune system agents.

          “And it appears that tumour cells can lie in proximity to these non-tumour cells and that can influence their behaviour,” Dick says.

          “So that is one of the properties we should be looking for, we should be looking for where tumour cells are sitting, who they’re close to and what kind of signals they are receiving.”

          Dick, whose team grew human colorectal cancers in mice for the research, says only one in every several thousand cells in a tumour can actually drive its growth.

          And many of these tumour drivers are susceptible to chemotherapies because most of the drugs now used in cancer treatment target cells that multiply at abnormal speeds — a signature of the disease in all its forms.

          But if some of these stem-cell-like cancer drivers are dormant — in effect hiding their ability to rapidly replicate — the drugs will pass them over.

          “Some of (the cancer driver cells) are actually quite sensitive (to chemotherapy) and other ones, particularly those ones that come from these so-called dormant cells are much more resistant,” Dick says.

          “And that can be responsible for relapse.”

          Dick says scientists now need to look for ways to kill these skulking cells or to control the factors that can awaken them.

          “We need to understand the biological properties — not necessarily the genetic properties — that are driving dormancy,” he says.

          An understanding of these nongenetic properties could lead to an entirely new generation of cancer medications, Dick says.

          Slatkovska, whose society has funded Dick in the past but was not involved in the current study, says she can imagine the creation of drugs that could wake up the sleeping cells and expose them to killer chemo.

          Drugs that could interfere with the external signals that call the dormant cells out of sleep could also become a weapon in the oncology arsenal, Dick says.

          “What our paper is saying is that on top of (targeting) the genetic properties of these cells you have to target the biological properties to be more effective,” Dick says. “Everything doesn’t just rest on genetics.”
          Gregory D. Pawelski


            Disease depends on surrounding normal cells to spread

            This is the second significant cancer advance out of Toronto hospitals just this month, and the second to home in on the healthy tissues that lie in proximity to tumours.

            In a major breakthrough, Toronto scientists have discovered a new approach to cancer treatment that would target the “normal” cells embedded around tumours.

            In a study just released, researchers at Mount Sinai Hospital show that it’s the non-cancerous cells that grow in and around a tumour that actually coax it to spread to other parts of the body.

            “Basically the normal cells and the cancer cells are engaged in a dialogue which is controlling (spread),” says Dr. Jeff Wrana, the study’s senior author.

            “The tumour cells are tweaking the normal cells, causing them to misbehave a little bit and causing those normal cells to produce signals, words if you will, that flow back to the tumour cells and promote the tumour cell’s growth.”

            Wrana’s study, which appears in the journal Cell, revealed that the words delivered by the normal cells, in a tiny protein vocabulary, were actually telling their cancerous counterparts to spread or metastasize.

            In particular, his team identified a protein signal labelled Cd81 — a so-called exosome — as the key instructional culprit in kicking off tumour spread.

            Classical oncology research has almost always searched for ways to kill or halt the mutant cancer cells themselves.

            But Wrana’s team, at the hospital’s Samuel Lunenfeld Research Institute, suggested that stopping the successful transmission of Cd81 from normal to cancer cells could arrest metastasis, the tumour spread that causes most deaths from the disease.

            “It (Cd81) is a mass of information, not just a word or two, but a whole collection of information,” Wrana says.

            “And these signals weren’t just telling cancer cells to metastasize, what they were doing is sort of teaching the cancer cells how to use their own machinery to spread,” he says.

            Wrana says scientists can now search for drugs that would stop normal cells from sending out their signals or that would block those Cd81 instructions from attaching to tumour cells.

            Researchers at the Princess Margaret Cancer Centre speculated that some cancer cells evaded chemotherapy treatment by going dormant.

            This dormancy, which would essentially hide them from cancer drugs, could well have been caused by instructions from the healthy tissues nearby, the Princess Margaret study said.

            Wrana says the common understanding of cancer sees tumours as separate entities from normal tissues, an alien lump of horror growing inside one or other of our organs.

            But cancer is in fact hooked into our normal tissues, dependent on them for food and — as it turns out — directions on how to spread.

            “People think of cancer as a kind of independent tissue growing inside them, the same way they might think of a bacterial infection,” Wrana says.

            “But in reality cancer grows within the context of the normal tissue that surrounds it. So cancer really is a part of us that’s transformed and changed.”

            Normal cells sending out the spread signals could include the organ tissues in which a tumour is growing or the blood vessel and immune system cells that are actually embedded within.
            Gregory D. Pawelski


              Gene Mutations Alone Cannot Explain Drug-Resistant Cancer

              (ChemotherapyAdvisor) - The appearance of new genetic mutations during cancer therapy has long been correlated with drug resistance, treatment failure, and ultimately, relapse. But using single-cell genome sequencing, researchers at the Ontario Cancer Institute and Princess Margaret Cancer Center in Toronto, Canada have shown that gene mutations alone cannot explain drug-resistant cancer.

              Tracking individual human colorectal tumor subclone cells that had been xenografted into mice, and sequencing their exomes (the gene-encoding regions of subclone genomes), the team discovered dramatic functional heterogeneity even among genetically identical clones; these included different tumor propagation patterns and different susceptibilities to oxaliplatin, which was reported by the the researchers in Science.

              The findings represent “a major conceptual advance in understanding tumor growth and treatment response,” said senior author John Dick, PhD, a pioneer in cancer stem cell research. “The data show that gene sequencing of tumors to find the spectrum of their mutations is definitely not the whole story when it comes to determining which therapies will be most effective.”

              While some cells of a subclone contributed to tumor growth, others quickly became dormant, even though they harbored the same mutations as the more active cells, Dr. Dick's team found—and these dormant cells survived oxaliplatin therapy.

              “This is a paradigm shift that shows research also needs to focus on the biological properties of cells,” Dr. Dick said. Treatments that force dormant cells back into growth cycles could make them more sensitive to chemotherapies, he theorizes.

              “Targeting the biology and growth properties of cancer cells could expand the repertoire of usable therapeutic agents and provide better outcomes for patients,” he added.

              The study is “avante garde in its documentation that types of subcloning can happen against a stability of genetic changes—a clone within a given set of genetic changes can evolve into subpopulations within that clone without changing their genetic background, their mutations,” said Stephen Baylin, MD, Professor of Oncology and Deputy Director of the Cancer Center at the Johns Hopkins University School of Medicine.

              Epigenetic factors, such as different DNA-methylation patterns that can silence gene expression, might help explain behavioral heterogeneity among genetically identical subclones, Dr. Baylin postulates.

              “If you have got such genetic stability, then it's likely that the other facets of the subclones that emerged could have an epigenetic basis—long-term changes in gene expression,” he told ChemotherapyAdvisor. “Things like epigenetic abnormalities could be contributing to the emergence of new subclones with distinct properties.”

              The new study “emphasizes those possibilities,” he said. When dormant tumor cells “come out and replenish the tumor,” other studies have shown that they do so with a “different epigenetic state” that appears to contribute to their drug resistance, he noted.

              The traditional paradigm, with new mutations causing some tumor cells' drug resistance, is not completely wrong, Dr. Baylin is quick to point out. “That can happen,” he said of mutation-driven resistance. However, Baylin believes,the new findings reported by Dr. Dick and his colleagues strongly suggest epigenetics is another “big player” in drug resistance.

              Epigenetics-targeting drugs already exist, he notes. For example, azacitidine (5-azacytidine) and decitabine (5-aza-2′deoxycytidine) inhibit DNA methylation and are approved by the FDA for myelodysplastic syndrome. Histone deacetylase inhibitors might also target epigenetic pathways in tumors.

              At low doses, ongoing studies in Dr. Baylin's lab suggest that azacitadine “sensitizes patients to subsequent chemotherapies or a new form of immunotherapy,” he said.

              The findings reported by Dr. Dick's team indeed suggest that nongenetic targets for personalized anticancer agents are waiting to be identified, agrees Charis Eng, MD, PhD, FACP. Candidate targets include both epigenetic alterations and tumor microenvironments (healthy cells adjacent to tumors), she said.

              Dr. Eng is the Hardis and American Cancer Society Professor and founding Chair of the Genomic Medicine Institute and directs the Institute's clinical component, the Center for Personalized Genetic Healthcare at the Cleveland Clinic. She believes that even though tumors' subclone gene mutations were identical from cell to cell, their functional genomics—“the ways they interact with each other, the ways they signal and make transcripts”—might still be quite variable.

              Gene mutations, in other words, are just one part of a larger puzzle. Epigenetics, proteomics, even microbiomes, or the genomes of bacteria living on epithelial tissues in which tumors emerge, may all help explain why some subclone cells go dormant and evade chemotherapeutic attacks, while others succumb to treatment, she believes.

              “Genomic changes are like the skeleton. The genome is the skeleton and everything else—the methylation, microenvironment, the microbiome—will be the flesh, the meat, the muscle and the skin,” Dr. Eng explained to ChemotherapyAdvisor. “So a look at everything, a snapshot profile of all the –omes, or what I call ‘integrated –omics,' which is the strength of my lab, integrates all the –omic platforms to see whether we can come up with an integrated view of what a cancer looks like.”

              Even the Cancer Genome Atlas Project has added RNA and epigenetic assays to its profiling of tumor genomes, she notes.

              The “sum total of the integration of all the ‘-omes' from all the cancer cells,” rather than any one component, may dictate chemotherapy responses in many cancers, she suspects. If that's the case, gene mutation-targeting drugs could one day represent just one part of clinical oncology's personalized-therapy arsenal.

              “I have a funny feeling that even the three-dimensional positioning of the cells (within tumors) and how they talk to each other—whether by message or protein or exchanging genes—also matters,” Dr. Eng said.

              But she is quick to point out that the Science study involved xenografting human tumors into mice. Even though that model worked elegantly to show that subclone heterogeneity is not attributable to genetic mutations alone, it may not be the best way to find out exactly what else is responsible, she cautioned—especially if tumor microenvironments are involved.

              “When the microenvironment is not represented well, alterations in the microenvironment might be missed,” she explained. “We have to ask: what is the interaction of each of these subclones with the mouse environment?”

              Taking human tumors out of their human microenvironmental context might itself “have effects on different expressions of genes in the cancer,” Dr. Eng noted.

              “We'd been assuming the enemy was simple-minded,” she said. “The enemy is complex. We need a multidisciplinary approach to look at the DNA and to understand the microenvironment, how it turns genes off and on in different contexts and even in different (cell) positions within tumors.”

              Dr. Baylin agrees that the new findings will open doors to new avenues of research.

              “We need to work on extending these observations to other tumors and to really keep studying the mechanisms that account for how these subclones emerge,” he said. “And then we need to correlate those changes really carefully with drug resistance so we can understand the molecular underpinnings in resistance patterns, and learn how to tailor therapeutic approaches to those molecular mechanisms.”

              Reference: Kreso A, O'Brien CA, van Galen P, et al. Variable clonal repopulation dynamics influence chemotherapy responses in colorectal cancer. Science.

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              Gregory D. Pawelski


                Yet Another Study Agrees: Functional Profiling Provides Insight

                Robert A. Nagourney, M.D.

                It was during the last weeks of December that a particularly interesting article crossed my desk. The study done by a group from Toronto, Canada, is entitled Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer. The study examined the proliferative capacity and drug sensitivity in colorectal cancer cells that were tracked using a process known as lentiviral lineage tracking. The investigators showed that despite serial passages, the cell populations remained stable from a genomic standpoint.

                What was most interesting was the finding that these genomically related subpopulations became progressively more resistant to oxaliplatin after drug exposure, suggesting what they described as “inherent functional variability.”

                As one of several investigators engaged in the field of functional profiling, I found the article both interesting and extremely consistent with our laboratory observations. First, cancer cells display biological differences that may reflect environmental (microenvironmental) influences, epigenetics and other drivers not readily identified at the DNA level.

                Second, these investigators, using extremely sophisticated molecular techniques, found, as the lead investigator said, “We should not be putting our eggs exclusively in the genetics basket.” This quote from the lead investigator, John Dick, was particularly resonant.

                As many of you who read my blogs know, a recurring theme in these pages is the need to broaden our scope and examine the protein, metabolic and functional characteristics of the cancer cells in their native state. Once again we find that as our most accomplished molecular brethren drill down to the bedrock of cancer biology, they are confronted by complexities and crosstalk that can only be effectively studied at the level of cell biology.

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                Gregory D. Pawelski


                  Cancer Patients Who Get Better, Get Better

                  Robert A. Nagourny, M.D.
                  Rational Therapeutics

                  A study published in the October 20 Journal of Clinical Oncology (Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with Cetuximab (Erbitux), Piessevaux H. et al, 31:3764-3775,2013) described “early tumor shrinkage” as a predictor of long-term survival in patients with metastatic colorectal cancer. These Belgian and German investigators re-analyzed two large clinical trials in colon cancer, CRYSTAL and OPUS, to evaluate the impact of early tumor shrinkage at eight weeks of therapy. Both studies were in patients with wild type (non-mutated) KRAS colon cancer who received chemotherapy with or without the monoclonal antibody Cetuximab (Erbitux).

                  They used a cutoff of 20 percent tumor shrinkage at eight weeks to separate “early responders” from “non-responders.” Early responders were found to have a significantly better survival. The accompanying editorial by Jeffrey Oxnard and Lawrence Schwartz (Response phenotype as a predictive biomarker to guide treatment with targeted therapies, J Clin Oncol 31:3739-3741, 2013) examined the implications of this study.

                  The measurement of tumor response has been a lynchpin of cancer therapeutics for decades. This was later refined under what is known as RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Despite this, there remained controversy regarding the impact of early response on long term survival. The current Piessevaux trial however, is only the most recent addition to a long history of studies that established the correlation between tumor shrinkage and survival. Earlier studies in colorectal, kidney, esophagus and lung cancers have all shown that early response correlates with superior outcomes.

                  What is gratifying in the accompanying editorial is the discussion of the “response phenotype” as a predictor of survival. Phenotype, defined as “the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment” reflects the totality of human biology not just its informatics (genotype). This renewed appreciation of tumor phenotype in oncology is important for it re-focuses on tumor biology over tumor genetics.

                  The ex-vivo analysis of programmed cell death (EVA-PCD) that we utilize, is itself a phenotypic platform that measures actual cellular behavior, not gene profiles, to gauge drug sensitivity. We have previously shown that the measurement of chemotherapy effect on human tumor tissue predicts response, time to progression and survival. The current study used clinical response (early tumor shrinkage) to successfully measure the same.

                  This analysis of early response by Piessevaux is bringing our most sophisticated investigators back to what they should have known all along.

                  1. Responding patients do better than non-responding patients.

                  2. Early measurement of response is predictive of long term outcome.

                  3. These measurements can and should be done in the laboratory.

                  Taken together, the current study supports early tumor shrinkage and by inference, ex vivo analyses, as important predictors of patient response and survival.
                  Gregory D. Pawelski


                    thanks for all the information