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Scientists discover melanoma-driving genetic changes caused by sun damage
By Dross at 2012-07-20 00:03
Scientists discover melanoma-driving genetic changes caused by sun damage

HOUSTON — It's been a burning question in melanoma research: Tumor cells are full of ultraviolet (UV)-induced genetic damage caused by sunlight exposure, but which mutations drive this cancer?

None have been conclusively tied to melanoma. The sheer abundance of these passenger mutations has obscured the search for genetic driver mutations that actually matter in melanoma development and progression.

By creating a method to spot the drivers in a sea of passengers, scientists at the Broad Institute of MIT and Harvard, the Dana-Farber Cancer Institute and The University of Texas MD Anderson Cancer Center have identified six genes with driving mutations in melanoma, three of which have recurrent 'hotspot' mutations as a result of damage inflicted by UV light. Their findings are reported in the July 20 issue of the journal Cell.

"Those three mutations are the first 'smoking gun' genomic evidence directly linking damage from UV light to melanoma," said co-senior author Lynda Chin, M.D., Professor and Chair of MD Anderson's Department of Genomic Medicine. "Until now, that link has been based on epidemiological evidence and experimental data."

"This study also is exciting because many of the recent large-scale genomic studies have not discovered new cancer genes with recurrent hot-spot mutations, a pattern strongly indicative of biological importance," said Chin, who also is scientific director of MD Anderson's Institute for Applied Cancer Science.

The six new melanoma genes identified by the team are all significantly mutated and provide potential targets for new treatments.

Puzzle has thousands of potential pieces, but only requires a few dozen

A number of important mutations had previously been identified as melanoma drivers. These include BRAF (V600) mutations, present in half of all melanomas, and NRAS (Q61) mutations. However, the vast majority of these mutations do not appear to be caused by direct damage from UV light exposure.

Those known mutations are important, but don't tell the whole story. Melanoma, the authors note, has higher genetic mutation rates than most other types of solid tumors. The majority are attributable to passenger mutations caused by UV light damage resulting in a DNA alteration called a cytidine (C) to thymidine (T) transition.

Chin together with Levi A. Garraway M.D, Ph.D., associate professor at Dana-Farber Cancer Institute and Harvard Medical School and senior associate member at the Broad Institute, sequenced the exons – active portions of DNA involved in protein synthesis – in 121 melanoma samples paired with normal DNA and found 86,813 coding mutations. The resulting mutation rate was higher than that ever reported in any other tumor type.

Among the most frequently mutated genes, 85 percent of the active coding mutations resulted from C to T transitions caused by UV light exposure.

Statistical approaches to identify driver mutations have often assumed that the baseline mutation rate is uniform across the genome. The abundance of UV-induced passenger mutations that vary in frequency confounds this assumption in melanoma, the researchers report.

"When a gene is found to be repeatedly mutated, we naturally assume that it must be important to the cancer," said Garraway, who is co-senior author with Chin on the study. "However, melanoma can fool us – in that cancer, the very high mutation rate means that many genes can be recurrently mutated purely by chance. We needed a solution to this problem."

To counter this effect, the researchers turned to parts of the genome that don't code for proteins, called introns, and other inactive DNA segments that flank exons. By comparing the frequency of mutations in the inactive segments to the frequency of mutations in the exons, the researchers built a framework for assessing the statistical significance of functional mutations.

Approach identifies six known cancer genes, six new ones

The analysis identified functional mutations in the well-known cancer genes BRAF, NRAS, PTEN, TP53, CDKN2A and MAP2K1.

It also uncovered five new genes, RAC1, PPP6C, STK19, SNX31, and TACC1. Most are associated with molecular pathways involved in cancer but had not been previously recognized as significantly mutated in melanoma. Their presence in the tumor samples ranged from 3 percent to 9 percent.

The sixth new gene tied to melanoma was ARID2, an apparent tumor-suppressor gene possessing a significant number of loss-of-function mutations found in 7% of patient samples.

"Six new melanoma genes have been picked out from thousands of mutated genes," said Eran Hodis, co-lead author who is a computational biologist in the Garraway lab at the Broad Institute and an M.D.-Ph.D. student at Harvard and MIT. "The same approach may bring clarity to genome sequencing studies of other cancers plagued by high passenger mutation rates, for example lung cancer."

UV damage causes 46 percent of driver mutations

The team then cross-referenced their findings with a database of recurrent mutations called COSMIC and gained new insights in the frequency and characteristics of driver mutations, old and newly discovered, in 21 genes.

Out of 262 driver mutations in the 21 genes, 46 percent were caused by UV-induced damage. The well-known tumor-suppressing gene TP53 had the greatest number of UV-caused mutations. Other tumor-suppressors also had loss-of-function mutations and all of the newly identified genes had a high percentage of mutations caused by UV damage.

Most exciting, three of the discovered genes possessed 'hotspot' mutations found in the exact same position in multiple patients providing another line of evidence indicating these mutations contribute to melanoma.

"We have now discovered the third most common hotspot mutation found in melanoma is present in a gene called RAC1, and unlike BRAF and NRAS mutations, this activating mutation is attributable solely to characteristic damage inflicted by sunlight exposure" said Ian R. Watson, Ph.D., co-lead author of the study and postdoctoral fellow in the Chin lab at MD Anderson.

New insights provide opportunity to better understand, treat melanoma

Much work remains following the most comprehensive analysis of the genetics of melanoma, the authors noted. If diagnosed early, melanoma is highly curable, but in its metastatic stage is lethal. Determining the role these mutated genes play in biological processes important for melanoma progression and metastasis provides a new avenue of investigation into the molecular basis of this disease.

With the advent of the BRAF inhibitor vemurafenib, melanoma has emerged as the latest success story for genomics-guided targeted therapy in treatment of patients with metastatic disease. However, melanoma eventually resists this therapy and effective treatment options for patients that do not possess a BRAF (V600) mutation are limited.

Determining whether these newly discovered genes are amenable to targeted therapy, or whether their mutations predict sensitivity to currently available drugs, Chin said, will be an important next step in translating these findings into the clinic.



5 comments | 3543 reads

by gdpawel on Wed, 2012-07-25 03:50
Robert Nagourney, M.D., PhD., Medical and Laboratory Director at Rational Therapeutics, gave a presentation on signal transduction inhibitors at the AACR annual meeting last year. Using MEK/ERK and PI3K/mTOR inhibitors, he explored the activities, synergies and possible clinical utilities of these novel compounds, alone and in combination in human tumor primary culture microclusters. Exploration of horizontal pathway targeting.

He saw disease-specific activity for both compounds. For the MEK/ERK inhibitor (vemurafenib), melanoma appeared to be a favored clinical target. After all, many melanomas carry mutations in the BRAF gene and BRAF signals downstream to MEK/ERK. Between 40 to 80 percent of melanoma patients have a mutated BRAF gene, which turns on cellular growth and division signaling pathway.

Vemurafenib exploits the fact that BRAF proteins in healthy cells pair up with other BRAF proteins to form a multiprotein complex, while the mutated BRAF protein acts as a lone compound. This solitary structure can be hundreds of times more effective in activating cell division than the normal paired BRAF complexes. Vemurafenib targets tumor cells by only inhibiting the stand alone mutant version, while allowing the twinned version in healthy cells to act unimpaired.

However, besides melanomas, colon cancers and lung cancers seem to have similar propensities to drive along these paths. Once again, we find that cancer biology is non-linear.

The FDA-approved assay that Dr. Nagourney utilized for his studies applied the functional profiling platform in actual human tumor primary culture microspeheroids (microclusters). While Zelboraf (vemurafenib), a tyrosine kinase inhibitor, acts specifically in patients who carry the BRAF (V600E) mutation, a second drug ipilimumab, offered commerically as Yervoy, is a monoclonal antibody that acts by blocking CTLA-4, thereby enhancing T-cell response to tumor antigens. While Zelboraf (vemurafenib) has a somewhat narrow target population, Yervoy (ipilimumab) targets may extend to a broader range of melanoma patients and will likely find a role in other cancers, like lung.

The responses from Nagourney's laboratory results in most patients unfortunately have not been very durable, with relapses generally occurring months or the first year after starting therapy. Interestingly, secondary pathways, like N-RAS and C-RAF, may step to the fore and overtake the effect of the BRAF inhibition. This offers hope that third generation small molecules will address these resistant clones. The laboratory is currently examining small molecules that inhibit the RAS and other pathways to determine whether new strategies may overcome these resistance mechanisms, in melanoma at least.

Molecular testing methods detect the presence or absence of selected gene or protein mutations which theoretically correlate with single agent drug activity. Cells are never exposed to targeted agents. Just identifying molecular predisposing mechanisms still does not guarantee that a drug will be effective for an individual patient. Nor can it discriminate the potential for clinical activity among different agents of the same class. On can chase all the mutations they want, because if you miss just one, it may be the one that gets through.

I am underwhelmed by genomic analyses for drug selection. Trying to mate a notoriously heterogeneous disease into one-size-fits-all targeted treatments is disingenuous to all who are inflicted with it. The fact that normal genes can function abnormally under the control of small RNA sequences is just one more example of the genotype-phenotype dichotomy that cannot be adequately examined on static contemporary genomic platforms.

Although the theory behind targeted therapy is appealing, the reality is more complex. For example, cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

In other words, cancer cells have 'backup systems' that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to functionally target multiple pathways in a cancer cell.

Another challenge is to identify which of the targeted treatments will be effective (enzyme inhibitors, proteasome inhibitors, angiogenesis inhibitors, and monoclonal antibodies).

Targeted therapy is still trial-and-error treatment.

A conservative estimate of the number of targeted therapies tested in patients with cancer in the past decade is 700, yet no patients with solid tumors have been cured by targeted therapies over that time period, said Antonio Tito Fojo, PhD, head of the Experimental Therapeutics Section and senior investigator for Medical Oncology Branch Affiliates at the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland. Zero is the number of targeted therapies that have prolonged survival by one year, when compared to a conventional treatment. Finding what targeted therapies would work for what cancers is very difficult.

A lot of trial-and-error goes along trying to find out.

Besides being trial-and-error treatment, there is a disconnect between the costs of these targeted drugs and the magnitude of benefit they deliver. Dr. Fojo (at NCI) noted, at one of the symposiums, that a targeted drug could cost close to $100,000 per year to treat the "average" patient, yet it does not extend "overall survival" rate. Worse, the chance that the patient would experience a grade 3/4 toxicity can more than double. These targeted drugs are not the innocuous drugs that we are led to believe. To tell a patient that you're going to have a two-and-a-half-fold increase in toxicity and no benefit in terms of overall survival is really unacceptable. The only "benefit" was a prolonged progression-free survival of questionable value.

I'm not saying targeted drugs are not worthwhile pursuing, but it's time to change the efficacy and effectiveness curve by identifying therapies that deliver solid value. Just identifying molecular predisposing mechanisms still does not guarantee that a targeted drug will be effective for an individual patient. Nor can it, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class. Most cancers cannot be effectively treated with targeted drugs alone. The core understanding is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a targeted drug could perturb any of these pathways, it is important to examine the effects of drug combinations within the context of the cell. You still need to measure the net effect of all processes, not just the individual molecular targets.

Truly personalized care represents the application of validated predictive models to select candidates for specific therapies. Good outcomes can then be ascribed to the intelligent selection and application of effective treatments.

The cancer research community’s single-minded focus on genomic platforms, to the exclusion of functional platforms, forces patients to continue to participate in randomized trials to test hypotheses of interest to the investigators, largely at the expense of the patients in need. These types of advances could be more rapidly made utilizing functional profiles.

As one clinician has described it, what genomic investigators are expecting their patients to say to them is “You may not be able to treat me any better, but I like the way you think.” What informed patients should be saying instead is, “I don’t care how you think. I want you to treat me better!”

[url]http://cancerfocus.org/forum/showthread.php?t=3486

Driver Mutations and Passenger Mutations on the road to cancer

[url]http://cancerfocus.org/forum/showthread.php?t=278

by gdpawel on Thu, 2012-08-30 00:03
Combining the recently approved BRAF inhibitor, Zelboraf with an engineered T cell immunotherapy to treat metastatic melanoma significantly increased tumor responses and survival in an animal model, researchers at UCLA's Jonsson Comprehensive Cancer Center have shown.

The animals in the study that received the combination therapy had better tumor responses and lived more than twice as long as those getting the BRAF inhibitor or immunotherapy alone. The findings provide strong support for testing the combination therapy in human clinical trials, which Jonsson Cancer Center researchers hope to launch within two years.

About 50 percent of patients with metastatic melanoma, or 4,000 people a year, have the BRAF mutation and can be treated with Zelboraf. More than 50 percent of those respond well to the drug, but the responses usually last only a few months. With immunotherapy, fewer patients respond, but the responses are more durable.

By pairing the combination therapy in a one-two punch, researchers hope to maintain the high response rates associated with Zelboraf and combine them with the longer disease-free progression times seen with immunotherapy, said study first author Dr. Richard Koya, a Jonsson Cancer Center scientist and an assistant professor of surgical oncology.

"The idea was to target two different aspects of anti-cancer biology, hitting the tumor cells themselves with the BRAF inhibitor and adding in T cells educated to induce a specific anti-tumor immune response," Koya said. "The results we saw in this study were very promising."

The findings of the two-year study appear Aug. 15, 2012 in the peer-reviewed journal Cancer Research.

The researchers also found that the BRAF inhibitor helped boost the power of the immunotherapy, creating a greater combination effect, said study senior author Dr. Antoni Ribas, a Jonsson Cancer Center scientist and a professor of hematology/oncology.

"We found that both treatments were more effective when administered together, and we were surprised to see that a drug that should only be targeting the BRAF-mutant cancer cells was also having a beneficial effect on the T cells," Ribas said.

In the immunotherapy technique, called adoptive T cell transfer or ACT, lymphocytes are genetically engineered to express a receptor that recognizes melanoma cells, creating an army of immune cells that attack the cancer. The lymphocytes are modified genetically to become specific to the melanoma cells and are injected into the body.

The study was done using a model based on unique cell lines developed at UCLA. Previously, no implantable BRAF mutation-driven melanoma model able to grow progressively in a mouse with a fully competent immune system was available.

It is vital to develop new drugs to treat metastatic melanoma as few options are available for patients. Zelboraf works well, but most patients eventually relapse.

"This is a patient population that we are not able to cure," Koya said. "With what we have now we are just prolonging their lives. We need to have more options, and we hope this combination therapy proves to be an effective alternative."

About 70,000 new cases of melanoma are diagnosed each year in the United States. Of those, 8,000 people will die of the disease.

"In conclusion, combined therapy with the BRAF-specific inhibitor Zelboraf and T cell receptor engineered adoptive cell transfer resulted in superior anti-tumor effects," the study states. "Although the absolute number of T cells infiltrating the tumor was not increased by Zelboraf, the combination increased the functionality of antigen-specific T lymphocytes. Therefore, our studies support the clinical testing of combinations of BRAF targeted therapy and immunotherapy for patients with advanced melanoma."

The study was funded by the National Cancer Institute at the National Institutes of Health (P50 CA086306 and P01 CA 132681), Seaver Institute, Louise Belley and Richard Schnarr Fund, Wesley Coyle Memorial Fund, Garcia-Corsini Family Fund, Fred L. Hartley Family Foundation, Ruby Family Foundation, Jonsson Cancer Center Foundation, Caltech-UCLA Joint Center for Translational Medicine, UCLA Tumor Biology Program, U.S. Department of Health and Human Services, Ruth L. Kirschstein Institutional National Research Service Award, Eugene V. Cota-Robles Fellowship and National Science Foundation Competitive Edge Fellowship.

Reference: UCLA's Jonsson Comprehensive Cancer Center. "Combining BRAF Inhibitor And Immunotherapy Increases Antitumor Activity In Metastatic Melanoma." Medical News Today. MediLexicon, Intl., 17 Aug. 2012.

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