Corporate Banner
Satellite Banner
Scientific Communities
Become a Member | Sign in
Home>News>This Article

Predicting Cancer’s Next Move

Published: Monday, November 11, 2013
Last Updated: Monday, November 11, 2013
Bookmark and Share
Research offers a new approach to studying drug resistance in cancer.

The approach helped them identify which biological pathways could be enabling melanoma to circumvent available anti-cancer treatments. Targeting the output of these pathways for treatment could potentially hinder the course of this often-fatal disease.

The researchers initiated the study to address a vexing clinical problem: on the rare occasions that drug treatments are found that effectively inhibit tumor growth, that success is often short-lived. As resistance mechanisms emerge, the therapies cease being effective and the tumors return.

Such is the case in melanoma. Roughly 50% of these cancers have been traced to a mutation in BRAF, a gene responsible for directing cell growth. Only a few years ago, drugs were developed that disrupt parts of the biological pathway that leads the mutation to spur unchecked growth in skin cells. Patients who have received the treatment have seen their tumors disappear – only to return an average of nine months later. Garraway's team, which includes researchers from the Broad Institute and Dana-Farber Cancer Institute, wanted to find out in a comprehensive fashion what mechanisms might be involved in the development of drug resistance in these cases.

To find out, the team systematically mimicked gene activation by expressing over 15,000 genes to test their role in drug resistance. (For scale, the human genome contains approximately 20,000 genes.) This large-scale screen was conducted using the Open Reading Frame (ORF) gene expression library developed by the Broad's RNAi Platform and Dana-Farber’s Center for Cancer Systems Biology. ORFs are pieces of genetic material that researchers can use to "turn on" specific genes in order to investigate their function.

The team used the ORF library to activate each of the 15,000 genes individually in a cell line generated from a BRAF mutant melanoma tumor. The cells were then treated with drugs commonly used to combat this form of cancer, and the results were confirmed in seven additional BRAF mutant melanoma cell lines.

"Each time we expressed a gene, we asked, 'Does this change the sensitivity of this cell line to these drugs?” explained Cory Johannessen, a postdoctoral researcher in Garraway’s lab and the paper’s first author. “Observing each response gave us a picture of what the landscape of resistance mechanisms looked like for this particular type of melanoma."

This systematic approach turned up a comprehensive list of mechanisms that could possibly play a role in the development of drug resistance. The team then looked for patterns in their data and found that they could, in fact, identify commonalities – entire signaling pathways or networks – from the functional information derived from their approach.

One of the team’s most promising findings was also one of the most surprising: a central pathway contributing to drug resistance in BRAF mutant melanoma is one that oversees an aspect of normal skin development.

"It turns out that the pathway that's causing the resistance isn't random,” Johannessen said. “It's a pathway that is essential to skin cell biology; it's critical to the development of those cells and their sustained growth."

One critical component of normal skin is a type of cell known as melanocytes; these cells create skin pigment and protect the body from damage from the sun’s UV rays. In contrast to the normal course of melanocyte development, the melanocyte development pathway is turned off in BRAF mutant melanoma, and a pathway triggered by the BRAF mutation takes over. Instead of producing normal melanocytes, the BRAF mutation causes a chain of events that leads to the activation of a group of proteins (known as “transcription factors”) that tell cells to reproduce uncontrollably, forming cancerous tumors.

Current treatments for BRAF mutant melanoma target the chain of events that lead to the activation of these transcription factors, not the transcription factors, themselves – and that approach is successful for a time. The drugs disrupt the cancerous pathway, presenting an opportunity for the normal melanocyte development pathway to be turned back on. However, as the team discovered, if the melanocyte pathway is turned back on, it activates the same cancer-causing transcription factors previously controlled by the BRAF mutation. Once those transcription factors are activated, melanoma returns.

Johannessen said that they don’t yet know why these formerly healthy melanocyte pathways start producing the aberrant transcription factors. Nevertheless, knowing that the transcription factors are involved in drug resistance provides a new target for therapeutics.

While transcription factors have traditionally been viewed as “impossible” to target, the team suspected that they could hit them indirectly using chromatin-based therapeutics that are currently in clinical trials. These therapeutics target gene-regulating proteins in chromatin, which is one part of the cellular machinery that controls gene expression. In turn, these proteins modify the expression of a large number of other proteins in the cell.

When Garraway’s team tested a number of these chromatin-based therapeutics in cancer cells together with traditional BRAF mutant melanoma drugs, the combination did appear to head off drug resistance and reduced the expression of the transcription factors that had been driving resistance. The treatment has yet to be tested clinically, but if its inhibitory effects bear out, the therapy could potentially be used not only to treat BRAF mutant melanoma, but other forms of melanoma that involve the same transcription factors as well.

Garraway, who is also an associate professor of medicine in the Department of Medical Oncology at the Dana-Farber Cancer Institute and at Harvard Medical School, said that the systematic approach his team used to probe the mechanisms underlying drug resistance in BRAF mutant melanoma can be applied to other forms of cancer, and is already being leveraged in other cancer types. The approach is not only comprehensive, but also relatively cost-effective. It is also not reliant on large quantities of cancer tumor samples, the collection of which can be a burden on patients.

"This method enables us to track drug resistance much more systematically,” he said. “If we can identify and understand the mechanisms underlying drug resistance, we are in a better position to identify clinically relevant resistance mechanisms. We are hopeful that this information will help us design new therapies and drug combinations that lead to more durable control of melanoma and eventually many other types of cancer.”

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More Than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Screen of Human Genome Reveals Set of Genes Essential for Cellular Viability
Using two complementary analytical approaches, scientists at Whitehead Institute and Broad Institute of MIT and Harvard have for the first time identified the universe of genes in the human genome essential for the survival and proliferation of human cell lines or cultured human cells.
Monday, October 19, 2015
DARPA Awards $32 Million Contract to MIT, Broad Institute Foundry
A facility at the Broad Institute of MIT and Harvard and MIT that aims to achieve the full potential of engineering biology has received a five-year, $32 million contract from the Defense Advanced Research Projects Agency (DARPA).
Monday, September 28, 2015
Diagnostics Breakthrough Brings Viral Sequencing to Doctors’ Toolkit
New screening tool produces up to 10,000-fold improvement in viral matches compared with traditional high-throughput methods.
Monday, September 28, 2015
Scientists Discover New System For Human Genome Editing
CRISPR-Cpf1 system could disrupt both scientific and commercial landscape.
Monday, September 28, 2015
Researchers Develop a New Means of Killing Harmful Bacteria
Engineered particles are capable of producing toxins that are deadly to targeted bacteria.
Friday, June 26, 2015
Broad Institute & Google Genomics Combine Bioinformatics and Computing Expertise
Both companies explore how to break down major technical barriers that increasingly hinder biomedical research.
Thursday, June 25, 2015
CRISP-Disp Leverages CRISPR-Cas9 to Deliver RNA Structures to Targets in the Genome
A team of researchers from the Broad Institute and the Harvard Stem Cell Institute has developed CRISP-Disp, a method that expands on the CRISPR-Cas9 system, allowing researchers to display multiple, large RNA structures on the Cas9 protein.
Wednesday, June 10, 2015
GTEx: Useful Expression For Cancer Research
GTEx Project has recently published several papers reporting on findings from its two-year pilot phase.
Tuesday, May 26, 2015
Single-cell Analysis Hits its Stride
Advances in technology and computational analysis enable scale and affordability, paving the way for translational studies.
Saturday, May 23, 2015
Highly Efficient New Cas9 for In Vivo Genome Editing
New finding is expected to expand therapeutic and experimental applications of CRISPR.
Tuesday, April 07, 2015
Broad Institute of MIT and Harvard and Bayer Healthcare Expand their Partnership
Collaboration to develop therapies for cardiovascular disease.
Thursday, April 02, 2015
In vivo CRISPR-Cas9 Screen Sheds Light On Cancer Metastasis And Tumor Evolution
Genome-scale study points to drivers of tumor evolution and metastasis, provides roadmap for future in vivo Cas9 screens.
Friday, March 06, 2015
Scientists Map the Human Loop-ome, Revealing a New Form of Genetic Regulation
Researchers describe the results of a five-year effort to map, in unprecedented detail, how the 2-meter long human genome folds inside the nucleus of a cell.
Tuesday, December 23, 2014
Disorder in Gene-Control System is a Defining Characteristic of Cancer, Study Finds
Findings indicate that the disarray in the on-off mechanism is one of the defining characteristics of cancer.
Tuesday, December 23, 2014
Two Studies Identify A Detectable, Pre-Cancerous State In The Blood
Findings pave way for new lines of cancer research focused on detection and prevention.
Thursday, November 27, 2014
Scientific News
High Throughput Mass Spectrometry-Based Screening Assay Trends
Dr John Comley provides an insight into HT MS-based screening with a focus on future user requirements and preferences.
How a Genetic Locus Protects Adult Blood-Forming Stem Cells
Mammalian imprinted Gtl2 protects adult hematopoietic stem cells by restricting metabolic activity in the cells' mitochondria.
Genetic Basis of Fatal Flu Side Effect Discovered
A group of people with fatal H1N1 flu died after their viral infections triggered a deadly hyperinflammatory disorder in susceptible individuals with gene mutations linked to the overactive immune response, according to a recent study.
New Tech Vastly Improves CRISPR/Cas9 Accuracy
A new CRISPR/Cas9 technology developed by scientists at UMass Medical School is precise enough to surgically edit DNA at nearly any genomic location, while avoiding potentially harmful off-target changes typically seen in standard CRISPR gene editing techniques.
The MaxSignal Colistin ELISA Test Kit from Bioo Scientific
Kit can help prevent the antibiotic apocalypse by keeping last resort drugs out of the food supply.
"Good" Mozzie Virus Might Hold Key to Fighting Human Disease
Australian scientists have discovered a new virus carried by one of the country’s most common pest mosquitoes.
Non-Disease Proteins Kill Brain Cells
Scientists at the forefront of cutting-edge research into neurodegenerative diseases such as Alzheimer’s and Parkinson’s have shown that the mere presence of protein aggregates may be as important as their form and identity in inducing cell death in brain tissue.
Closing the Loop on an HIV Escape Mechanism
Research team finds that protein motions regulate virus infectivity.
New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Potential Treatment for Life-Threatening Viral Infections Revealed
The findings point to new therapies for Dengue, West Nile and Ebola.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos