Target set on cancer gene MCL1
A research team pursuing one of the most commonly altered genes in cancer has laid a critical foundation for understanding this gene that could point the way toward developing drugs against it. A recent study of cancer genetics pointed to the gene MCL1, which encodes a protein that helps keep cells alive. The new research pinpoints compounds that repress MCL1's activity and highlights an important companion gene that predicts if a tumor is dependent upon MCL1 for survival. Together, these tools suggest a path toward new therapeutics directed at MCL1.
"It was not immediately obvious that MCL1 was such an attractive therapeutic target in cancer," said Todd Golub, director of the Broad's Cancer Program and Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute. Golub is also a professor at Harvard Medical School and investigator at Howard Hughes Medical Institute. "But once it became clear that MCL1 was something that we wanted to turn off in tumor cells, we faced two additional problems: we didn't know which tumors depend on it for survival and there wasn't an obvious path to drug discovery. This paper addresses those two challenges."
In a paper appearing in the April issue of the journal Cancer Cell, Golub and colleagues from the Broad Institute and Dana-Farber identify several chemical compounds that tamp down the expression of the MCL1 gene and describe the relationship between MCL1 and a related pro-survival gene, BCL-xL. The research team leveraged several critical Broad Institute resources, including the recently published Cancer Cell Line Encyclopedia (CCLE) and RNAi screening capabilities, to better understand how to target MCL1.
MCL1 is frequently amplified in human cancer, meaning that multiple copies of the gene are often present in tumors. The research team suppressed MCL1 in cancer cell lines, allowing them to determine which ones depended on MCL1 for survival. The researchers then looked for a genetic signature that accurately predicted which cell lines were dependent on MCL1 for survival. The gene BCL-xL, another gene protective against cell death, was clearly the best predictor. In its presence, cancer cells can survive even when MCL1 is turned off.
"That was gratifying not only because BCL-xL was a clear winner as a predictive marker, but also because it encodes a protein in the same pathway as MCL1," said Guo Wei, the paper's first author. Wei is a research scientist at the Broad Institute and a research fellow in pediatrics at Dana-Farber. "It's not just right statistically it also makes sense given the biology."
Drugs targeting BCL-xL are currently in clinical trials. The new study predicts that in cancer cells where both genes are highly expressed, combination therapies targeting both genes could be effective in treating the tumor.
The researchers also tested almost 3,000 chemical compounds, searching for ones that turned off the expression of MCL1. One of the compounds that this screen revealed was the natural compound triptolide. To find out how triptolide has its effect, the researchers turned to another Broad-created resource: the Connectivity Map, a database researchers can use to connect drugs, genes, and diseases.
"Based on the Connectivity Map, triptolide appears to be a classical inhibitor of transcription, meaning that it should tamp down the expression of all genes," said Wei. "However, it disproportionately affects MCL1. If you give a dose of transcriptional inhibitor, most gene transcripts decrease at a gentle rate, but MCL1 levels decline sharply."
Transcriptional inhibitors like triptolide may be useful tools for probing MCL1 biology, but Golub emphasizes that specific, targeted therapies for MCL1 are also needed. "We used clever chemical genomic approaches to find a way to inhibit MCL1, but the results further our resolve to find more specific MCL1 small molecule inhibitors," Golub, senior author of the study, said.
"The work suggests a path for the clinical development of an MCL1 inhibitor," said Wei. "A number of anti-cancer drugs currently in use have the effect of turning off MCL1 expression. Our study suggests that we're beginning to get a handle on which tumor types might be most responsive to these drugs. And, as newer MCL1-specific drugs are developed, this study suggests the patient population to focus on in clinical trials."
Provided by Massachusetts Institute of Technology
- Knocking Out Survival Protein Could Aid Leukemia Treatment Apr 23, 2007 | not rated yet | 0
- PBS-Bio uncovers how Unibioscreen drug kills cancer Mar 09, 2011 | not rated yet | 0
- Novel RNA interference screening technique identifies possible path for malignant glioma treatment May 25, 2010 | not rated yet | 0
- First volume of the Cancer Cell Line Encyclopedia made public Mar 28, 2012 | not rated yet | 0
- New use for a cell toxin found to inhibit survival proteins in cancer cells Jul 11, 2007 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
Marie Curie's leukemia
May 13, 2013 Does anyone know what might be the cause of Marie Curie's cancer
- More from Physics Forums - Medical Sciences
More news stories
The use of a smartphone application significantly improves patients' preparation for a colonoscopy, according to new research presented today at Digestive Disease Week (DDW). The preparation process, which begins days in ...
Cancer 14 hours ago | not rated yet | 0
Research presented at Digestive Disease Week (DDW) explores new methods for managing digestive health through diet and lifestyle.
Cancer 14 hours ago | not rated yet | 1
A ground-breaking advance in colonoscopy technology signals the future of colorectal care, according to research presented today at Digestive Disease Week(DDW). Additional research focuses on optimizing the minimal withdrawal ...
Cancer May 18, 2013 | 5 / 5 (2) | 0
(HealthDay)—Concurrent use of two immune checkpoint antibodies—ipilimumab and nivolumab—may be effective for the treatment of advanced melanoma, according to a proof-of-principal study presented in ...
Cancer May 17, 2013 | not rated yet | 0
(HealthDay)—The risks of metastasis and death associated with cutaneous squamous cell carcinoma (CSCC) are low, but significant, and risk factors for poor outcome include tumor diameter, invasion beyond ...
Cancer May 17, 2013 | not rated yet | 0 |
Researchers at the University of Wisconsin have identified a potential new risk factor for obstructive sleep apnea: asthma. Using data from the National Institutes of Health (Heart, Lung, and Blood Institute)-funded Wisconsin ...
2 hours ago | not rated yet | 0 |
A new study looking at sleep-disordered breathing (SDB) and markers for Alzheimer's disease (AD) risk in cerebrospinal fluid (CSF) and neuroimaging adds to the growing body of research linking the two.
2 hours ago | not rated yet | 0 |
In their quest to learn more about the variability of cells between and within tissues, biomedical scientists have devised tools capable of simultaneously measuring dozens of characteristics of individual ...
3 hours ago | 5 / 5 (1) | 0 |
Scientists at Johns Hopkins have turned their view of osteoarthritis (OA) inside out. Literally. Instead of seeing the painful degenerative disease as a problem primarily of the cartilage that cushions joints, ...
3 hours ago | 5 / 5 (1) | 0 |
The hunt for an HIV vaccine has gobbled up $8 billion in the past decade, and the failure of the most recent efficacy trial has delivered yet another setback to 26 years of efforts.
6 hours ago | not rated yet | 0
Gourmands and foodies everywhere have long recognized ginger as a great way to add a little peppery zing to both sweet and savory dishes; now, a study from researchers at Columbia University shows purified components of the ...
2 hours ago | not rated yet | 0