Navigation Links
Target set on cancer gene MCL1
Date:4/16/2012

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."


'/>"/>

Contact: Haley Bridger
hbridger@broadinstitute.org
617-714-7968
Broad Institute of MIT and Harvard
Source:Eurekalert

Related medicine news :

1. Marker of Ewing sarcoma: Potential new drug target?
2. Dana-Farber and Sanford-Burnham Institute license flu-targeting antibodies to Genentech and Roche
3. New therapeutic target for most common solid cancer in childhood?
4. Fans Spread the Love on Target Facebook Page and Help Donate $1 Million to Five Charities
5. New Multivitamins Target Concern Over China's Quality Problems
6. Targeted delivery of losartan reduces liver inflammation and scarring
7. New Study: Improved Immune System with Gene-Eden, a Natural Antiviral Supplement that Targets Chronic Viruses
8. TV Ads Target House Members Who Voted for Obamacare
9. Targeting leukemia cells gene addiction presents new strategy for treatment
10. Hot Pepper Itch Remedy Targets Kidney Disease Patients Suffering From Chronic Pruritus
11. Americans for Responsible Health Care Launch Radio Ads Targeting Seven Democrats, Warning The People Are Watching...
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/29/2016)... ... April 29, 2016 , ... ... Accreditation Council for Graduate Medical Education (ACGME) that it has received accreditation for ... first accreditation of three residency programs that Memorial is currently pursuing, including Pediatrics ...
(Date:4/29/2016)... ... April 29, 2016 , ... Our bodies are bombarded daily by environmental and ... with these stressors is to adopt a more healthful diet, but too many people ... a certified Holistic Nutritionist and the creator of the Newport Beach Cleanse and 14-Day ...
(Date:4/29/2016)... ... April 29, 2016 , ... The American workforce ... stability, even security. Most importantly, employees are the single most important asset in ... workers so unhappy? , Just under half of American workers are emotionally checked ...
(Date:4/29/2016)... ... April 29, 2016 , ... The White House announced efforts ... more information about their loan terms and accounts, and more protections for borrowers. ... federal and private loans, has reached $1.3 trillion, with 43 million Americans holding ...
(Date:4/29/2016)... ... April 29, 2016 , ... Coast Dental Fort Stewart is celebrating its grand ... in the Exchange Furniture Mall at 112 Vilseck Road in Fort Stewart. There will ... Plus attendees will have the opportunity to meet general dentists Thomas Richards, DDS, and ...
Breaking Medicine News(10 mins):
(Date:4/27/2016)... 2016  Hologic, Inc. (Nasdaq: HOLX ... the fiscal second quarter ended March 26, 2016.  ... increased 41.2%, and non-GAAP diluted EPS of $0.47 ... on a reported basis, and 6.3% on a ... another good quarter, highlighted by 14.6% growth in ...
(Date:4/27/2016)... , April 27, 2016   ... 42% Growth in Recurring Consumable Sales  Clinical ... Mauna Kea Technologies (Euronext: MKEA, OTCQX: MKEAY) inventor of ... its sales for the first quarter ended March 31, ... the execution of its commercial strategy. First ...
(Date:4/27/2016)... 2016   Zillion Group today announced ... platform, which specializes in live video consultation. Turning ... products, Zillion enables companies to realize the true ... take control of their health. ... including one-to-one, group and webcast scheduled or on-demand ...
Breaking Medicine Technology: