Navigation Links
Blocking molecular target could make more cancers treatable with PARP inhibitors
Date:6/29/2011

BOSTON--Researchers at Dana-Farber Cancer Institute have demonstrated a molecular strategy they say could make a much larger variety of tumors treatable with PARP inhibitors, a promising new class of cancer drugs.

Currently, the role of PARP inhibitors has mainly been restricted to cancers whose cells lack functioning versions of the damage-repair proteins BRCA1 or BRCA2 -- chiefly certain breast and ovarian cancers.

In a paper published online by Nature Medicine, Geoffrey Shapiro, MD, and colleagues report that the BRCA1 repair protein is dependent on another protein, CDK1, known primarily as a regulator of the cell division cycle. When the scientists blocked CDK1 in cancer cell lines and in a mouse model of lung cancer, BRCA1 function was disrupted, making them susceptible to being killed by a PARP inhibitor.

Because most types of tumors don't have a mutated BRCA1 protein, they are less likely to be affected by PARP inhibitor treatment. The new findings, said Shapiro, "suggest that by blocking CDK1, we can disable BRCA1 in many types of cancers and make them sensitive to a PARP inhibitor. It could extend the use of these drugs to a much larger group of patients."

Shapiro, who heads Dana-Farber's Early Drug Development Center, said a clinical trial combining a CDK1 blocker and a PARP inhibitor in a variety of solid tumors is being planned.

Cells are equipped to heal damage to their DNA strands, which are constantly being nicked or broken by exposure to environmental contaminants or randomly during cell division. Cancer cells, in addition, become adept at repairing potentially lethal DNA damage caused by radiation and chemotherapy drugs, and use their DNA repair machinery to survive and grow uncontrollably.

A major thrust in cancer research currently is developing ways to disable tumor cells' repair toolkits to make them more vulnerable to DNA-damaging agents. PARP inhibitor drugs prevent tumor cells from repairing less-serious damage to the DNA strands of cancer cells; if those cells happen to lack a normal BRCA protein, the damage becomes more serious and the cells can't repair it, and then the cells die.

Most types of cancer cells, however, have normal BRCA proteins, making PARP inhibitors less effective. The Dana-Farber scientists sought a way to get around this and convert "BRCA-competent" tumor cells to "BRCA-less" cells that would be sensitive to anti-PARP drugs. Their studies revealed that BRCA1 molecules depend on the cell-cycle protein CDK1 to activate them.

CDK1 was previously identified as a regulator of the cell division cycle that can be overactive in many types of cancers, leading to unchecked growth. Currently several CDK1 inhibitors are in clinical trials as potential weapons against cancer. Shapiro and his colleagues implicated CDK1 for the first time as a control point in the DNA repair circuit that contains BRCA1. This suggested that blocking CDK1 activity might prevent BRCA1 from rescuing cancer cells from life-threatening DNA damage.

In a study involving lung cancer cells in the laboratory and implanted in mice, the researchers "found that if we deplete cancer cells of CDK1, we disrupt DNA repair and the cells become very sensitive to PARP inhibitors," said Shapiro, the senior author of the report. The researchers obtained their results using an existing CDK1- blocking drug along with a PARP inhibitor.

As a more stringent test, they tried the same strategy in mice genetically engineered with an oncogene, KRAS, that drives the most aggressive lung cancers in humans.

"We achieved tremendous responses in this mouse model," Shapiro said. "The survival curve of the animals nearly doubled."

In addition, he said, his team collaborated with pathologists at Brigham and Women's Hospital to show that the CDK1-PARP inhibiting strategy is selective for cancer cells -- normal cells were unaffected. Accordingly, Shapiro said, they did not observe significant toxicity from the drug treatment.

"We're quite excited about this and looking forward to evaluating this combination in clinical trials," said Shapiro.


'/>"/>

Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
Source:Eurekalert  

Related medicine news :

1. New study finds compounds show promise in blocking STAT3 signaling as treatment for osteosarcoma
2. UIC researcher unveils new approach to blocking malaria transmission
3. Adiponectin shows potential in blocking obesity-related carcinogenesis
4. Blocking an oncogene in liver cancer could be potential therapy option
5. Can blocking a frown keep bad feelings at bay?
6. Blocking DNA repair protein could lead to targeted, safer cancer therapy
7. Blocking Protein May Stem COPD
8. Notch-blocking drugs kill brain cancer stem cells, yet multiple therapies may be needed
9. Scientists discover new molecular pathway involved in wound-healing and temperature sensation
10. Molecular glue sticks it to cancer
11. Molecular movements could lead to new way to treat cancer
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Blocking molecular target could make more cancers treatable with PARP inhibitors
(Date:2/8/2016)... ... ... Coast Dental has a new way to help parents keep their children's ... Yvonne Dorrian, DMD, is hosting a free seminar on Friday, February 19 from 2 ... 1207 North Peachtree Parkway in Peachtree City. Dr. Dorrian will have healthy snacks, activities, ...
(Date:2/8/2016)... York, NY (PRWEB) , ... February 08, 2016 , ... ... are too much to handle, you are not alone. According to the Center for ... include heart disease, stroke, type 2 diabetes and certain types of cancer, some of ...
(Date:2/8/2016)... San Francisco, CA (PRWEB) , ... February 08, 2016 , ... ... helped raise $792,000 to help combat pancreatic cancer. , Gary D. Radine, who recently ... who also was the American Cancer Society’s 2015 CEO of the Year , ...
(Date:2/8/2016)... ... February 08, 2016 , ... Discover the Rocky Mountain region’s longest ... and 700 companies. Attendees also get to see the most incredible gardens and ... Home Show , at the Colorado Convention Center - 700 14th St. Denver CO, ...
(Date:2/8/2016)... , ... February 08, 2016 , ... Guruji Mahendra Kumar ... 10th and 11th, 2016 in honor of his birthday on February 10th. During ... Mahendra Trivedi is known by over 250,000 people from over 40 different countries ...
Breaking Medicine News(10 mins):
(Date:2/8/2016)...  The University of Michigan Health System in ... part of the development of four new operating rooms, ... the U.S. to start using new top-of-the-line neurosurgical imaging ... of neurosurgery. --> Karin Muraszko , ... The BrightMatter technology from Synaptive Medical – a highly ...
(Date:2/8/2016)... 2016  Aoxing Pharmaceutical Company, Inc. (NYSE MKT: AXN) today ... ended December 31, 2015, the Company achieved revenue of $8,195,839, ... same quarter in fiscal 2015. --> ... fiscal year 2016 was $2,068,635, or $.03 per share, up ... share, in the Q2 of fiscal year 2015. Gross margin ...
(Date:2/8/2016)... , Feb. 8, 2016 ... the addition of the "Label-Free Detection ... Forecasts to 2020" report to their ... announced the addition of the "Label-Free ... Global Forecasts to 2020" report to ...
Breaking Medicine Technology: