Ganetespib showed activity in KRAS-mutant NSCLC as monotherapy and in combinations

January 11, 2012

The investigational drug ganetespib, a synthetic second-generation Hsp90 inhibitor, slowed the growth of cancer cells taken from non-small cell lung cancer tumors with a mutation in the KRAS gene. The drug was even more active when combined with traditional lung cancer treatments and other investigational targeted therapies, according to preclinical study data.

David A. Proia, Ph.D., and Jaime Acquaviva, Ph.D., scientists at Synta Pharmaceuticals Corp., presented the data at the AACR-IASLC Joint Conference on of Lung Cancer: Biology, Therapy and Personalized Medicine, held Jan. 8-11, 2012.

Currently, patients with non-small cell lung cancer () with KRAS mutations have no effective treatment strategy. A phase 2 trial showed in more than 60 percent of patients with KRAS-mutant NSCLC at eight weeks after treatment with ganetespib administered once weekly as a monotherapy, indicating the drug's potential effectiveness, according to Proia.

He and his colleagues examined whether ganetespib was effective against several different cell lines of KRAS-mutant NSCLC and confirmed it was effective in 15 different cell lines. They then sought to determine which would enhance the activity of ganetespib in this .

First, the researchers combined ganetespib with several standard-of-care chemotherapies currently available in the clinic for KRAS-mutant NSCLC tumor samples. They found that the combination of ganetespib with , antimitotics and topoisomerase inhibitors resulted in an increased cell death of 1.4-, 1.5- and 2.6-fold, respectively, compared with ganetespib alone.

"We saw great activity with, for example, docetaxel and [ganetespib]," Proia said. "What we are doing now is conducting a large phase 2b/phase 3 trial with docetaxel and [ganetespib] in NSCLC patients. Activity in the KRAS-mutant subpopulation is a coprimary endpoint in this trial."

The researchers also tested ganetespib in combination with two therapies that target pathways known to be involved in NSCLC: a MEK inhibitor or a PI3K/mTOR inhibitor. Results in tumor samples revealed that combining ganetespib with either therapy was also more active in slowing tumor growth compared with ganetespib alone.

"Not only was ganetespib activity enhanced in combination with traditional chemotherapies, which may be understood in terms of the ability of Hsp90 inhibition to block certain resistance or repair mechanisms, but activity was also enhanced in combination with a number of targeted therapies for which recent work has shown very interesting complementary inhibition of signaling pathways," Proia said.

Finally, the researchers further validated their results by combining ganetespib with the PI3K/mTOR inhibitor in mice with KRAS-mutant NSCLC. Both drugs alone promoted tumor shrinkage, but the combination resulted in a greater inhibition of tumor growth.

If further validated, this research could open up avenues for future treatment options for patients with KRAS-mutant NSCLC.

Explore further: Antifolates show promise against NSCLC subtype

Related Stories

Antifolates show promise against NSCLC subtype

November 14, 2011
Patients with non-small cell lung cancer who have mutations in the KRAS gene should respond well to the antifolate class of drugs, according to results of a recent study conducted by Quintiles comparing human lung cancer ...

Combination therapies for drug-resistant cancers

October 10, 2011
Some cancers can be effectively treated with drugs inhibiting proteins known as receptor tyrosine kinases, but not those cancers caused by mutations in the KRAS gene. A team of researchers led by Jeffrey Engelman, at Massachusetts ...

Sorafenib effective in patients with non-small cell lung cancer, but low survival rates reported

January 10, 2012
Sorafenib was effective in patients with non-small cell lung cancer and a KRAS mutation, but survival rates were reportedly "unsatisfactory," according to data presented at the AACR-IASLC Joint Conference on Molecular Origins ...

Novel drug combination offers therapeutic promise for hard-to-treat cancers

September 12, 2011
Researchers at Brigham and Women's Hospital (BWH) have identified a new combination of targeted therapies that, together, may treat two aggressive tumor types that until now have not had effective treatments. These findings ...

Lung cancer ALK rearrangement may predict pemetrexed efficacy, study shows

September 1, 2011
Patients with ALK-rearranged non-small cell lung cancer (NSCLC) responded significantly better to pemetrexed (brand name: Alimta) than patients whose cancer did not show ALK translocation, according to research published ...

Recommended for you

Study may explain failure of retinoic acid trials against breast cancer

July 25, 2017
Estrogen-positive breast cancers are often treated with anti-estrogen therapies. But about half of these cancers contain a subpopulation of cells marked by the protein cytokeratin 5 (CK5), which resists treatment—and breast ...

Physical activity could combat fatigue, cognitive decline in cancer survivors

July 25, 2017
A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk.

Breaking the genetic resistance of lung cancer and melanoma

July 25, 2017
Researchers from Monash University and the Memorial Sloan Kettering Cancer Center (MSKCC, New York) have discovered why some cancers – particularly lung cancer and melanoma – are able to quickly develop deadly resistance ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.