Navigation Links
Targeted investigational therapy potential to overcome crizotinib resistance in lung cancers

BOSTON PF-06463922, an investigational drug being developed by Pfizer Inc., has the potential to become a new treatment option for patients who have lung cancer harboring abnormalities in the ALK gene, according to preclinical results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.

About 3 to 5 percent of lung cancers harbor ALK gene abnormalities. The drug crizotinib (Xalkori), which blocks ALK protein kinase activity, was approved in August 2011 by the U.S. Food and Drug Administration for the treatment of patients who have these lung cancers. Although robust responses to crizotinib are observed for lung cancers harboring ALK gene abnormalities, the majority eventually become resistant to the effects of the drug. In many cases, resistance arises because of genetic mutations in ALK.

"Resistance to targeted therapies such as crizotinib is a major challenge when treating patients with cancer," said Tod Smeal, Ph.D., associate research fellow in the Oncology Research Unit at Pfizer Inc. in San Diego, Calif. "Our goal is to take advantage of everything we have learned about designing drugs that target kinases like ALK and the ways in which lung cancers become resistant to crizotinib to develop the best next-generation ALK inhibitor we can.

"Our preclinical studies suggest that we are making progress toward achieving our goal: PF-06463922 has potent ALK-inhibiting activity, it is capable of inhibiting all the crizotinib-resistant ALK mutants so far detected in patients, and it can efficiently access the brain. We are excited about these preclinical results and very hopeful that they will translate into meaningful responses in the clinic."

After carefully designing PF-06463922, Smeal and colleagues first showed in cell assays that it potently inhibited the activity of ALK and all eight of the mutant forms of ALK known to cause resistance to crizotinib in patients with lung cancer. They then showed that PF-06463922 inhibited the growth of tumors harboring three of the crizotinib-resistant ALK mutants, including the most resistant ALK mutant, G1202R, in mice.

Further analysis indicated that PF-06463922 readily entered the brains of mice, rats, and dogs. In mice, levels of PF-06463922 in the brain were 20-30 percent of levels of PF-06463922 in the blood. This is potentially clinically relevant because a significant number of lung cancer patients will develop brain metastasis during the course of their disease, according to Smeal, although he noted that it will be important to see if these results in animals hold true in humans.

Smeal and colleagues also found that PF-06463922 potently inhibited the protein ROS1, a close relative of ALK recently implicated in a number of cancer types, including some lung and brain cancers. Further, PF-06463922 had antitumor effects in two mouse models of cancers driven by ROS1 gene abnormalities, leading the researchers to suggest that PF-06463922 has potential as a treatment for this subgroup of cancers, in addition to its promise as a new treatment for ALK-driven cancers.


Contact: Lauren Riley
American Association for Cancer Research

Related medicine news :

1. Targeted therapeutics for colon cancer to be presented at AACR meeting
2. First targeted nanomedicine to enter human clinical studies
3. Highly targeted irradiation as good as whole breast radiotherapy in early stage cancer
4. Dana-Farber: Study reports first success of targeted therapy in type of non-small cell lung cancer
5. Inflammatory pathway spurs cancer stem cells to resist HER2-targeted breast cancer treatment
6. Killer infections targeted by hospital study
7. Lower risk of serious side-effects in trials of new targeted drugs
8. Treating drug resistant cancer through targeted inhibition of sphingosine kinase
9. Pitt: Targeted oxidation-blocker prevents secondary damage after traumatic brain injury
10. Deadly witch hunts targeted by grassroots womens groups
11. Large lung cancer study shows potential for more targeted therapies
Post Your Comments:
(Date:11/27/2015)... , ... November 27, 2015 , ... ... largest, most successful and prominent nonprofit healthcare organizations in the country. They have ... with various organizations, and helped advance the healthcare industry as a whole through ...
(Date:11/27/2015)... ... November 27, 2015 , ... Indosoft Inc., developer and ... of Asterisk 11 LTS (Long Term Support) into its Q-Suite 5.10 product line. ... 5.10 up-to-date with a version of Asterisk that will receive not only security ...
(Date:11/26/2015)... ... November 26, 2015 , ... CognisantMD and Cambridge Memorial ... in the Waterloo region. Using the Ocean Platform, family physicians can now order ... electronic medical record (EMR) without the need for redundant patient entry or an ...
(Date:11/26/2015)... ... ... Jobs in hospital medical laboratories and in the imaging field lead the ... Aureus Medical Group . These fields, as well as travel nursing, ranked ... jobs through the company’s website, , The leading healthcare staffing agency ...
(Date:11/26/2015)... Viejo, CA (PRWEB) , ... November 26, 2015 ... ... users a new set of retro-fused, self-animating trailer titles with ProTrailer: Vintage. This ... style options. These classically-influenced trailer titles work with any font, giving users limitless ...
Breaking Medicine News(10 mins):
(Date:11/25/2015)... Nov. 25, 2015 AAIPharma Services Corp./Cambridge ... of at least $15.8  Million to expand its ... NC . The expansion will provide additional ... the growing demands of the pharmaceutical and biotechnology ... expansion will provide up to 40,000 square feet ...
(Date:11/25/2015)... -- ARKRAY USA , Inc., a leader ... the accuracy of its blood glucose meter systems. Last ... and Cardiovascular Disease in Los Angeles ... 01 meter and the Assure ® Prism ... accurately measure glucose levels in blood is essential for ...
(Date:11/25/2015)... 2015 Kitov Pharma ceuticals ... a biopharmaceutical company focused on the development of therapeutic ... today announced the closing of its previously announced underwritten ... ), each representing 20 ordinary shares of the Company, ... ADSs and warrants were issued in a fixed combination ...
Breaking Medicine Technology: