Navigation Links
Research yields new agent for some drug-resistant non-small cell lung cancers
Date:12/23/2009

BOSTON--The ability to make, test, and map the atomic structure of new anti-cancer agents has enabled a team of Dana-Farber Cancer Institute scientists to discover a compound capable of halting a common type of drug-resistant lung cancer.

In a study to be published in the December 24/31 issue of the journal Nature, the researchers report that non-small cell lung cancers that had become invulnerable to the drugs Iressa and Tarceva were stymied by a compound designed and formulated in a Dana-Farber lab. The compound, whose basic chemical framework is different from that of other cancer drugs, acts against a protein known as an epidermal growth factor receptor (EGFR) kinase that carries a specific structural defect.

"This type of drug discovery, in which an agent is developed for a specific gene or protein target, and then screened against cancer cells as well as in laboratory models, is rare in academic medicine," says the study's senior author Pasi A. Jnne, MD,PhD, of Dana-Farber and Brigham and Women's Hospital (BWH). "This requires contributions from researchers in multiple disciplines and a coordinated approach to planning experiments and sharing results. That we accomplished this is evidence of the contribution academic medical centers can make to the quest for new cancer treatments."

The study also illustrates how rapidly lung cancer research and treatment are advancing. It was less than five years ago that investigators at Dana-Farber and elsewhere traced some non-small cell lung cancers (NSCLCs) to mutations in the EGFR gene and discovered that Iressa and Tarceva slowed such tumors' growth by targeting the abnormal EGFR protein. While the discovery has extended the lives of thousands of NSCLC patients around the world, EGFR blockers are only temporarily effective: after about eight months of treatment, the tumors begin to grow back. And because the drugs target normal EGFR protein as well as abnormal, many patients have severe side effects such as skin rashes and diarrhea.

All current EGFR inhibitors have a structural "backbone" known as a quinazoline core. They lodge in a notch on EGFR normally reserved for a molecule known as ATP, which delivers chemical energy to the cell. By blocking ATP from binding to EGFR, the inhibitors prevent EGFR from sending signals that are essential to keep the tumor cells growing.

Over time, however, the tumor cells develop additional abnormalities in EGFR, enabling them to recommence their growth, even in the presence of Iressa or Tarceva. The most common of these abnormalities present in about 50 percent of patients with drug-resistant tumors is known as EGFR T790M.

Dana-Farber investigators hypothesized that current agents lose their potency because they don't bind as tightly or fully to the EGFR T790M protein as they ideally should. To improve the fit, researchers led by chemical biologist Nathanael Gray, PhD, prepared a group of inhibitors with a different structural scaffold, known as a pyrimidine core, which, it was thought, would mesh more thoroughly. They lab-tested the agents in NSCLC cells with EGFR T90M and found several that were up to 100 times more potent than quinazolines in restricting cell growth. As an unexpected bonus, these compounds were nearly 100 times less powerful at slowing the growth of cells with normal EGFR, suggesting they would be less likely to produce side effects than current drugs. The agent which performed the best is the pyrimidine WZ4002.

"This work provides a possible therapeutic chapter to a longstanding record of validating EGFR as a drug target," says Gray. "This has involved the identification of activating mutations in EGFR as a predictor of drug response, the discovery of multiple drug resistance mechanisms, and the elucidation of how these mutations work at an atomic level."

In follow-up experiments, Dana-Farber and BWH's Kwok-Kin Wong, MD, PhD, screened the pyrimidine agents in mice with Iressa- and Tarceva-resistant NSCLC tumors driven by EGFR T790M, and found them to be highly effective at impeding tumor growth. Dana-Farber's Michael Eck, MD, PhD, conducted crystallography studies to determine the molecular structure of the pyrimidines, providing a better picture of why they are so potent and how they target EGFR T790M cells so precisely.

"Not only did we determine that the compound WZ4002 could slow tumor growth, we also demonstrated that it is possible to selectively target the drug-resistant mutant EGFR in tumors, with relatively less effect on the normal EGFR in healthy tissues," says Wong.

Much work remains to determine if WZ4002 and its chemical cousins will be effective therapies, the authors caution, but the discovery demonstrates the power of screening specially designed compounds against cancers with certain genetic quirks.

"Obviously these are very early days with respect to the possible use of these compounds in patients we still have much to learn about their possible liabilities," Eck remarks. "But I am optimistic that our approach is correct and that it will lead to an effective treatment for the thousands of non-small cell lung cancer patients worldwide who development resistance to Iressa and Tarceva every year."


'/>"/>

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

Related biology news :

1. Scott & White Healthcare researcher finds success with new anti-cancer drug
2. Scott & White Healthcare researcher finds success with new anti-cancer drug
3. Researchers to investigate the genetics of congenital heart disease
4. Poisonous prehistoric raptor discovered by research team from Kansas and China
5. UC Riverside plant scientists research ranked on top ten breakthrough list for 2009
6. Research project yields better understanding of the defective protein that causes cystic fibrosis
7. JDRF announces diabetes research program with Johnson & Johnson
8. Researchers design a tool to induce controlled suicide in human cells
9. Researchers work on vaccine to improve immune system in newborns
10. Springer signs agreement with British Society of Research on Ageing
11. NTU and EDB launch S$50 million ($36 million) integrated circuit design research center
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Research yields new agent for some drug-resistant non-small cell lung cancers
(Date:2/7/2017)... --  MedNet Solutions , an innovative SaaS-based eClinical technology ... is pleased to announce that the latest release of ... and award winning eClinical solution, is now available for ... a proven Software-as-a-Service (SaaS) clinical research technology platform that ... delivers an entire suite of eClinical tools to support ...
(Date:2/6/2017)... DENVER , Feb. 6, 2017 ... national security are driving border authorities to continue ... Acuity reports there are 2143 Automated Border Control ... Kiosks currently deployed at more than 163 ports ... between 2013 to 2016 achieving a combined CAGR ...
(Date:2/2/2017)... JACKSONVILLE, Fla. , Feb. 2, 2017 /PRNewswire/ ... ), a clinical-stage immuno-oncology company specializing in the ... vaccines for the treatment of cancer and metastatic ... multi-gram scale-up and GMP manufacturing of a second ... T-cell vaccine targeting folate receptor alpha. The manufactured ...
Breaking Biology News(10 mins):
(Date:2/23/2017)... and NEW YORK , ... Lumeon , a leading digital health company, ... a provider of telemedicine and remote patient monitoring, ... for telemedicine reimbursements.  DN Telehealth ... patients, in real-time, extending consultations beyond a physical ...
(Date:2/23/2017)... Atlanta, it seems everyone has a chance to express their ... expressive and dynamic community unlike any other. The businesses that ... With their newest salon in ... on that tradition with a unique, fresh approach to head ... the newest of 13 nationwide locations, each of them well-situated ...
(Date:2/23/2017)... Ind. (PRWEB) , ... February 23, 2017 , ... ... Award during the 12th annual Inventors Recognition Reception at Purdue Research Park ... to a faculty member in recognition of outstanding contributions to, and success with, ...
(Date:2/23/2017)... SAN DIEGO and SAN FRANCISCO ... , a privately-held regenerative medicine company, and Beyond Type ... living with type 1 diabetes, today announced a grant ... develop a functional cure for type 1 and other ... decade, ViaCyte has been developing innovative stem cell-derived cell ...
Breaking Biology Technology: