CPRIT-supported scientists launch lung cancer cell study

By Debbie Bolles / June 2011

By painstakingly analyzing the genetic makeup of 14 lung cancer cell lines and then testing each for sensitivity to nearly a quarter-million compounds, researchers at UT Southwestern hope to find new drugs to combat the biggest cancer killer in America.

In the process, the research team aims to learn more about what makes certain types of non-small cell lung cancer spread and to develop a plan targeting treatments to specific lung cancer subtypes.

Achievement of this lofty goal could revolutionize the way doctors treat lung cancer, a disease that has a poor long-term survival rate and afflicts 200,000 new patients annually in the U.S.

“There is the hope that at the end of this time, we’ll set the road map for the next 50 to 100 years of treatment,” said Dr. John Minna, one of six principal investigators from
UT Southwestern involved in the five-year project.

Members of the CPRIT-supported lung cancer cell study at UT Southwestern are (from left) Dr. Bruce Posner, Dr. John Minna, Dr. Michael White, Dr. Noelle Williams, Dr. Michael Roth and Dr. Joseph Ready. Also a member of the team, but not pictured, is Dr. Steven McKnight.

The Cancer Prevention and Research Institute of Texas (CPRIT) recently awarded investigators at UT Southwestern $10.99 million for the medical center’s primary role in this monumental project, led by Dr. Steven McKnight, chairman of biochemistry at UT Southwestern. Researchers from UT M.D. Anderson Cancer Center, UT Austin and Baylor College of Medicine also are collaborating on the grant.

“I think this is fundamentally going to change how we approach looking for therapeutics in cancer,” said Dr. Minna, who directs the W.A. “Tex” and Deborah Moncrief Jr. Center for Cancer Genetics and the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research. “I think there will be something referred to as the UT Southwestern Functional Classification of Lung Cancer.”

Work at UT Southwestern over the past two years on a separate National Cancer Institute grant project set the stage for the new CPRIT grant. Under the NCI grant, Dr. Minna, Dr. Michael Roth, professor of biochemistry; Dr. Michael White, professor of cell biology; and Dr. Bruce Posner, associate professor of biochemistry and director of the High Throughput Screening Core, screened 14 non-small cell lung cancer lines for sensitivities to 220,000 chemical compounds and natural product extracts. The same 14 lines – actually two lung cancer cell lines from seven different subtypes, or clades – also were screened through two whole genome ribonucleic acid interference (RNAi) libraries.

Seeking cancer cell line killers

With the new CPRIT funding, the research team will break down that screening process even further, first identifying the 200 to 400 most clade-sensitive RNAi agents and 100 to 200 most clade-sensitive chemical toxins emerging from the primary screen. Further screening and then testing of the most promising agents in mice should reveal potential compounds for drug development.

“We are looking to see which genes are necessary for the survival of these cancer cell lines and which compounds will kill them,” said Dr. Roth.

Principal investigators on this UT Southwestern CPRIT grant team are Drs. McKnight, Minna, White and Posner, as well as Drs. Joseph Ready and Noelle Williams, both associate professors of biochemistry.

The project is a collaborative research effort of UT Southwestern’s Harold C. Simmons Cancer Center. As the only National Cancer Institute-designated cancer center in North Texas, the Simmons Center brings together pioneering treatments and breakthrough research in one facility, combining multidisciplinary experts in disease-oriented teams. The NCI designation means the best in care and access to new treatments for cancer patients, combining basic, translational and clinical research with personalized clinical care.

Dr. Roth said the research team plans to sequence the cancer cell lines to discover what mutations are present in each. The team also will try to determine which regulatory or metabolic pathways might be vulnerable in these cell lines for potential development into therapeutic targets.

“Lung cancer is a whole slew of orphan diseases,” Dr. White said. “Each one is presumably defined by a particular combination of mutations that lead to aberrant tissue growth. This grant is allowing us to clearly define the subtypes of lung cancer, identify the mutations that specify subtype membership, and isolate chemical compounds customized to eliminate each subtype.”

Teams focused on the big picture

Specific roles of the principal investigators from UT Southwestern are:

  • Dr. McKnight will oversee the project.
  • Dr. Posner will lead the High-Throughput Screening (HTS) Cor
  • Dr. White will lead the compound target ID project that entails evaluating RNAi results. The goal is to use a combination of genetics and biochemistry to identify targets of clade-specific chemical toxins, and to identify molecular targets to screen by the HTS core.
  • n Dr. Ready will take the most promising compounds and attempt to improve them. The aim is to identify and validate new molecular targets for chemotherapy and discover drug leads that display selective toxicity toward specific lung cancer types.
  • Dr. Williams will head the pharmacology core, with plans to study how the top compounds kill cancer in mice. This project also will assess metabolic stability, protein binding, solubility and formulation of the initial drug leads.
  • Dr. Minna, as head of the molecular biomarker ID project, will look for genetic cancer biomarkers in the lung cancer cell lines. This project aims to identify tumor-acquired DNA mutations or patterns that will predict response of the lung cancer lines to small interference RNA (siRNA) knockdowns and clade-specific chemical toxins.

“This is the first time I’ve seen the possibility of literally looking for all possible therapies now and in the future for lung cancer, based on molecular changes in the lung cancer cells themselves,” Dr. Minna said. “It is a two-pronged attack: on the one hand screening big chemical libraries, and on the other, going gene by gene and seeing if we remove one, does it kill a lung cancer cell?”

Dr. McKnight holds the Distinguished Chair in Basic Biomedical Research and the Sam G. Winstead and F. Andrew Bell Distinguished Chair in Biochemistry.

Dr. Minna holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology.

Dr. Roth holds the Diane and Hal Brierley Distinguished Chair in Biomedical Research.

Dr. White holds the Sherry Wigley Crow Cancer Research Endowed Chair, in Honor of Robert Lewis Kirby, M.D., and the Grant A. Dove Chair for Research in Oncology.