Big Science

Deepak Nijhawan, M.D., Ph.D., (left) and Steven McKnight, Ph.D., are members of a research team identifying new biological markers linked to different families of lung cancers.
Deepak Nijhawan, M.D., Ph.D., (left) and Steven McKnight, Ph.D., are members of a research team identifying new biological markers linked to different families of lung cancers.

Decades of dedication

For a quarter-century, UT Southwestern has been blazing the path for the lung cancer treatments of tomorrow, as well as the care of today.

It started with the arrival at UT Southwestern in 1991 of longtime collaborators Drs. John Minn and Adi Gazdar, formerly of the National Cancer Institute (NCI). The two have carefully curated lung cancer cell lines since the 1970s—a collection of about 300 that now is the world’s largest. Those cell lines are regularly tapped to develop and test new therapies not just by investigators at UT Southwestern’s Simmons Cancer Center but by thousands of researchers around the globe.

Each line, derived from a different patient’s cancer, is indexed to a tumor sample plus information on how the person was treated and other clinical data. “In the past year, we have the complete genome sequence of most of these lines, which makes them much more valuable,” Dr. Minna says.

The early, intense focus on the biology of lung cancer put UT Southwestern at the forefront internationally of lung cancer research’s molecular revolution. It also laid the foundation for the university’s research award in 1996, in collaboration with the University of Texas MD Anderson Cancer Center, of a highly competitive Specialized Program of Research Excellence (SPORE) grant from the NCI. The grant, with annual funding totaling $2.5 million, leverages the talents of some of the world’s top lung cancer scientists, along with progress in genomics, to advance the dream of personalized medicine—not just through discovery, but with innovation that makes that discovery practicable.

“The SPORE has to move research into the clinic, or if there are things that happen in the clinic, take them back to the lab,” says Dr. Minna, the program’s principal investigator. “This is one of the few places in the world where the whole package is here—the clinical, surgical, medical, and radiation oncology expertise, the mechanisms to get the specimens into the lab and study them, and then the comprehensive approach that involves biology and genetic and chemical analysis of the tumors.”

The comprehensive scientific and clinical infrastructure that supports the SPORE, along with other expertise and resources deployed across UT Southwestern, have provided a framework for innovative lung cancer research and care throughout Simmons Cancer Center, including:

  • Work pinpointing new genetic markers that might help identify the most aggressive lung tumors;
  • Novel studies of cancer metabolism to decipher mechanisms of lung cancer cell growth;
  • Development of a multigene test to predict which surgical patients stand to benefit most from chemotherapy;
  • Identification of an inherited gene mutation that boosts risk of lung cancer in nonsmokers;
  • A focus on how to treat cachexia more effectively, and sooner;
  • Studies of attitudes surrounding lung cancer diagnosis and treatment; and
  • Clinical trials that complement discovery science at UT Southwestern and bring new therapies to patients, such as trials of the antifungal drug itraconazole and of the monoclonal antibody bavituximab.

Size, scope, longevity

The University of Texas SPORE, now in its 18th year, is the largest thoracic oncology effort in the U.S. Only a handful of other institutions nationwide are similarly recognized for excellence in lung cancer research.

Among their achievements, scientists working in the SPORE have discovered alterations between the normal-to-malignant DNA tissue of lung cancer patients that may yield new therapeutic avenues; elucidated differences between individuals that make some more susceptible to lung cancer or more likely to survive, or that indicate greater risk of toxicities during treatment; described the role of cancer “stem cells” in lung cancer recurrence; and shed light on potential ways to block cancer growth, invasion, and metastasis in patients.

The SPORE has four main research arms:

  • One, co-led by Dr. Minna and Dr. John Heymach of MD Anderson and in collaboration with UT Southwestern’s Dr. Luc Girard, focuses on analyzing lung tumors for genetic vulnerabilities and selecting therapies based on the findings.

“When we started, we were talking about whether we could analyze one or two tumors and know what that meant for patients in terms of prognosis and specific treatment,” Dr. Minna says. “Now we’ve analyzed more than 1,000. It’s taken all this time to assemble the tools to do these analyses on tumors, to develop preclinical models to test this outside patients’ bodies, and to have analyzed a large enough number of tumors to know this was the right approach.”

The approach is now being implemented at the bedside, with drugs already on the market or in clinical studies being matched with patients’ molecular profiles.

  • A second SPORE project, led by Dr. Xifeng Wu of MD Anderson, involves epidemiological studies that are finding genetic markers indicating individual differences, including who is at greatest risk of developing lung cancer.
  • A third project, co-led by UT Southwestern’s Dr. Pier Paolo Scaglioni and MD Anderson’s Dr. Jonathan Kurie, is developing new molecularly targeted therapies aimed at metastatic lung cancer and at sensitizing tumors to radiation. The project has linked particular microRNAs, or bits of genetic material, to highly metastatic versus nonmetastatic tumors.
  • The fourth arm, led by UT Southwestern’s Drs. Jerry Shay and Joan Schiller, leverages the vast expertise developed by Dr. Shay and colleagues in telomerase, an enzyme related to cell immortality, to develop therapies to kill cancer stem cells, hobbling a tumor’s ability to regenerate.

Researchers recently completed a phase II study of the telomerase inhibitor imetelstat as maintenance therapy for patients with advanced non-small cell lung cancer.

The SPORE also has three supporting arms: an administrative core led by Dr. Minna and SPORE co-principal investigator Dr. Jack Roth of MD Anderson; a pathology core overseeing specimens and clinical annotation, led by Dr. Gazdar and Dr. Ignacio Wistuba of MD Anderson; and a bioinformatics-biostatistics core, led by Dr. Yang Xie, that is managing the flood of data related to the project and that has developed a massive database available to researchers worldwide. The database, called Lung Cancer Explorer, contains genome-wide mRNA expression and clinical data for nearly 5,500 lung cancer patients’ tissue samples.

Well-connected

Much as UT Southwestern scientists are lung cancer leaders, UT Southwestern leaders are lung cancer scientists—with a slate of department chairs, Cancer Center principals, and institution luminaries focused on the disease. As a research powerhouse, the lung cancer program is plugged in with investigators around the world and with resources across Texas and the U.S.

In one large project, funded by the Cancer Prevention and Research Institute of Texas (CPRIT), UT Southwestern scientists are evaluating many facets of radiotherapy, the primary treatment in more than half of lung cancer patients. Led by Radiation Oncology Chair Dr. Hak Choy in collaboration with Dr. Chul Ahn, the project seeks to propel technology to improve cancer control and reduce toxicity for patients with early stage or locally advanced tumors. A key goal is to export these advances via training programs throughout the state.

Another research collaboration funded by CPRIT applies the unique cancer-fighting properties of stereotactic ablative radiotherapy (SABR), which delivers high-dose radiation in fewer visits than with traditional radiation therapy, to lung tumors located centrally in the chest, where radiation sufficient to treat cancer can be risky for nearby organs. The research is led by radiation oncologist Dr. Robert Timmerman and involves Drs. Ralph Mason, Rolf Brekken, Debu Saha, and Dr. Ahn.

Two arms of the project focus on overcoming radiation therapy resistance caused by low oxygen concentrations in the tumor, and the impact of using the antibody bavituximab—a treatment developed at UT Southwestern—to specifically sensitize tumors to radiation, allowing the cancers to be treated effectively with lower, more tolerable doses.

Meanwhile, in work funded by NASA, UT Southwestern researchers, including Drs. Minna, Shay, and Xie, and Drs. Michael Story and David Chen, are investigating how the additional radiation exposure that occurs during spaceflight increases lung cancer risk and how lung cancers respond to radiation. “We know that some are very sensitive and some resistant, and we have a molecular profile that looks like it identifies those,” Dr. Minna says.

The research, also of interest to the NCI, should elucidate how radiation exposure from procedures such as CT scanning affects lung cancer risk, including in patients undergoing repeated low-dose scans for cancer.

UT Southwestern scientists also are among the leaders of the national Lung Cancer Mutation Consortium (LCMC), a high-profile alliance of 16 top academic cancer centers and hospitals across the U.S. that is helping to lead the charge nationally to personalize lung cancer treatment—and providing direct benefit to Simmons Cancer Center’s lung cancer patients.

Institutions in the consortium are collaborating to match 1,000 lung cancer patients each year to therapies based on genetic mutations in each individual’s tumors. “The key goals,” says Dr. Schiller, UT Southwestern’s principal investigator for the LCMC, “are to learn all the types of mutations that occur—and how frequent they are—in non-small cell lung cancer, and to determine through clinical trials whether patients given drugs targeting those mutations will fare better than with standard treatments.”

UT Southwestern is also a Cancer Target Discovery and Development (CTD2) center, part of a network of sites honing and leveraging massive amounts of genomics data to advance precision medicine.

Less formal collaborations also abound. Dr. Minna estimates that at least half of UT Southwestern’s published research in lung cancer involves other institutions. “In many cases we provide resources as part of the national scientific fabric, but we have a very high amount of inter-institutional collaboration.”

From left: Mahboubeh Papari, Boning Gao, Ph.D., Victor Stastny, John Minna, M.D., and Adi Gazdar, M.D., are among scientists working to advance new therapies from discovery to drug development.
From left: Mahboubeh Papari, Boning Gao, Ph.D., Victor Stastny, John Minna, M.D., and Adi Gazdar, M.D., are among scientists working to advance new therapies from discovery to drug development.

Gene-by-gene quest

Collaboration is also a hallmark within the Cancer Center of a sweeping, multimillion-dollar lung cancer drug discovery effort funded by CPRIT and the NCI’s CTD2 Network.

To lay a foundation for the drug discovery work, UT Southwestern scientists have been pioneering new ways to classify non-small cell lung cancers functionally based on their vulnerabilities. As lung tissue develops from normal to cancerous, hundreds of mutations in genetic coding can arise, says project investigator Dr. Michael White—and they can differ widely from tumor to tumor. But only a few of those mutations matter. By figuring out which genes appear significant, the researchers have been able to group lung cancer cell lines into families, with cell lines in the same families having similar vulnerabilities and sensitivities to certain chemical compounds.

A team with diverse talents—including Dr. Minna, Dr. White, Dr. Michael Roth, and Dr. Xie; Chair of Biochemistry Dr. Steven McKnight; and Drs. Bruce Posner, Deepak Nijhawan, John MacMillan, Joseph Ready, and Noelle Williams—is pursuing the quest for new therapies from discovery to drug development. The researchers are identifying new biological markers linked to potential vulnerabilities in the different families of lung cancers, pinpointing the vulnerabilities themselves along with potential biological and chemical therapies that can exploit them, and learning how to predict the cases in which the new potential therapies are likely to work. Team members are also developing promising chemicals into therapeutic compounds that are more potent, tolerable, and accessible in the body, and creating cutting-edge mouse models of lung cancer in which the compounds can be tested.

The effort is enormous, knocking out some 25,000 human genes one by one and testing the effects of a quarter-million chemical compounds, plus thousands more natural products, on more than 100 lung cancer cell lines. So far, the team has identified approximately 100-150 gene products and 100-200 new chemical compounds that can hit lung cancer targets while sparing normal epithelial cells.

Dr. Minna says some of these potential therapeutic targets seem very common in other tumor types. “People who have smoked have a lot of mutations, so lung cancer is a testing ground to find targets that could apply in many other tumors. We’re just beginning to explore that.”

New frontiers in tailoring therapy

Simmons Cancer Center scientists are also taking a systematic approach to understanding how cells’ nuclear hormone receptors work in concert to influence genes that affect the development and growth of lung, as well as breast cancers. Chair of Pharmacology Dr. David Mangelsdorf is leading a CPRIT grant of more than $7.4 million that unites UT Southwestern with Baylor College of Medicine and MD Anderson in the effort. The work includes UT Southwestern investigators Drs. Minna, Xie, Ralf Kittler, and Scaglioni.

Together, the researchers are exploring how the body’s 48 nuclear hormone receptors, along with more than 100 coregulators, can be activated or suppressed by hormone therapies, many of which are already on the market as cancer medicines.

“The whole idea is to be able to come up with a way to individualize and tailor treatment based on a nuclear hormone receptor expression and activity profile,” says Dr. Mangelsdorf, who envisions the strategy as complementary to other, non-hormonal treatments. “We want to come up with something that will be clinically useful.”

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