A Singular Focus on Lung Cancer

David Carbone joins Ohio State’s lung cancer team to organize a thoracic oncology center


David CarboneDavid Carbone, MD, PhD, a renowned lung cancer specialist recently recruited to The Ohio State University, believes that integrating basic and clinical research with patient care is essential for improving patient outcomes and the dismal statistics associated with this malignancy.

Lung cancer is the leading cancer killer of both men and women in the United States. In 2012, the disease was expected to kill 160,300 Americans, more people than breast, prostate and colorectal cancer combined. Only 16 percent of lung cancer patients are alive five years after diagnosis.

“I’ve focused my whole career on lung cancer,” Carbone says. “I’m determined to make a difference in the field through research, caring for patients and training other physicians.”

Carbone specializes in the molecular biology of lung tumors – the genetic, proteomic and metabolic features of each patient’s cancer – and in developing drugs to better treat the disease. He came to Ohio State’s Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) in autumn 2012 to establish a thoracic oncology center.

Formerly, Carbone directed the Experimental Therapeutics Program and the Thoracic and Head and Neck Cancer programs at Vanderbilt-Ingram Cancer Center. He welcomes the challenge of developing a thoracic oncology center at the OSUCCC – James.

“All the structural elements here, from committed leadership to an outstanding clinical team, are aligned to build a major and effective lung cancer program,” Carbone says. “The institution has an almost unparalleled financial and philanthropic base. We are in a growth mode, and I believe we have tremendous potential.”

Longtime members of Ohio State’s lung cancer team are working closely with Carbone to develop the center that ultimately would provide multidisciplinary care in one location, similar to Ohio State’s Stefanie Spielman Comprehensive Breast Center.

“An integrated center that provides the full spectrum of care, from screening to survivorship, and that leverages translational research, will help us change outcomes for patients,” says Patrick Ross Jr., MD, PhD, a surgical oncologist and researcher who directs Ohio State’s Division of Thoracic Surgery.

Gregory Otterson, MD, a lung cancer specialist and researcher at the OSUCCC – James, notes that the multidisciplinary center would bring together the range of specialties required to care for lung cancer patients, which includes medical oncology, radiation oncology, pulmonary medicine, thoracic surgery, pathology, diagnostic radiation and interventional radiation.

“The center would also bolster clinical and translational research,” Otterson says. “Seeing patients at a single locale will enhance the process of obtaining biopsies onsite and the collection of tissue for biomarker analyses.”

“Ohio and surrounding states have a relatively higher proportion of lung cancer cases than other parts of the country,” adds Miguel Villalona, MD, a lung cancer specialist and OSUCCC – James researcher who directs Ohio State’s Division of Medical Oncology. “Having a center that provides comprehensive care at the epicenter of this epidemic will be a dream come true. To alter the catchy phrase, ‘Build it, and they will come,’ I say, ‘Build it, they are already here.’”

Targeted Research

Translational research at the proposed center is expected to lead to innovations in screening, molecular-based diagnosis, stereotactic radiation, robotic-assisted surgery, photodynamic therapy and early-phase drug design.

Carbone’s research focuses on gene sequencing/proteomics, the NOTCH gene signaling pathway, immunosuppression and discovery of biomarkers for predicting clinical outcome.

Protein-expression patterns in lung cancer cells are of key interest. He believes the genetic mutations that cause cancer are important only by virtue of their impact on cellular proteins.

“Trying to understand the causes and behavior of cancer by studying single genes is worse than the ‘blind men and the elephant’ parable – you get a different impression depending on where you look,” he says. “We’re taking a more comprehensive look at lung cancer by studying proteome and protein expression patterns in addition to RNA expression and mutations in the genome.

“We now have tools to inventory all the genetic alterations, RNA expression changes and protein alterations found in tumor cells as distinct from normal cells,” he continues. “I’m interested in studying all this information in cancer cells with particular clinical characteristics so we can determine why the cancer developed or behaved a certain way, and then come up with candidate targets for therapy.”

One such target is the NOTCH3 gene. A dozen years ago, Carbone’s lab team discovered a chromosome rearrangement in a lung cancer that activated this gene, which they have since determined is overexpressed in a majority of cases. “We are characterizing its potential as a direct therapeutic target and other elements of this pathway as a modulator of the immune response,” he says.

Equally important, his lab is studying biomarkers – molecular features of lung cancer cells – that will help identify optimal therapy for each patient. “We have studied many candidate biomarkers in peripheral blood using proteomic technologies,” Carbone says.

He notes that his research complements that of several OSUCCC – James investigators, such as Villalona, who specializes in drug development.

“We are at the dawn of a new era in lung cancer. Many molecular changes that can be pharmacologically targeted have been discovered, and others will follow,” Villalona says. “The new center will help my efforts to develop the right drug for the right group of patients in the right clinical trial.”

One molecular target Villalona is studying is the KRAS gene. Mutations in this gene occur at high frequency in lung cancer. No drugs exist yet that target it, but Villalona and his colleagues are working with a naturally occurring virus combined with chemotherapy as a promising strategy for treating these patients.

Otterson’s research team has joined the Lung Cancer Mutation Consortium (LCMC), a group of 18 thoracic oncology centers that performs extensive molecular characterization of patients with lung adenocarcinoma (the most common form of lung cancer).

“The LCMC is predicated on obtaining adequate tissue specimens followed by extensive molecular characterization,” Otterson says.

Ross says his work, too, will benefit from collaborating with Carbone.

“We provide cutting-edge therapy for lung cancer with minimally invasive approaches such as robotic-assisted surgery and photodynamic therapy (PDT),” Ross says. His team will present its innovative robotic cases at the next meeting of the Society for Surgical Oncology, and Ohio State’s PDT program was featured in the October 2012 Journal of the National Comprehensive Cancer Network.

“Our collaborations with Dr. Carbone focus on earlier detection and multidisciplinary therapy to shrink tumors,” he says. “In this way, more patients will benefit from the less invasive surgical techniques that we perform.”

Innovative Early Screening

As with all cancers, Carbone says, the importance of early detection in lung cancer cannot be overemphasized.

“Until recently, there was no early-detection test for lung cancer that was proven to reduce deaths from this disease,” he says. “Without screening, most cases are diagnosed when they are metastatic – through the pain of bone metastases or seizures from brain metastases, for example – and at that point they are typically incurable.”

But, he notes, the National Lung Screening Trial (NLST) – a National Cancer Institutes-ponsored study of more than 53,000 current or former heavy smokers – compared computed tomography (CT) scans with standard chest X-rays and showed that lung CT scans lowered the risk of dying from lung cancer by 20 percent by catching the disease earlier, when it is more treatable.

“CT scanning has the potential for a much greater impact on saving lives than multiple regimens of chemotherapy performed later when the cancer is more advanced,” Carbone says.

Based on the NLST findings, the OSUCCC – James began providing lung cancer CT scans in the spring of 2012 for high-risk patients (see sidebar), but Carbone says that more research is needed to optimize the way screening is done, and there are risks to screening outside of academic centers.

“Medicare doesn’t cover these scans, and most insurance companies don’t pay for them,” he explains. “Plus, not everyone is qualified to perform or interpret them.”

He points out that 95 percent of positive findings on test results are not cancer, “so it takes a well-trained team of multidisciplinary experts to examine the results and determine whether a patient has cancer or something else. At the OSUCCC – James, our scans are backed by an expert team that can analyze and best manage what is found.”

Carbone notes that studies of CT screening are blending with another promising area of research: identifying patterns of abnormal microRNA (miRNA) molecules in the blood of lung cancer patients. In 2011, an OSUCCC – James team led by Carlo Croce, MD, reported in the Proceedings of the National Academy of Sciences that they had identified miRNA patterns in plasma that might reveal the presence and aggressiveness of lung cancer, and perhaps who is at risk for developing it. The study compared miRNA expression profiles of lung tumors, normal lung tissues and plasma samples from lung cancer cases identified in a CT screening trial.

Importantly, the researchers had evidence that these patterns might be detectable up to two years before the tumor is found by CT scans. They also showed that it might be possible to use the miRNA patterns to detect lung cancer in a blood sample – findings that could lead to a blood test for lung cancer.

“We are working with several groups to study the development of blood tests for CT screening, and we want to take advantage of the microRNA expertise at Ohio State for that purpose,” Carbone says.

Hopeful Horizon

Ultimately, everything at the new thoracic oncology center will be geared toward improving outcomes for patients, with whom Carbone can empathize from his own experience with cancer. In 1999 he was diagnosed with mediastinal large B-cell lymphoma, a rare and aggressive form of non-Hodgkin’s lymphoma. His therapy involved removing part of his left lung and receiving chemotherapy and chest radiation – similar to treatments he often recommends for his lung cancer patients.

“The experience gave me a better understanding of the psychological impact of receiving a life-threatening diagnosis, both on me as a patient and on my family,” he says. “It also gave me an appreciation of how hard chemotherapy can be in both acute and chronic toxicities, how inefficient our medical system is in many ways, the effects of ‘scan anxiety’ and the chronic consequences of cancer and its treatment.”

In addition, it gave him insights that could be of value to all healthcare professionals working with lung cancer patients, no matter how bleak the prognosis.

“Be very cautious about taking away hope,” Carbone says. “Statistics apply to populations and

not individuals. I have seen patients literally on death’s door come back to a normal lifestyle, for a while at least. And I’ve seen patients with metastatic lung cancer who have lived only a few weeks and those who have lived 20 years with the disease. Nobody can predict the future with certainty.”

Progress is being made against lung cancer, Carbone says, and that progress will continue through research.

“The management of lung cancer and the expectations for outcomes are changing,” Ross says. “The OSUCCC – James is influencing how these patients will be managed.”

Otterson says patients will benefit from “the expansion of our molecular pathology resource, which will enable us to open more clinical studies directed toward those with various subsets of lung cancer.”

“We provide expertise in genomics, access to new agents and a multimodality approach to diagnosis and treatment,” Villalona says, noting that patients can fare better from this comprehensive approach. “To all who are afflicted with lung cancer or who know someone who is, there is hope."

CT Scans Offer Earlier Detection of Lung Cancer

After the National Lung Screening Trial (NLST) showed that lung computed tomography (CT) scans lowered the risk of dying of lung cancer by 20 percent compared with standard chest X-rays, the OSUCCC – James began offering CT scans to those at high risk for developing the disease.

The screenings involve one low-dose CT scan annually for three consecutive years. To qualify, participants must be 55-74 years old, be a current smoker with a history of smoking two packs per day for 15 years or one pack per day for 30 years, or be an ex-smoker who has quit within the past 15 years.

“Our lung cancer screening program provides results to the patient within a few minutes,” says Director Patrick Nana-Sinkam, MD, a pulmonologist who is part of the multidisciplinary lung cancer team at the OSUCCC – James. “The goal is to look for asymptomatic spots on the lung. About 85 percent of lung cancers are smoking-related, which is why this group is targeted to have these early screenings, before the cancer is advanced.”

“Even better than early detection is preventing lung cancer altogether, so smoking cessation is also an integral part of our screening program,” says David Carbone, MD, PhD, a lung cancer specialist who is working to establish a thoracic oncology center at the OSUCCC – James.

Carbone notes that CT scanning is not the entire answer. Many people develop lung cancer who have never smoked, are not considered high risk and therefore do not qualify for screening. “We need methods for early detection for the 15 percent of lung cancer patients who never smoked, and we are working on this as well.”

The CT scans cost $99 and are offered every other Monday from 4-6 p.m. at Ohio State’s Martha Morehouse Medical Pavilion, Second Floor Clinic, 2050 Kenny Road, Columbus. To schedule, call The James Line at (614) 293-5066.

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