October 30, 2013 | by ckitchens
Lung cancer is not unbeatable. Each day, doctors and researchers in City of Hope’s Lung Cancer and Thoracic Oncology Program aggressively pursue innovative approaches to bring new treatments and cures to patients with all forms of this devastating disease. During November, also known as Lung Cancer Awareness Month, we highlight some of those efforts.
Tumor microenvironment: Looking beyond cancer cells
Karen Reckamp, M.D., M.S., co-director of the Lung Cancer and Thoracic Oncology Program; Hua Yu, Ph.D., associate chair of the Department of Cancer Immunotherapeutics and Tumor Immunology; and Wang Zhang, Ph.D., a postdoctoral fellow, are analyzing how the tumor microenvironment — the normal cells and molecules surrounding a tumor cell — might help predict which patients are most at risk of their disease spreading.
Examining the lymph nodes of 67 patients with the most common type of lung cancer, the researchers identified potential indicators of a “pro-metastatic environment,” a complex set of biochemical conditions that triggers tumor cells to spread. Specifically, the researchers found that patients whose lymph nodes had groups of cells known as myeloid cell clusters and who had elevated levels of STAT3, a protein highly activated in cancer cells, were less likely to survive their cancer than other patients.
In addition, the presence of myeloid cell clusters alone was found to predict poor survival for patients with a history of smoking. Reckamp and her colleagues believe that further research on myeloid cells clusters and STAT3 will provide key information on how lung cancer spreads.
The tumor microenvironment may also serve as a new therapeutic target, leading to the development of treatments to prevent lung cancer from spreading and ultimately increasing survival rates in patients whose tumors are likely to metastasize. A study about the work was recently published in the peer-reviewed journal PLoS One.
Combining aspirin and triptolide to prevent lung cancers
Binghui Shen, Ph.D., chair of the Department of Radiation Biology, in collaboration with his physician colleagues Reckamp and Dan Raz, M.D., co-director and surgical director of the Lung Cancer and Thoracic Oncology Program, is studying the effectiveness of anti-inflammatory drugs in preventing lung cancer.
The researchers demonstrated that, when administered separately, aspirin and the drug triptolide (a derivative of a Chinese anti-inflammatory herb known as thunder god vine) each have the effect of moderately suppressing lung cancer development in mice. When combined, however, these two agents reduced the incidence of lung cancer in mice from 70 percent to only 5 percent.
Shen hypothesizes that the drug combination creates an anti-tumor microenvironment and directly kills lung cancer cells by blocking their key survival mechanisms. His new research seeks to increase understanding of how triptolide and aspirin might lower the risk of lung cancer recurrence and eliminate cancer.
Promising new advances to improve treatment
A recent study led by Raz has identified a new biomarker — a distinct molecular trait called WNT-3A — that can be targeted for diagnosis or treatment. Raz showed that lung cancer cells with excessive WNT-3A are more likely to have the highest response rates to the anti-inflammatory drug triptolide. This promising discovery gives scientists new insight into treatments for patients whose tumors have the biomarker.
Raz and his team are also studying MRx102, a new compound that is a modified form of triptolide. Preclinical studies have shown MRx102 and triptolide to be equally effective in destroying lung cancer cells, but MRx102 has significant advantages over triptolide — it's less toxic and lasts longer in the body, potentially improving how patients tolerate the drug and perhaps prolonging the drug’s effectiveness.
Next, Raz plans to further collaborate with the drug developer to seek Food and Drug Administration approval for MRx102 as an investigational drug in clinical trials.
Disabling DNA repair mechanisms
Jae Kim, M.D., chief of the Division of Thoracic Surgery, is studying lung cancer cell samples and comparing them to normal lung tissue to assess how lung tumors develop resistance to chemotherapy and other treatments.
Already he's found that, compared to normal lung tissue, the majority of tumor samples he's tested had excessive amounts of a protein called flap endonuclease, which acts to repair DNA.
Some types of chemotherapy and radiation destroy tumor cells by breaking apart strands of their DNA, and studies have shown that flap endonuclease helps fix these breaks. This is an important finding in understanding why some patients develop resistance to chemotherapy and radiation therapy.
Kim now seeks to determine how cancer cells increase their levels of flap endonuclease. This information could lead to treatments to target the protein, thus disabling a cancer cell’s ability to repair its DNA and making anti-cancer therapies more effective for patients.
Targeting numerous signaling pathways
Marianna Koczywas, M.D., a clinical professor of medical oncology, and her colleagues recently completed a phase II clinical trial to study the effectiveness of the drug ganetespib in patients with advanced nonsmall lung cancer.
Ganetespib is a targeted compound that blocks the activity of heat shock protein 90 (Hsp90), a molecule critical to the growth and spread of tumors. In the study, the researchers found that blocking Hsp90 simultaneously disrupts numerous molecular pathways that stimulate lung cancer cells, thereby attacking the disease at multiple targets.
Scientists are using these findings to determine how blocking numerous lung cancer pathways with ganetespib could boost the effectiveness of conventional chemotherapy and help patients live better, longer lives. Koczywas has begun a phase III trial to combine ganetespib with the chemotherapy drug docetaxel in patients with advanced nonsmall cell lung cancer to confirm whether this treatment is more effective than chemotherapy alone.
Detecting early-stage disease
Lung cancer screening increases the chance of diagnosing the disease at an early stage when it is more likely to be cured, and at the same time can detect other tobacco-related diseases such as emphysema and heart disease.
As a National Center of Excellence, City of Hope in December 2012 began to screen former or current heavy smokers age 50 and over. These individuals did not have a chest computed tomography (CT) scan over the past year or symptoms of lung cancer. Led by a team of providers that included Rachel Dunham, M.S.N., N.P.; Raz; Arnold Rotter, M.D., chief of the Computed Tomography Section at City of Hope; and Argelia Sandoval, M.D., an assistant clinical professor of respiratory diseases, the screening program uses the most advanced equipment and techniques to perform CT scans of the lungs using low-dose radiation.
One hundred patients have enrolled in the program, and 4 to 6 percent of those who have been scanned were identified as potentially having lung cancer, empowering them to take action to improve their health — even save their lives. In July, the U.S. Preventive Services Task Force proposed annual lung cancer screening for high-risk individuals. If the test becomes covered by insurance, as expected, many lives could be saved.
Research has shown that secondhand smoke is a risk for many of the health problems related to smoking. In fall 2013, City of Hope will begin a five-year study to examine nearly 1,000 people age 40 and over who have never smoked but have been exposed to significant amounts of secondhand tobacco smoke. The goal of this project is to examine the serious health effects of secondhand smoke on nonsmokers, particularly the development of lung cancer and emphysema. City of Hope is the only center on the West Coast offering this screening program.
The benefits of supportive care
Betty Ferrell, Ph.D., R.N., is collaborating with colleagues from several departments on a National Cancer Institute-funded research project to create comprehensive care for patients with lung cancer.
The project team consists of members of medical oncology, thoracic surgery, social work, chaplaincy, nutrition, rehabilitation services, pulmonary rehabilitation, nursing and other departments involved in lung cancer care. The team reviews the case history for each patient and recommends a supportive care plan, including referrals for services to help patients manage their daily lives. A research nurse follows up with the patient and provides the oncologist with reports on the patient’s status.
The study aims to show how caring for the physical, psychological and spiritual needs of patients during lung cancer treatment may improve their symptoms and quality of life. The study also includes a project focused on the family caregivers of patients with lung cancer. Nine articles detailing the results from the first phase of the project have been published in oncology and palliative care journals. The study continues through 2014.
Research into the tumor microenvironment, new drug combinations, DNA repair mechanisms, biomarkers, screenings, palliative care ... all hold the potential to change the future for lung cancer patients.