Lung Cancer: Advances in Current Treatment Modalities and Patient Classification
Posted May 28, 2014
Like other cancers of the internal organs not often diagnosed until late stages of disease, lung cancer is among the deadliest. In the U.S., the 5-year survival rate after diagnosis is lower than 15%. Lung cancer is also among the most common cancers, in part because of the continued prevalence of tobacco smoking. The American Cancer Association estimates that in 2014, 224 210 people will be newly diagnosed with lung cancer and 159 260 deaths will be associated with the disease. On March 25, 2014, the Biochemical Pharmacology Discussion Group convened physicians and scientists for the Lung Cancer: Advances in Current Treatment Modalities and Patient Classification symposium, to discuss advances in treatment as well as new information about genetic heterogeneity that may inform future trials. Despite poor outcomes for current treatments, the speakers were optimistic that therapeutic innovations will gradually improve prognoses for this seemingly intractable disease.
From refinements in surgical techniques to drugs targeting specific oncoproteins, the range of precision therapeutic tools to combat lung cancer is growing. Several speakers cautioned, however, that technological innovation alone will not dramatically transform lung cancer treatment. Rather, physicians must tailor treatments for each patient and deploy tools discriminately, biopsying and sequencing each tumor, for example, and choosing the most appropriate drugs among many. Roy Herbst and Balazs Halmos both related adaptive treatments that resulted in several rounds of remission in patients. However, successes like these have been achieved in large medical centers where clinicians had access to drug trials. Adapting protocols for personalized medicine in a wide range of clinical settings remains challenging.
In his introduction to the symposium, Shashidhar S. Jatiani of the Forest Research Institute reviewed the sub-classification of lung cancer into small cell and non-small cell types. The former is a grim diagnosis: patients almost always present with advanced disease because metastasis occurs early. Chemotherapy is the standard treatment. More common, however, is a diagnosis of non-small cell lung cancer (NSCLC), which accounts for approximately 85% of new cases. The speakers focused on the treatment of NSCLCs, which usually arise in the epithelium of the branched lung, most commonly as an adenocarcinoma.
When NSCLC is identified as a pre-metastatic tumor, the most effective treatment is surgery. Jessica S. Donington of NYU Langone Medical Center explained that a balance must be achieved between complete removal of cancerous cells and preservation of lung function. The standard of care is removal of the lobe containing the tumor, one of five lobes in the lungs. A complete lobectomy is an invasive procedure, requiring the surgeon to break several ribs to access the thoracic cavity. The average age of patients at diagnosis is 70 years old, and many patients require substantial care to recover from such a surgery. But it has become possible to perform more precise surgery: rather than remove the lobe entirely, many surgeons now resect a minimal amount of tissue, directed by the branched morphology of the lung, in a procedure called a segmentectomy. In addition, the use of laparoscopic cameras in a technique known as video-assisted thoracic surgery (VATS) now limits the size of the incision to the circumference of the tumor itself. An increasing number of hospitals now support robot-assisted surgery using the da Vinci Surgical System, which can also be used to achieve less-invasive segmentectomies. Both techniques decreased morbidity and mortality when compared to open thoracic surgery. Although purchasing and maintaining a da Vinci system is a substantial investment, significantly less money is required for postoperative intensive care and respiratory therapy when VATS and robot-assisted surgery are used compared to open surgery.
Inoperable tumors that arise close to the main airways, or in patients too frail to undergo surgery, are treated with radiation therapy. In an adaptation of a radiotherapy technique originally applied to brain tumors, lung tumors are now targeted more precisely and with higher doses of radiation using hypo-fractionated stereotactic body radiation therapy (SBRT). In the Netherlands, where practitioners have aggressively phased out older modes of radiation therapy in favor of SBRT, a greater than 36% increase in 8-month survival has been observed concurrent with the change.
Underlying the success of VATS, robot-assisted surgery, and SBRT is the theme that "less is more," Donington said. Less healthy tissue is destroyed, less time and resources are required for patient recovery, and patients are ideally better prepared to undergo adjuvant therapy.
When the primary tumor has metastasized, as in more advanced cases, chemotherapy is often prescribed in addition to surgical or radiological interventions. Unfortunately, in most patients traditional chemotherapy regimens afford delayed progression at best and are rarely curative. No progress has been achieved in developing more potent chemotherapies or combinations of cytotoxic drugs for lung cancer in over ten years. In response, many physician-scientists, including symposium speakers Roy S. Herbst, Balazs Halmos, and Suresh S. Ramalingam, have begun studying the efficacy of new drugs targeting specific oncogenic pathways. Through whole exome sequencing of lung tumors, a portrait of the most common genetic aberrations has emerged. Mutations in KRAS have been known to occur in lung adenocarcinomas for at least ten years, and comprehensive sequencing efforts have additionally implicated oncogenes, including the receptor tyrosine kinases EGFR, MET, RET, NTRK1, ROS1, and HER2; the serine threonine kinase BRAF; and the atypical receptor tyrosine kinase ALK. In fact, only 37% of examined lung adenocarcinomas do not harbor mutations in any of these genes.
Providing some historical perspective, Roy S. Herbst of Yale School of Medicine told participants that the first-generation receptor tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib entered the clinic in 1997, delivering modest response rates of less than 10%. Ten years later, with the emergence of deeper tumor exome sequencing, it became clear that responders were much more likely to harbor specific EGFR mutations, such as deletion of exons 19 or 21, which encode parts of the catalytic domain. Tumors with EGFR exon 19 deletion, in particular, exhibit susceptibility to erlotinib, which functions as a competitive inhibitor at the ATP binding site. Balazs Halmos of Columbia University Medical Center observed that based on the specificity of the TKIs, the conscientious clinician will need to become something of a "mutation aficionado," to be able to match the most efficacious TKI to each patient. At present, such choices are largely confined to clinical trials because erlotinib, gefitinib, imatinib, and afatinib are the only TKIs approved for lung cancer. Physician training will be needed as more of these drugs achieve FDA approval. To illustrate the complexity of genetics-based drug choice, Herbst mentioned the BATTLE-2 clinical trial, which he oversees. It compares several TKIs and employs a full-time statistician to conduct a Bayesian learning method to help oncologists to make the best drug/tumor match.
Receptor tyrosine kinase (RTK) inhibitors may target the mutated pathways that manifest in many lung adenocarcinomas, but a considerable proportion of tumors do not exhibit obvious mutations. From a therapeutic perspective, therefore, drugs must be developed to target more general molecular pathways that are active in tumor cells. Suresh S. Ramalingam of Emory University reviewed one such strategy, which targets the heat-shock protein HSP90. Heat-shock proteins bind and stabilize client proteins, including oncoproteins, thus preventing their degradation through the proteasome. Drugs that inhibit HSPs, such as the second-generation HSP90 inhibitor ganetespib, should theoretically facilitate the indirect degradation of oncoproteins. Moreover, such drugs will only target cancer cells, because HSP90 remains at very low levels in healthy tissue. Ramalingam outlined an active phase III study of ganetespib, the GALAXY-2 trial.
The TKIs are indeed revolutionary tools in the field of molecular oncology, but frustratingly, these novel agents only delay disease progression and do not increase survival rates among lung cancer patients. Selective pressures in the tumor microenvironment favor either cells that acquire subsequent mutations or the activation of downstream effectors that thwart the loss of the RTK. As Halmos explained, these mutations often occur in the RTKs themselves. In the case of epidermal growth factor receptor (EGFR), insertions into exon 20, or a threonine to methionine substitution in a part of the protein encoded by exon 20, render the mutant receptor resistant to TKIs. The speakers speculated that combinations of drugs targeting several oncoproteins may circumvent the problem of tumor resistance, but available agents are limited and there are no obvious putative combination therapies.
Rolf Brekken of UT Southwestern Medical Center outlined the rationale for using immunotherapy to combat lung cancer. A hallmark of tumor cells is their evasion of immune detection, achieved in part by the presentation of phosphatidylserine (PS) in the outer cell membrane. In healthy cells, this phospholipid is confined to the inner leaflet of the cell membrane. When PS becomes externalized, as in normal apoptosis, PS receptors in macrophages that detect the dying cell trigger the release of immunosuppressive cytokines. Brekken hypothesized that if this process can be inhibited, an adaptive immune response might ensue. The monoclonal antibody bavituximab, developed by Peregrine Pharmaceuticals, targets glycoprotein-bound PS. Preclinical data using bavituximab to combat a rodent tumor model is encouraging, with tumors completely regressing in some rats. Brekken's lab has observed several lines of evidence suggesting that an innate immune response occurred in bavituximab-treated rats, leading to the development of anti-tumor T cells. As several speakers noted, the best test of this therapy would be to reintroduce tumor cells to the rats and observe whether the cells are targeted and destroyed by an immune response. Such a result would be astonishing. Indeed, the potential of immunotherapy in cancer treatment has recently received considerable attention from the popular media. Several antibodies have entered clinical trials, including bavituximab, which is in a phase III NSCLC trial called SUNRISE.
From new developments in surgery and radiation therapy to a rapidly expanding collection of drugs in the field of molecular oncology, we are poised to improve the prognosis for many lung cancer patients. Key to success will be a continued emphasis on personalized medicine, augmenting the standard diagnostic regimen to include molecular testing to match each patient with a targeted therapeutic approach.
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Presentations available from:
Rolf Brekken, PhD (UT Southwestern Medical Center)
Jessica S. Donington, MD (NYU Langone Medical Center)
Balazs Halmos, MD (Columbia University Medical Center)
Roy S. Herbst, MD, PhD (Yale School of Medicine)
Shashidhar S. Jatiani, PhD (Forest Research Institute)
Suresh S. Ramalingam, MD (Emory University)
The Biochemical Pharmacology Discussion Group is proudly supported by
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Advances in surgery and radiotherapy
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Magdalena Alonso-Galicia, PhD
Forest Research Institute
Magdalena Alonso-Galicia is a senior principal scientist at the Forest Research Institute, a subsidiary of Forest Laboratories Inc. As a non-clinical pharmacologist, she is responsible for developing and directing pharmacology studies to support approved products and early- and late-stage drug candidates in the respiratory and cardiovascular therapeutic areas. She is also the pharmacology reviewer of new licensing opportunities in multiple therapeutic areas such as cardiovascular, respiratory, renal, and metabolic disorders. Prior to joining Forest in 2010, she worked in drug discovery at Boehringer Ingelheim and Merck & Co. in the areas of hypertension, heart failure, and chronic kidney disease. She holds a PhD in physiology and biophysics from the University of Mississippi and underwent postdoctoral training at the Medical College of Wisconsin.
Shashidhar S. Jatiani, PhD
Forest Research Institute
Shashidhar S. Jatiani has worked in preclinical anticancer drug discovery and development since 2005. He obtained his PhD in molecular biology from Tata Institute for Fundamental Research, India. He currently works as a research scientist in the pharmacology group of Forest Research Institute. Jatiani has extensive preclinical experience in myeloproliferative neoplasms, leukemias, solid tumors, and immuno-oncology.
Huiping Jiang, PhD
Boehringer Ingelheim Pharmaceuticals
Huiping Jiang holds a PhD in molecular cell biology. Her postdoctoral research focused on mammalian genetics and cellular signal transduction. Huiping started her pharmaceutical career at AstraZeneca as a research scientist, and later moved to Boehringer Ingelheim Pharmaceuticals as a principal scientist specializing in transgenic pharmacological models. She is now director of regulatory affairs. Huiping is an active steering committee member of the Biochemical Pharmacology Discussion Group and has contributed to several Academy symposia.
George Zavoico, PhD
George B. Zavoico joined HC Wainwright & Co. (HCW), a boutique investment bank and institutional broker-dealer, as managing director and senior equity analyst in early 2014. He has over 10 years of experience as a life sciences equity analyst, working at MLV & Co., Westport Capital Markets, and Cantor Fitzgerald. Before becoming an equity analyst, Zavoico established his own consulting company serving the biotech and pharmaceutical industries and wrote extensively on health care and the biotechnology and pharmaceutical industries. Zavoico began his career as a senior research scientist at Bristol-Myers Squibb, and later worked at Alexion Pharmaceuticals and T Cell Sciences (now Celldex Therapeutics Inc.). He holds a PhD in physiology from the University of Virginia and completed postdoctoral fellowships at the University of Connecticut School of Medicine and at Harvard Medical School and Brigham & Women's Hospital.
Jennifer Henry, PhD
The New York Academy of Sciences
Jennifer Henry is the director of Life Sciences at the New York Academy of Sciences. Henry joined the Academy in 2009, before which she was a publishing manager in the Academic Journals division at Nature Publishing Group. She also has eight years of direct editorial experience as editor of Functional Plant Biology for CSIRO Publishing in Australia. She received her PhD in plant molecular biology from the University of Melbourne, specializing in the genetic engineering of transgenic crops. As director of Life Sciences, she is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology. She also generates alliances with organizations interested in developing programmatic content.
Rolf Brekken, PhD
Rolf Brekken received his PhD in cell and molecular biology from UT Southwestern Medical Center, where he trained under Dr. Philip Thorpe. His graduate studies focused on developing novel therapies that target the vascular compartment of tumors. He was a postdoctoral fellow in the Department of Vascular Biology at the Hope Heart Institute in Seattle, where he studied how the extracellular matrix contributes to vascular function and tumor progression. He joined the Department of Surgery at UT Southwestern as faculty in 2002 and was promoted to associate professor with tenure in 2009. Brekken is now the Effie Marie Cain Scholar in Angiogenesis Research. His laboratory is located in the Hamon Center for Therapeutic Oncology Research and he is a member of the Simmons Comprehensive Cancer Center. Brekken's laboratory studies the tumor microenvironment, particularly how therapy affects the tumor microenvironment and how stromal elements influence response to therapy. He is also a senior editor for Cancer Research.
Jessica S. Donington, MD
Jessica S. Donington is a general thoracic surgeon at NYU School of Medicine. She is an associate professor in the Department of Cardiothoracic Surgery, director of the NYU Thoracic Oncology Translational Laboratory, and chief of the Thoracic Surgery Service at Bellevue Hospital. Her laboratory work focuses on the discovery and validation of diagnostic and prognostic biomarkers for thoracic malignancies and on the role of osteopontin, a ubiquitous protein, in carcinogenesis. Her clinical interests focus on the diagnosis and treatment of mesothelioma and non-small cell lung cancer. Areas of clinical expertise include the use of multimodality therapy for thoracic malignancies, treatment options for high-risk patients with early-stage lung cancer, and cancer in women. Donington holds an MD from Rush Medical College of Rush University.
Balazs Halmos, MD
Balazs Halmos is an associate professor of medicine at Columbia University and section chief of thoracic oncology at New York Presbyterian Hospital. Besides maintaining an active clinical practice focused on the management of patients with malignancies of the thoracic cavity, Halmos oversees the thoracic clinical trials program at Columbia University. He also runs a translational research laboratory investigating novel ways to overcome resistance to conventional as well as targeted therapeutics. He is chair of the Cancer Institutional Review Board of Columbia University. Halmos holds an MD from Semmelweis Medical University, Hungary.
Roy S. Herbst, MD, PhD
Roy S. Herbst is the Ensign Professor of Medicine, a professor of pharmacology, chief of medical oncology, director of the Thoracic Oncology Research Program, and associate director for translational research at Yale Cancer Center (YCC) and Yale School of Medicine. Herbst has led the phase I development of several new generation targeted agents for non-small cell lung cancer (NSCLC), including gefitinib, erlotinib, cetuximab, and bevacizumab. He is co-lead for the BATTLE-1 trial, co-lead for the subsequent BATTLE-2 clinical trial program, and a co-program lead of the Developmental Therapeutics Program for the YCC Cancer Center Support Grant (CCSG). He is a member of the National Cancer Policy Forum, for which he has organized an Institute of Medicine meeting focused on policy issues in personalized medicine. His laboratory work is focused on angiogenesis and dual EGFR/VEGFR inhibition in NSCLC. Herbst previously served at the University of Texas MD Anderson Cancer Center. He holds a PhD from The Rockefeller University and an MD from Cornell University Medical College.
Suresh S. Ramalingam, MD
Suresh S. Ramalingam received his MD at Kilpauk Medical College, India. He completed his residency in internal medicine at Wayne State University, where he also served as a chief medical resident, then completed a fellowship in hematology and medical oncology at the University of Pittsburgh Medical Center. Ramalingam is an associate professor at Emory School of Medicine and chief of medical oncology in the Department of Hematology & Medical Oncology. He plays an active role in the ECOG-ACRIN Cancer Research Group as the chair of the Thoracic Malignancies Committee. He also serves on the editorial board of leading cancer journals such as the Journal of Clinical Oncology; Cancer; Clinical Lung Cancer; and Cancer, Chemotherapy and Pharmacology. Ramalingam is the recipient of awards including the James Eckman Award for Excellence in Teaching, the Distinguished Cancer Scholar Award from Georgia Cancer Coalition, and the ASCO Career Development Award (2006–2009).
Paul Riccio is a postdoctoral research scientist at Columbia University. He has a broad interest in the genetic regulation of development and is currently using new genetic techniques to study kidney patterning and regeneration.
This program is supported in part by a grant from Genentech Inc.