|Honokiol in Combination with a Low Dose Oxaliplatin Can Induced Apoptosis of the Human Lung Adenocarcinoma A549 Cells|
|Abstract||Honokiol is a kind of compounds with hydroxypropyl joint hydroquinone.It is separated from a kind of traditional Chinese medicine Magnolia, which have biological activity and a variety of pharmacological effects. Among of effects, the most attention is its anti-tumor effect. Mainly it manifests in the following areas:induced apoptosis of tumor cells and promote tumor cell differentiation, inhibit tumor cell proliferation, inhibit tumor cell metastasis, inhibit angiogenesis, the role reversal of multi-drug resistance.Oxaliplatin is considered of the third-generation platinum-type antineoplastic agents. Currently oxaliplatin is widely used. In vitro, the effect of oxaliplatin is better than cisplatin. However, as chemotherapy drugs, oxaliplatin are peripheral neuropathy and other serious side effects.In this study, different concentrations of honokiol, low-dose oxaliplatin, or both combined effects on the human lung adenocarcinoma A549 cells.After the A549 cell is cultured for 48 hours incorporation of these drugs, MTT is employed to investigate proliferation of drugs on human pulmonary gland carcinoma A549 cells. Flow cytometry is used to investigate the cell apoptosis.The results showed that Compared to honokiol or oxaliplatin alone, significant improvements in cell apoptosis and growth inhibition indexes were observed in the combined treatment. These findings indicate that parthenolide could markedly enhance sensitivity of A549 cells to low dose oxaliplatin by inducing apoptosis in vitro experiments. honokiol in combination with a low dose oxaliplatin may be a beneficial chemotherapeutic strategy for patients who cannot tolerate the severe side-effects of the drug at therapeutic concentrations.Buy This Research Paper Now!|
Archive for the ‘Lung Cancer’ Category
Honokiol in Combination with a Low Dose Oxaliplatin Can Induced Apoptosis of the Human Lung Adenocarcinoma A549 Cells
Category Combination Treatments, Honokiol, Lung Cancer, Oxaliplatin
Category Finance and Politics of cancer research and treatment, Fraud, Lung Cancer
By Ivan Oransky, MD
NEW YORK (Reuters Health) – In a reminder of how much a once-heralded area of lung cancer research has crumbled, a former Duke oncologist and his colleagues issued their eighth study retraction late last week.
On Friday, Dr. Anil Potti and his co-authors formally withdrew a 2008 study in the Journal of the American Medical Association (JAMA) that purported to offer a “genetic signature” that would show which patients with breast cancer would respond to a particular treatment.
The authors write in a statement on the JAMA website — available at bit.ly/AeIufY — that they are retracting the paper because it was based on a method they now believe is unreliable. That approach — which no one has been able to reproduce — was described in a now-withdrawn paper in the journal Nature Medicine in 2006.
The case is yet another example of researchers — some of whom had financial interests in the method — being overly enthusiastic about findings that held great promise for very sick patients, but that did not hold up to scrutiny.
The retraction is the eighth of what Duke officials said this past summer would be about a dozen, along with another dozen corrections and partial retractions. The Duke team had published about 40 papers, many of which have been cited hundreds of times by other scientists, according to Thomson Scientific’s Web of Knowledge.
The now-retracted JAMA study garnered a fair amount of media coverage, too, including a story by Reuters Health on April 1, 2008.
Journals and universities began subjecting the work to intense scrutiny, however, after it emerged that Potti had claimed awards and scholarships that he never received, in biographical sketches for grant applications.
The whole episode has been a “huge setback,” said Dr. Otis Brawley, chief medical officer of the American Cancer Society.
“What happened at Duke is that you have a whole bunch of folks worried that this genomic information is just too complicated, making it too easy for someone to basically create fraudulent science,” Brawley told Reuters Health.
UNDONE BY RESUME ‘INACCURACIES’
Keith Baggerly, who studies genomics at the M.D. Anderson Cancer Center in Houston, has been looking into the Duke team’s data since shortly after the Nature Medicine report came out. A colleague approached him and Kevin Coombes excitedly at the time, hoping he could use the work to improve the treatment of patients at M.D. Anderson.
But Baggerly and Coombes found numerous problems in the research, including mislabeling of data. He began asking the Duke team for their data, but they were slow to provide it. Eventually, some journals began publishing his critiques, often alongside defenses of the work by Potti and his colleagues. Meanwhile, clinical trials making use of the genetic signature continued at Duke.
Baggerly’s questions went largely unheeded until July 2010, when The Cancer Letter, a trade publication, reported that Potti had falsely claimed to be a Rhodes Scholar on an American Cancer Society grant application. Within months, the trials were halted, and Duke returned $729,000 to the cancer organization.
Potti resigned from Duke in November 2010, and has since joined a private oncology practice with offices in North Carolina and South Carolina. He and his colleagues, along with Duke, face two lawsuits from nine patients who took part in the trials. Eleven other such cases have already been settled for at least $75,000 each, according to the North Carolina Medical Board, which reprimanded Potti for the “inaccuracies” on his biographical sketch and CV.
According to the JAMA retraction notice, Potti works at the Myrtle Beach, South Carolina office of Coastal Cancer Center. But a person answering the phone there said he did not work in that office and was unavailable because he was in clinic.
For plaintiffs’ attorneys, proving that patients were actually harmed by being in the trials will be difficult, said Brawley.
“I don’t myself think that patients were harmed by being steered to a particular chemotherapy, at one level,” he said. The choices in the trial were widely accepted therapies that their own doctors would have likely given them.
That wasn’t the only risk, however.
“I’m a little bit concerned that some of the patients may have gone back and had new biopsies, for new analysis in the laboratory,” Brawley said. “If that was purely for this trial, those were unnecessary procedures, with risks. I hope no one was harmed by that.”
The episode is fueling soul-searching at Federal agencies.
There are “some positive things coming out of this whole mess,” Baggerly said. One potential move being considered as part of a review of cancer genomics studies by the U.S. Institute of Medicine (IOM), for example, is to require genetic tools such as the one the Duke team used to go through the same approvals that a medical device would go through at the Food and Drug Administration.
The IOM’s report is expected out in the next few months, and there are similar changes being considered at the National Cancer Institute — which funded some of the Duke team’s work — and the Food and Drug Administration. Duke itself has created a team to establish new safeguards as genetic research moves into the clinic.
But the dark lessons remain.
“To a certain extent, what I’m worried about is that this may show aspects of how it is becoming increasingly difficult to check the scientific literature and how that difficulty stems at least in part from lack of immediate access to data but also lack of code and documentation,” Baggerly told Reuters Health.
Given the highly technical nature of the work, it’s not surprising that the flaws in the papers weren’t caught before they were published, according to Baggerly.
“That’s actually OK,” he said. “It’s not OK that it took so long for the challenges to be accepted once the research was questioned.”
“The other thing that is not OK is the fact that it made it into guiding clinical trials,” Baggerly added.
Brawley said the story “is a tragedy in a number of different ways.”
“I’m actually more concerned right now with the systemic issue across the country that it’s up to universities to police their researchers,” he said. “But as science progresses, those universities are more and more interested in how many patents they have, and how many licenses they have for those patents.”
“The universities that are responsible for assuring academic integrity actually have a conflict of interest,” said Brawley, pointing out that Duke had an ownership stake in CancerGuide Diagnostics (formerly Oncogenomics, Inc.).
CancerGuide, which cut ties with Potti in July 2010 after the Rhodes misrepresentation came to light, had licensed technology based on Potti’s work from Duke, the student newspaper The Duke Chronicle reported in 2010. Duke has since divested from the company.
‘A 21ST CENTURY DEFINITION OF CANCER’
Despite the setback, cancer treatment will continue to make more and more use of genetic information, Brawley said. Oncologists already use tools such as the OncotypeDX genetic test to tailor treatments for breast cancer and colon cancer.
“Since the 1840s, we’ve been using a light microscope to define cancer,” he said. “Now with all the other advances we have, even the needle biopsy, we often find a one-centimeter tumor, and we’re saying ‘this looks like cancer,’ according to a 19th-century definition. What we need is a 21st century definition of cancer.”
“We’ve got these new tools, and people are very excited about using them,” Baggerly said. “Some of these genetic level screw-ups are indeed what cause the disease, so there is the potential there. That said, some of the initial claims about how quickly we’re going to be able to turn these (findings) into clinically useful assays have been overoptimistic.”
“We’re going to get there, but a number of the early studies thought this would be an easy problem,” he said. “The biology turns out to be quite complex.”
(This story corrects the date in paragraph 12 and adds Kevin Coombes’ name to paragraphs 10 and 11.)
SINGAPORE, Jan. 6 (Xinhua) — A team of Singaporean scientists have identified a gene responsible for lung cancer, the Agency for Science, Technology and Research said on Friday.
A small number of cells, known as cancer stem cells or tumor- initiating cells (TIC), are responsible for the promotion of tumor growth. The team of scientists found a marker, known as CD166, to identify these cells, it said.
The team, led by Bing Lim, associate director of cancer stem cell biology at the Genome Institute of Singapore, and Elaine Lim, medical oncologist affiliated with Tan Tock Seng Hospital and National Cancer Center Singapore, did more genomic study of the TICs, and discovered several genes that were important for the growth of cancer cells.
The scientists discovered that in abnormal instances when the level of a metabolic enzyme known as glycine decarboxylase rises significantly, it causes changes in the behavior of the cell, making it cancerous.
The glycine decarboxylase is a normal occurring enzyme in cells, present in small quantities.
The finding is reported in the online advance issue of Cell on Jan. 5 and is believed to be a huge step towards finding a cure for the disease.
The Power of Preservation: Minimally Invasive Lung Cancer Treatment at South Nassau Communities Hospital
Category Lung Cancer, Osteosarcoma surgery, Surgery, Surgery, Thoracic Surgery
A decade ago, a lung cancer diagnosis left both patients and physicians with few options. Today, while surgery remains the gold standard, the approach to this treatment has changed. Thoracic surgeons at South Nassau Communities Hospital are forging innovative surgical ground and safeguarding patients’ lungs.
According to the American Cancer Society, 221,130 new cases of lung cancer will be diagnosed in 2011. Almost 17,000 cases of esophageal cancer will be diagnosed, and, though the incidence rate is extremely low, patients with these types of cancers can develop tumors within and around the heart. Before 2004, Long Island residents with disease of the chest cavity made the long trek to Manhattan for consultations, treatments and follow-up care.
With the arrival of Shahriyour Andaz, M.D., FACS, FRCS, Director of Thoracic Oncology at South Nassau Communities Hospital and associate professor in the Department of Surgery at Hofstra University, two principles of thoracic care on Long Island have shifted significantly. Patients now have an alternative to Manhattan medicine, and with the investment in advanced technologies at South Nassau Communities Hospital, they also have an alternative to traditional open chest surgery.
“In the past, surgeons would make a large incision to cut the ribs and access the chest. That was a painful operation, so we’ve moved away from major incisions to doing smaller and smaller cuts,” says Dr. Andaz. “Now, 80% to 90% of all the cancer we take out is done through small, minimally invasive incisions.”
A Renaissance of Surgical Technique
The robotic da Vinci Surgical System offers Dr. Andaz and his colleagues in the thoracic oncology program the visualization and maneuverability necessary to promote minimally invasive approaches to technically demanding procedures. The three-dimensional views and flexibility of robotic hands, which are carefully controlled by the surgeon, facilitate the delicate dissection of blood vessels and the resection of the lungs’ lobes through centimeter-long incisions.
In the case of a video-assisted thoracoscopy, which allows the surgeon to evaluate the chest cavity for lung cancer or remove a tissue sample for further analysis, the da Vinci Surgical System has supplanted the need for an open chest thoracotomy. Dr. Andaz makes two or three small incisions between the ribs, and the lung is deflated to allow for a greater space between the lung and chest wall. That vantage point provides access to the lung for an endoscope, which Dr. Andaz uses to view and sample any potentially malignant tumor on the lung. The sample is then sent to the laboratory for pathological testing.
While the da Vinci Surgical System is utilized for general, gynecologic, kidney, prostate and urologic procedures, the technology allowed Dr. Andaz to become the first health care provider on Long Island to perform a robotic thymectomy and robotic bilobectomy in 2010 and 2011, respectively.
Operating Across the Aisle
“Most surgeons will not do a bilobectomy for central tumors — the type of tumor that straddles the airway and involves blood vessels stuck to the tumor,” says Dr. Andaz. “The da Vinci can help with the tedious process of dissecting those blood vessels.”
The complexity of a bilobectomy is grounded in the need to remove both the lower and middle lobes of the lung — leaving only the upper lobe — to ensure that wide enough margins are created and no cancer cells are left behind. In addition, the complex network of blood vessels stretching over the fissures in the lungs poses a challenge in cleanly resecting the necessary portions of the lung.
To begin, the attending anesthesiologist puts the patient under and slowly deflates one lung. Dr. Andaz then makes four 2-centimeter-long incisions in the chest wall and guides the da Vinci Surgical System’s robotic arms into the chest through the incisions, allowing him to concentrate on excising the lower lobe. The precise instrumentation divides the blood vessels and pulmonary vein from the lung tissue without disrupting the blood flow to the heart.
Next, Dr. Andaz exposes the fissure between the lower and middle lobes to allow for visualization of the pulmonary artery. With the three-dimensional da Vinci Surgical System camera, he is able to safely encircle and divide the branches leading to the lower lobe. After removing the lower lobe tissue, Dr. Andaz begins dissecting the pulmonary artery branches to the middle lobe. That separation allows him to dissect and divide the bronchus to the middle and lower lobes.
Dr. Andaz explains that the ability to remove both the lower and middle lobes of the lung can often depend on how much reserve a patient has in his or her lungs. The resection of one lobe diminishes lung function by 10% to 15%; the loss of two lobes results in a 20% to 25% reduction in total capacity; and the removal of all three lobes — the entire right lung — equals a 40% to 50% loss of the combined lung capacity. All surgical candidates undergo pulmonary function testing before being cleared for robotic surgery.
After the final tissue resection, Dr. Andaz retracts the da Vinci Surgical System’s arms and closes the incisions while the anesthesiologist carefully re-inflates the lung. Patients typically remain in the inpatient unit at South Nassau Communities Hospital for four to five days.
Tackling the Thymus Gland
Just as the da Vinci Surgical System has allowed Dr. Andaz and his colleagues to move away from the open chest thoracotomy, the technology has opened up new avenues for removing the thymus gland. The traditional procedure involved splitting the sternum with a major incision to access the chest cavity. Dr. Andaz can perform a robotic thymectomy instead, which approaches the organ — located in a tight space between the heart and the breastbone — through small incisions placed on the side of the patient.
“Usually, as a person ages, the thymus gland — like the tonsils — becomes smaller and almost disappears,” says Dr. Andaz. “For some people, however, the thymus gland continues to grow and enlarge and can lead to myasthenia gravis, an autoimmune disease that allows small proteins to cling to muscle receptors and leads to a neuromuscular disorder.”
Myasthenia gravis can present through symptoms centering on fatigue, including drooping eyes, difficulty breathing, chewing and swallowing, and weakness in the arms and legs. As Dr. Andaz explains, removing the thymus gland in patients with the condition can provide significant relief for their symptoms.
For the robotic procedure, Dr. Andaz makes three 2-centimeter incisions at the side of the chest for lateral access. Seated at the da Vinci Surgical System console, Dr. Andaz manipulates the robotic arms to find the thymus gland behind the breastbone. He then completes the delicate separation of the gland from the adjacent fat, pericardium and the innominate vein.
After resecting the thymus gland, Dr. Andaz closes the incisions, and the anesthesiologist re-inflates the lung. Patients typically spend one to two days in the hospital and are back to work in one or two weeks.
Targeting the Right Site
For lung cancer patients whose poor lung reserves eliminate them from the surgical candidate pool, radiation has traditionally been the next treatment option. The choice is often made in an attempt to conserve what little function the lungs have. However, standard radiation often poses a significant threat not only to the tumor, but also to the surrounding healthy tissue.
“The problem with standard radiation is that the treatment can essentially cook the entire lung. The radiation can damage the surrounding lung tissue, which is difficult for someone who has poor lung reserve to begin with,” says Dr. Andaz. “The Novalis Tx radiosurgery technology uses advanced computerized techniques to focus an intense radiation beam on the tumor site only to preserve the rest of the lung.”
The radiosurgery platform offers a noninvasive, customizable treatment alternative to surgery. The system’s mechanical accuracy is within 0.5 millimeters of the tumor site during treatment, while the MV Portal Vision allows radiation oncologists to view the exact location of the tumor as the system targets it.
The Novalis Tx is also equipped with gating features to adapt the radiation to the patient’s natural respiration cycle. In addition, the system reduces the requisite number of treatments as compared to the standard radiation therapy. Patients undergo treatment once a week for only three to four weeks rather than six weeks.
The Communal Process
Every month, the specialists within the thoracic oncology program meet for a program-specific tumor board. The conference reviews patient cases one by one for insight from each physician, even those not directly involved in the treatment, which allows for a dynamic and multifaceted discourse. Medical oncologists, pathologists, pulmonologists, radiation oncologists, radiologists and surgeons are joined by primary care physicians to evaluate a patient from every possible perspective.
“These are very complicated decisions, and it requires lots of people to be involved in the decision-making process,” says Dr. Andaz. “I’m very open to the discussion of alternatives to the management of the case.”
In addition, staff with the thoracic oncology program participate in the weekly tumor board at South Nassau Communities Hospital and meet on a need-appropriate basis between the established conferences.
To learn more about thoracic oncology at South Nassau Communities Hospital, visit www.southnassau.org and click on “Surgical Services” and “da Vinci Robotic Surgery” under the “Services/Specialty Centers” tab.
A Measure of Change in Lung Cancer Detection
To maximize the rate of survival among women with breast cancer, the American Cancer Society recommends every woman receive a mammogram annually after age 40. To increase the survival rate among men and women diagnosed with colon cancer, the organization advises people older than 50 undergo a colonoscopy every 10 years. Now, lung cancer has a similar screening recommendation.
A 1991 initiative launched by a group of physicians from Cornell University Medical Center — investigating the impact of helical computed tomography (CT) imaging on the early detection of lung cancer — discovered that, when caught in Stage I, lung cancer isn’t as deadly.
“The traditional data has shown the overall survival rate is 15% at five years, meaning that 85% of patients will die,” says Shahriyour Andaz, M.D., FACS, FRCS, Director of Thoracic Oncology at South Nassau Communities Hospital and associate professor in the Department of Surgery at Hofstra University. “The participants in the Cornell study showed a survival rate far superior than any other data we have: 90% at 10 years. Even though lung cancer is three times as prevalent as breast cancer, there has been no test to detect early lung cancer — until this.”
In fact, the initiative has developed protocols to a) identify high-risk patients, b) distinguish between benign and malignant nodules detected by the CT scan, and c) determine when to biopsy or monitor the nodules, as well as timetables for when to follow up with patients. The International Early Lung Cancer Action Program (I-ELCAP) includes 48 institutions in nine countries, including South Nassau Communities Hospital, where Dr. Andaz pioneered the program.
Dr. Andaz recognized the significance of the I-ELCAP, and for the last three years, South Nassau Communities Hospital has contributed data to the program while offering free CT scans for high-risk patients in the community. The data is then sent to Mount Sinai Medical Center and incorporated into the I-ELCAP database. According to Dr. Andaz, of the 800 to 900 patients imaged at South Nassau Communities Hospital, 30 have been diagnosed with lung cancer, and 90% of the cases were detected within Stage I.
Green tea polyphenol EGCG suppresses lung cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-1α
Category Green Tea (Epigallocatechin-3-gallate), HIF-1α, Hypoxia, Lung Cancer, MicroRNA, miR-210
+ Author Affiliations
Susan L. Cullman Laboratory for Cancer Research, Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA
- ↵*To whom correspondence should be addressed. Tel: +1 732 445 3400; Fax: +1 732 445 0687;Email: firstname.lastname@example.org
- Correspondence may also be addressed to Chung S. Yang. Email: email@example.com
- Received May 3, 2011.
- Revision received September 21, 2011.
- Accepted September 24, 2011.
(−)-Epigallocatechin-3-gallate (EGCG) has been reported to affect many cellular regulatory pathways. This study aims to determine whether EGCG could target microRNA (miRNA), one of the mechanisms for cells to achieve subtle change in multiple targets. We found that, in both human and mouse lung cancer cells in culture, EGCG specifically upregulated the expression of miR-210, a major miRNA regulated by HIF-1α. Furthermore, we found that overexpression of miR-210 led to reduced cell proliferation rate and anchorage-independent growth as well as reduced sensitivity to EGCG. On the mechanisms of miR-210 regulation by EGCG, we demonstrated that the regulation was mediated through the hypoxia-response element in miR-210 promoter. Consistently, the upregulation of miR-210 was found to be correlated with the stabilized HIF-1α in lung cancer cell lines after EGCG treatment. This EGCG-induced stabilization of HIF-1α was further shown by the stabilization of HA-tagged HIF-1α but not the P402A/P564A-mutated HIF-1α by EGCG, suggesting that EGCG targets the oxygen-dependent degradation (ODD) domain. Direct evidence was obtained by affinity binding assay showing that EGCG specifically binds HIF-1α with a Kd = 3.47 μM. This result suggests that EGCG binding interferes with the hydroxylation of key Pro residues in the ODD domain, preventing HIF-1α from the Pro hydroxylation-dependent ubiquitination and subsequent proteosome-mediated degradation. In summary, our results demonstrated, for the first time, the elevation of miR-210 by EGCG in lung cancer cell lines and this is mediated by the stabilization of HIF-1α. This event contributes to the anticancer activity of EGCG.
- hypoxia-induced factor
- hypoxia-response element
- messenger RNA
- 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide
- oxygen-dependent degradation
- polymerase chain reaction
- superoxide dismutase
Category ALK, EGFR, Gene sequencing, genetic research, KRAS, Lung Cancer, Personalized, Tumor biomarkers
November 11, 2011 — Sending off a tumor sample for a broad screening of genetic aberrations, instead of just a single test, increases the chance of finding a therapy that the patient will respond to, and it might also improve survival, say researchers from Massachusetts General Hospital (MGH), in Boston, who are already using the screen in routine clinical practice.
The broad genetic screen, known as SNaPshot, is advertised around the hospital with a poster that depicts a fingerprint, declaring: “Our patients are unique. So are their tumors.”
The screen can test for more than 50 well-known mutation sites (hot spots) in 14 key cancer genes, and has a turnaround time of less than 3 weeks.
“To our knowledge, we are the first center to offer this broad multiplexed genetic screening to all nonsmall-cell lung cancer [NSCLC] patients,” said Lecia Sequist, MD, MPH, a thoracic medical oncologist at MGH and assistant professor of medicine at Harvard Medical School. She is first author of a paper that reports on the use of the screen in 552 patients with NSCLC, published online November 9 in the Annals of Oncology.
Broad Screen Found Extra Patients
Up to now, genotyping strategies have typically homed in on 1 genetic mutation; for example, lung cancer patients are tested for the epidermal growth-factor receptor (EGFR) gene to identify those who will respond to the EGFR inhibitors erlotinib and gefitinib.
However, “employing a broad gene panel enabled us to provide a therapeutic alternative to lung cancer patients whose tumors harbored much less frequent genetic abnormalities, such as mutations in PIK3CA and BRAF or rearrangements in ALK,” explained senior author Dora Dias-Santagata, PhD, director of the Translational Research Laboratory at MGH.
“These individuals accounted for about 10% of our patient population, but they would have remained ‘invisible’ in the absence of a comprehensive genotyping panel, like the one used here,” she said in a statement.
Identifying these genetic aberrations allowed the researchers to offer patients treatment with targeted therapies that act specifically on those aberrations, which increases the likelihood that the patient will respond to treatment. “Choosing the right therapy can raise response rates in NSCLC patients from around 20% to 30% to 60% to 70%, and may improve survival,” Dr. Sequist said
Use in Other Cancers
The team is currently offering the screening to patients with other solid tumors, such as colorectal and breast cancers, and gliomas, and they are planning to extend the analysis to hematologic malignancies.
“Our study is exciting because it demonstrates that it is possible today to integrate testing for multiple genetic biomarkers in a busy clinic and steer patients toward personalized therapies,” Dr. Sequist explained.
“My message to oncologists is that now is the time to begin thinking about how best to work with pathology — as well as surgery, radiology, and pulmonology — colleagues, to try to adapt their practice toward broad-based genotyping,” she told Medscape Medical News.
“It is something that can be done at most hospitals. We, as a field, need to update our diagnostic practices to accommodate this important test,” Dr. Sequist added.
This is a superb initiative.
“This is a superb initiative,” said Jean-Charles Soria, MD, PhD, current president of the European Society for Medical Oncology. This group at MGH is a pioneer in this field, and has “accomplished a tour de force by offering this comprehensive analysis to all their NSCLC patients since 2009,” he told Medscape Medical News.
Although ahead of the game, this work is not entirely unique, he said. A similar approach is being developed at many other large cancer centers, including the Dana-Farber Cancer Institute in Boston; the University of Texas M.D. Anderson Cancer Center in Houston; The Royal Marsden in London, United Kingdom; Val d’Hebron in Barcelona, Spain; and his own center, Institute Gustave Roussy in Villejuif, France.
Medscape Medical News has previously reported on the broad-screen genotyping carried out at M.D. Anderson and by the Lung Cancer Mutation Consortium, which involves 14 centers in the United States. However, these initiatives are focused on enrolling patients in clinical trials, whereas the MGH team is using their broad screen in routine clinical practice.
“This approach will become standard practice in all major academic centers in Europe and North America…in 3 to 5 years at most, in my opinion,” Dr. Soria predicted.
At the moment, this approach belongs in academia and large care centers, said Alex Adjei, MD, a thoracic oncologist who is senior vice president of clinical research and professor of medicine at the Roswell Park Cancer Institute in Buffalo, New York. He agrees that broad-based genotyping is something that oncologists need to think about, but argued that this approach is not ready for widespread use. “It will become relevant to community oncologists, but that is a few years away,” he told Medscape Medical News.
Dr. Adjei explained that, at the moment, the main problem with this approach is that a lot of the information obtained is of academic interest and has little practical relevance. There are currently only a few targeted drugs available that home in on genetic aberrations. Although there are many under development, the only way to get a patient on these is to enroll them in a clinical trial, which best done in academic hospitals and large cancer centers, he said.
It makes sense to screen for many different mutations and genetic aberrations all at once, rather than one at a time, but for this approach really to come into its own, “we need to have more drugs available,” he said.
Right now it’s not ready for general use.
“For this to become routine and for this to make sense, we have to have more actionable mutations,” he said. “There is no point looking at 15 genes and finding 50 mutations when you can treat only a few of them.”
“SNaPshot is a great idea and has great utility because it is going to simplify molecular testing. This is the way of the future, but right now it’s not ready for general use,” Dr. Adjei concluded.
A slightly different opinion comes from community oncologist Patrick Cobb, MD, from Billings, Montana. Some practices are sending off tumor samples for broad genotyping. “It is already starting to happen at the community level,” he said.
“It is relevant to us,” he explained. Community oncologists are having to keep up with research and to change their practices accordingly, Dr. Cobb said. It is already standard practice to test colorectal cancer for KRAS (and BRAF) mutations and to use Oncotype Dx in breast cancer. These test results are influencing treatment decisions, and sparing some patients unnecessary adverse effects, he said. His own practice is considering EGFR and ALK testing for lung cancer, but hasn’t done so yet; however, they are testing melanoma for BRAF mutations.
“There’s much more collaboration nowadays between medical oncologists and pathologists,” Dr. Cobb said. “We’ve always been tied at the hip,” but in recent years, with pathologists providing information on mutations as well as histology, that collaboration has intensified.
“As an oncologist, this is an exciting time. We are really seeing the benefit of bench research starting to affect the way we are treating our patients,” he said.
Between the top academic centers and community practices are the middle-sized hospitals. Curtis Miyamoto, MD, is a professor of radiation oncology at just such a hospital — Temple University Hospital in Philadelphia, Pennsylvania. He thinks that “this broad genetic testing will be mainstream in the future, probably 5 years from now, but it’s not mainstream yet.”
“SNaPshot is great idea,” Dr. Miyamoto told Medscape Medical News, “and I do think it will become a standard of care in the future…. It provides valuable information that can change the way a patient is treated and can make a big difference, especially for patients who are being treated nonspecifically and who may be missing opportunities to get well because they are not getting the testing done.”
However, such genetic testing needs to be placed in the larger picture of strained healthcare resources and decreasing investment in new drug development, he said. “It’s very nice to have these profiles, but what about the drugs to treat patients with these results?”
Dr. Miyamoto echoed the point made by Dr. Adjei — that for many of the mutations, targeted drugs “are not available yet…. How many will be developed under the current financial constraints…, and further down the line…, will we be able to afford to use them?”
First Cohort of Patients
In their paper, the MGH team reports on the first cohort of NSCLC patients screened with SNaPshot. A total of 589 patients were referred for genotyping, and 95% of these (n = 552) had sufficient tumor tissue for the screen.
The median age of the patients was 64 years (range, 22 to 89), 58% were female, and 92% were white, “reflecting our clinic’s racial homogeneity,” the researchers write. Histology was predominantly adenocarcinoma (81%), and about a quarter of the patients (24%) were never smokers.
The screen identified driver mutations in 51% of the patients. Most of the tumor samples had 1 mutation, but 5% had 2 mutations, and 2 tumors had 3 mutations.
The most commonly occurring mutations were KRAS (in 24% of tumor samples), EGFR (in 13%), and translocations involving ALK (5%).
There is wide agreement that it is important to identify patients with EGFR and ALK aberrations, the researchers note, because targeted therapies directed at the aberration (erlotinib and gefitinib for EGFR and crizotinib for ALK) are available.
There are also data that support directing patients with certain genotype findings “away” from therapies; for example, patients with KRAS mutations are directed away from erlotinib.
In addition, there are investigational therapies aimed at some of the other mutations that were found (such as MRK inhibitors for KRAS mutations), and therapies that are aimed at BRAF, PIK3CA, and HER2 mutations.
Of all the patients with genotypes, 22% have begun treatment with a genotype-specific therapy in response to SNaPshot results, the team reports.
Determining the percentage of these patients who would have received targeted therapy in the absence of SNaPshot is difficult, “because it would depend on whether any genetic testing was being done, and if it was, how much,” Dr. Sequist told Medscape Medical News.
Two steps are required before patients receive genotype-specific therapy: “step 1 is doing the testing and step 2 is having the drugs available,” she explained. “I think it is fair to say that EGFR mutation testing is fairly routine in most places around the world currently, and ALK testing is becoming more and more common because the new ALK inhibitor crizotinib has been approved by the US Food and Drug Administration in the United States. As the portfolio of drugs that target these various cancer mutations expands, not only through clinical trials but also through new drug approvals, there will be more of a pressing need to make broad genotyping the standard clinical practice of oncology. Our paper is important because it shows that this type of broad testing can be woven into the everyday care of patients already,” Dr. Sequist said.
What about the clinical outcomes of patients who are identified on screening and are then treated with targeted therapies?
“The field of targeted cancer therapy is still in its infancy, Dr. Sequist told Medscape Medical News. “At the current time, we have not seen that targeted drugs can cure cancers that were not curable otherwise. However, it is likely that survival can be lengthened by these types of treatments. Although not addressed in [our Annals of Oncology paper], our group recently published a study demonstrating that ALK-mutated patients receiving the ALK inhibitor crizotinib survived longer than ALK-mutated patients who did not get the drug” (Lancet Oncol. 2011;12:1004-1012). These data on crizotinib were previously reported by Medscape Medical News.
“We are getting much smarter in treating cancer, and focusing on these genetic changes and using targeted therapies is getting us closer to the ideal of personalized medicine,” said Dr. Cobb.
We are confident that these breakthroughs will make a difference in outcomes for patients, he noted. “There is really no reason why they shouldn’t, but we haven’t really proven that,” Dr. Cobb told Medscape Medical News. “To prove it, you have to marry what we see in the lab with what happens in the patient.”
There is a precedent here that bodes well for the future of this approach. Already in breast cancer, targeting treatment (tamoxifen to estrogen-receptor status and trastuzumab to HER2-receptor status) has led to a marked improvement in survival and cure rates, Dr. Cobb explained. However, this level of data is not available yet for treatment modified according to genetic mutations, he said.
“I don’t think anybody thinks that this is not going to be important,” he added. “There’s plenty of excitement about it; we just haven’t proven it yet.”
Dr. Sequist reports consulting for Clovis Oncology, Merrimack Pharmaceuticals, Daichi-Sankyo, and Celgene. Dr. Dais-Santagata and her colleague at the Translational Research Laboratory at MGH, John Iafrate, MD, PhD, have submitted a patent for the SNaPshot tumor genotyping assay. Dr. Soria reports receiving honoraria from Abbott, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, Merck, MSD, Servier, sanofi-aventis, and Eli Lilly. Dr. Adjei has disclosed no relevant financial relationships.
Ann Oncol. Published online November 9, 2011. Abstract
Category Breast Cancer, Lung Cancer, Prostate Cancer, Provenge, Vaccine
Posted: Nov 06, 2011 12:57 PM PST Updated: Nov 07, 2011 3:14 PM PST
There are vaccines for smallpox, polio, and hepatitis—but what about a vaccine for cancer? We’re closer to it than you think.
In their lifetimes, one in six men will be diagnosed with prostate cancer, more than 200,000 women will be diagnosed with breast cancer, and 63% of women will find out they have ovarian cancer—after it’s already spread.
Right now, there is no cure for cancer, but there is new hope.
“I want to be part of something that works and so people won’t die at a young age and can benefit from it,” says Bud Dougherty, who’s one of the first to use one of two new, FDA-approved vaccines to treat prostate cancer.
“We’re not talking about vaccines for preventing a virus like polio,” says Dr. Philip Kantoff with the Dana Farber Cancer Institute. “But we are talking about therapeutic vaccines that treat cancer by revving up the immune system.”
One of the vaccines is Prost-Vac. It’s made up of a smallpox related virus. It tells the immune system to attack prostate tumor cells.
Provenge is another prostate vaccine that’s made up of a patient’s own cells. It improved the median survival rate by 10% in one study.
“Basically, your immune cells will go looking for prostate cancer cells,” says Dr. Jorge Garcia, an oncologist with the Cleveland Clinic.
Doctors say that’s a significant benefit for men with such advanced diseases they’re told they have less than two years to live.
At the Mayo Clinic, doctors are beginning to test new vaccines targeting a protein that’s abundant in both ovarian and breast cancers. The drug immunizes patients immediately after therapy, when they’re healthy, to protect against relapse.
“It creates memory cells that can be stimulated to destroy a tumor,” says Dr. Keith Knutson with the Mayo Clinic.
At the Cleveland Clinic, researchers are targeting breast cancer even before it has a chance to form.
“It’s like weeds in a garden,” says Vincent K. Tuohy, PhD. ”You just can’t get rid of every weed, and I thought it would be easier to get them before they take root.”
The vaccine targets a protein that’s found in almost all breast cancer, but not in normal breast tissue. The vaccine prevented the disease in 100-percent of cases in the lab.
The idea is to vaccinate adult women in their post-childbearing, pre-menopausal years. That’s when they’re most at risk for developing the disease.
Another promising vaccine is targeting lung cancer. Studies show after surgery to remove the tumor, patients who get the vaccine have 43-percet lower risk of recurrence.
Ivanhoe Broadcast News also contributed to this piece
Category Cost, CT Scan, Diagnostic, Ethics of Science, Finance and Politics of cancer research and treatment, Lung Cancer, Prevention
The intervention group was offered annual posteroanterior-view chest radiographs while usual-care patients were not offered interventions. The study is published today, online in the November 2 issue of JAMA (doi:10.1001/jama.2011.1591) and will be presented at the annual meeting of the American College of Chest Physicians (CHEST 2011). The results are part of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Randomized Trial.
Martin M. Oken, MD of the University of Minnesota and Philip C. Prorok, PhD of the Division of Cancer Prevention at the NCI and colleagues analyzed participants at one of ten screening centers in the United States between 1993 and 2001. The demographics of the two groups were similar: half were women, about 45% had never smoked, 42% were former smokers, and 10% were current smokers. A total of 1,213 lung cancer deaths were observed in the x-ray screened group compared to 1230 in the usual care group over a 13-year follow up period. In total, 1,696 lung cancers were detected in the screened group and 1620 were detected in the usual care group. It was not possible to accurately detect overdiagnosis rates.
The authors conclude that “these findings provide good evidence that there is not a substantial lung cancer mortality benefit from lung cancer screening with four annual chest radiographs.” The Mayo Lung Project trial of chest radiograph and sputum cytology screenings completed in the early 1980s also did not show a mortality benefit.
In an accompanying editorial, Harold C. Sox, MD at Dartmouth Medical School highlights that this is one of two complementary lung cancer screening trial results released in the last two months The second is the National Lung Screening Study (NSLT), which found that annual low-dose computed tomography reduced lung cancer mortality by 20% relative to annual chest radiography (“NCI-Funded Study Finds Low-Dose CT Scans Better than X-Rays in Reducing Lung Cancer Mortality,” July 21, 2011, CancerNetwork).
Sox comments that the “PLCO lung cancer study provides convincing evidence that lung cancer screening with chest radiography is not effective.” He highlights that this study is important for putting the question of whether chest radiography is beneficial for decreasing the rate of mortality from lung cancer. According to Sox, “the NLST showed convincingly that early detection can lower the risk of death from lung cancer, a big step forward.” Now, he suggests that a real-world comparison between usual care and low-dose CT is warranted.
September 13, 2011
Scientists are developing a blood test to detect lung cancer, one of the most common and deadly cancers in the world. The test, which looks for certain proteins in the blood, is designed to find tumors at their earliest, most treatable stage.
According to the World Health Organization, lung cancer is the leading cause of cancer death worldwide, claiming an estimated 1.5 million lives each year. The disease is caused mainly by cigarette smoking. Early detection followed by prompt treatment is essential to surviving this deadly, fast-growing cancer.
Researchers at the Fred Hutchinson Cancer Research Center in the northwestern U.S city of Seattle, Washington, report they have developed a new blood test for lung cancer proteins. Those proteins are produced by tumor tissue early in the development of lung cancer and can be detected in plasma, a blood component that’s rich in proteins.
The scientists say the cancer test is so sensitive, it can detect the presence of markers or signatures that suggest tumor activity before they can be seen by advanced imaging devices such as a CT scan, which can spot tumors only a few millimeters across.
According to Sam Hanash, a scientist at Fred Hutchinson. and a lead researcher on the lung cancer blood test, using CT scans to detect tiny tumors can save the lives of patients at risk of lung cancer. But he says CT screening has a down-side: a high percentage of its images reveal nodules that appear as potentially malignant tumors.
“…That necessitate surgery, that turns out to be benign and a lot of other potential complications. So there’s a need for a blood test so that we can make CT scans more reliable,” Hanash said.
Hanash says the lung cancer blood test looks for protein signatures of the disease similar to the way other cancer blood tests work, including the CA 125 test for ovarian cancer and the prostate specific antigen, or PSA, test for prostate cancer.
In initial experiments with mice, Hanash and his colleagues discovered protein markers by switching on genes that gave the animals lung cancer, and then switching off the cancer-causing genes.
Hanash says scientists next looked to see whether they could find the same cancer protein signatures in human lung cancer cells.
“And the answer was “Yes!” So that was pretty satisfying that in fact we’re not dealing with a curiosity type of finding that only mice seem to display, but we are dealing with a real feature of cancer cells whether mice-derived or human-derived,” Hanash said.
Hanash says researchers detected protein biomarkers unique to a number of different lung tumors, as well as some of the molecular networks of genes that drive tumor development.
He says the next step is to develop a test that doctors can use with patients at risk for lung cancer, probably in about two years.
An article describing the development of a new diagnostic test for lung cancer protein signatures is published in the journal, Cancer Cell.