In a study published online in Nature today, researchers describe the discovery and development of the melanoma drug PLX4032. Dr. Gideon Bollag of Plexxikon and his colleagues reveal the drug’s chemical structure and describe how PLX4032 functions in the body. The authors detail their efforts to determine the proper doses for patients, including a critical reformulation of the drug that allowed patients to achieve the high levels needed for clinical responses.
The vast majority of patients with advanced melanoma who received an experimental targeted drug called PLX4032 responded to the treatment in a phase I clinical trial, researchers announced last month. The drug targets a common genetic change in melanoma tumors, and 26 of 32 patients (81 percent) who were treated with the recommended phase II dose had a partial or complete response. The tumors of some patients shrank or even went away, at least temporarily. Read more > >
The chief of NCI’s Pediatric Oncology Branch talks about the research in her lab at NCI and areas where pediatric cancer researchers are poised to make major advances. Read more > >
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Targeted Drug for Melanoma Shows Promise in Early Clinical Testing
The vast majority of patients with advanced melanoma who received an experimental targeted drug called PLX4032 responded to the treatment in a phase I clinical trial, researchers announced last month. The drug targets a common genetic change in melanoma tumors, and 26 of 32 patients (81 percent) who were treated with the recommended phase II dose had a partial or complete response. The tumors of some patients even went away, at least temporarily.
“The responses to this drug are clearly different than what other drugs have done for melanoma,” said Dr. Keith Flaherty of Massachusetts General Hospital (MGH), who co-led the multicenter trial. “Some patients are getting quite durable responses that are blowing the doors off what previous therapies have accomplished.”
The drug is a pill that primarily blocks growth-promoting signals caused by a mutation in a gene called BRAF. Based on the trial results, reported in the August 26 New England Journal of Medicine (NEJM), the researchers have launched a phase III study to see whether the drug can improve survival in patients whose tumors harbor the genetic mutation, known as V600E.
“The trial was needed to determine whether the drug is really altering the natural history of the disease in a profound way,” Dr. Flaherty noted. Although melanoma is treatable when detected early, the cancer is often fatal within a year once it has spread to other parts of the body. And only 10 to 20 percent of patients with advanced melanoma respond to FDA-approved drugs.
Patients in the phase I trial had seen their cancers progress despite one or more previous therapies, and some patients were running out of treatment options. In an extension cohort of 32 patients who carried the V600E mutation, the median time from initial response to PLX4032 until disease progression was more than 7 months and the longest responders have been taking the drug for approximately 2 years.
“These results represent a major breakthrough and provide proof of the principle that the treatment of metastatic melanoma can be individualized for a substantial percentage of patients,” said Drs. Kieran S.M. Smalley and Vernon K. Sondak of the H. Lee Moffitt Cancer Center & Research Institute in an accompanying editorial. “Over the past decade, great strides have been made in unraveling the unique biology of melanoma, and the research investment is paying off,” they wrote.
In 2002, researchers discovered that approximately half of human melanomas harbor the V600E mutation in BRAF that activates the gene. A non-specific BRAF inhibitor called sorafenib (Nexavar) was subsequently tested in the disease, but the results were not encouraging. Meanwhile, activating mutations in a gene called KIT were identified in a minority of melanoma cases, and studies have found that imatinib therapy leads to tumor regression in these patients.
In the future, patients with metastatic melanoma will likely be screened for mutations in key genes before starting on a therapy, the editorial predicts. (This is already happening for BRAF.) More work is needed to understand why some patients with the V600E mutation did not respond to the drug and why some developed resistance, Drs. Smalley and Sondak noted.
In the dose-escalation phase of the study, which tested increasing doses in 49 patients, the researchers observed tumor shrinkage at all sites of metastatic disease including the liver, small bowel, and bone. After the dose to be used in the phase II trial was determined, the drug was evaluated in the 32 additional melanoma patients with BRAF mutations. Among this group, 24 had partial responses and 2 had complete responses.
“We’re all excited about the responses we’ve seen in the phase I trial, but in melanoma we’ve learned over and over again that the responses don’t necessarily lead to improvements in overall survival,” said the study’s senior author, Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center. “So the purpose of the phase III trial is to see if we’re getting patients to live longer.”
In June, researchers announced that ipilimumab, a treatment that targets the immune system, helped patients with advanced melanoma live longer. Together, ipilimumab and PLX4032 have changed the landscape of melanoma research and raised the prospect that the new agents could be tested in combination or sequentially, said Dr. Claudio Dansky Ullmann, who oversees melanoma trials for the NCI Cancer Therapy Evaluation Program.
“These studies have opened the doors to a lot of possibilities for treating metastatic melanoma,” said Dr. Dansky Ullmann. “We can now test many treatments that were not available or proven until recently. This area of research is taking off.”
Several targeted therapies are in development for melanoma, including other BRAF inhibitors and agents directed at other pathways in the disease, he noted. Researchers are hopeful that different types of drugs, such as targeted therapies and immune-based therapies, could be combined to improve survival.
“This is all so new—there are many unknowns that will need to be clarified by future studies,” cautioned Dr. Dansky Ullmann. “And we need to get smarter about identifying specific patient populations in which to test a particular combination.”
The side effects of PLX4032 were mostly mild and included rash, nausea, fatigue, and low-grade tumors on the skin called squamous cell carcinomas. These were removed easily and did not cause any of the patients to discontinue treatment, the researchers said.
Melanoma is a genetically complex disease and determining which pathways are most important for therapies will require further research, Dr. Flaherty said. “Other pathways are definitely involved in the disease,” he added, noting that trials are under way to combine a BRAF inhibitor with an inhibitor of the MEK pathway.
“Most people were skeptical that targeting a single gene would have an impact,” Dr. Sondak said in an interview. Even the researchers themselves wondered whether the drug would work as they hoped. Many potential chemotherapy drugs for melanoma have looked promising in the lab, only to disappoint when tested in patients. PLX4032 could have been just another one of these.
There were other reasons to be skeptical, noted Dr. Chapman. No one knew whether blocking signals from the mutant BRAF gene would make a difference to patients. Mutations in the BRAF gene occur early in the development of the disease (they are also present in benign skin growths such as moles), and the researchers worried that advanced tumors might be driven by other genetic changes. What’s more, mice with BRAF mutations do not always develop a rodent form of melanoma.
“All of this information was telling us that BRAF mutations were necessary—but not sufficient—to make a cell a melanoma,” explained Dr. Chapman. If melanoma tumors were not dependent on signals from a mutant BRAF gene, there was a real possibility that blocking these signals might have no effect on the tumor.
“The astounding part of the study was that the drug worked as intended,” said Dr. Chapman.
A turning point in the trial, which was sponsored by Plexxikon and Roche, was the development of a new formulation of PLX4032 that allowed patients to achieve higher blood levels of the drug. (See the sidebar.) In the phase III trial, the drug is being compared to dacarbazine, which is a standard chemotherapy treatment for melanoma.
The researchers want to know as soon as possible whether the drug is increasing survival compared with standard treatment. Patients need new therapies for this disease, they say, and for the first time clinical trials are providing promising options.
“We now have a totally different mindset than we’ve ever had before for treating melanoma,” Dr. Flaherty said. “But until patients are in long remission, it’s hard to celebrate too much.”
—Edward R. Winstead
Cancer Research Highlights
For Women with BRCA Mutations, Prophylactic Surgery Reduces Cancer Risk
The diabetes drug metformin has helped prevent tumors in mice that were exposed to a cancer-causing agent found in tobacco, Dr. Phillip A. Dennis of NCI’s Center for Cancer Research and his colleagues reported this spring. Based on the findings, researchers are considering clinical trials of metformin in people at highest risk of developing lung cancer. Final results from the study in mice appeared September 1 in Cancer Prevention Research.
Prophylactic surgery to remove the breasts and ovaries is an effective way to reduce the risk of breast and ovarian cancer among women with inherited mutations in the BRCA1 or BRCA2 genes, according to one of the largest prospective studies on the subject to date. The findings, published September 1 in JAMA, provide estimates of the benefits of mastectomy and salpingo-oophorectomy (removal of the ovaries and fallopian tubes) in reducing the risk of cancer and death among carriers of disease-associated BRCA1 or BRCA2 gene mutations. These mutations confer a 56 to 84 percent lifetime risk of breast cancer.
The results also show that the risk reduction occurs regardless of whether the mutation is located in the BRCA1 or BRCA2 gene or whether a woman had cancer previously. Researchers at 22 medical centers in Europe and North America tracked nearly 2,500 women with a disease-associated BRCA1 or BRCA2 mutation. Almost half of the women had one of the prophylactic surgeries.
During 3 years of follow-up, none of the women who had a mastectomy developed breast cancer, while 7 percent of the women who didn’t have the surgery were diagnosed with breast cancer. And only 1 percent of the women who underwent risk-reducing salpingo-oophorectomy developed ovarian cancer during 6 years of follow-up, compared with 6 percent of women who did not have the surgery.
“This study reinforces the message that genetic testing has value,” said Dr. Timothy Rebbeck of the University of Pennsylvania, the study’s senior author. Women who know that they have inherited a high-risk mutation can, with the appropriate genetic counseling, take steps to reduce their risk of cancer through prophylactic surgery, he continued.
Although many women choose prophylactic surgery, many do not, the study authors noted. Just 10 percent of the women in the study chose prophylactic mastectomy and 38 percent chose salpingo-oophorectomy. “For women who have these genetic mutations, we think we can save lives,” Dr. Rebbeck stressed. “And that’s an important message.”
The authors of an accompanying editorial in JAMA echoed this message and noted that options for prophylactic surgeries have changed and improved. For example, laparoscopic salpingo-oophorectomy is a relatively low-risk procedure that can be done in an outpatient setting, while new techniques for mastectomy produce a more natural appearance, wrote Drs. Laura Esserman of the University of California, San Francisco, and Virginia Kaklamani of Northwestern University.
Less-intensive Treatment Regimen Effective against Multiple Myeloma
Treating patients who have multiple myeloma with less-intensive dosing of bortezomib (Velcade) reduced toxic side effects without making the treatment less effective, Spanish researchers found. Their study, reported online in The Lancet Oncology on August 23, concluded that less-intensive induction therapy with a bortezomib-based regimen, followed by maintenance treatments, was “a safe and effective treatment for elderly patients newly diagnosed with multiple myeloma.”
While bortezomib benefits many patients with multiple myeloma, some who take the drug have experienced severe nerve pain, known as peripheral neuropathy. To test less-intensive dosing, the researchers randomly assigned 260 patients to induction therapy of lower-intensity bortezomib plus melphalan and prednisone (VMP) or lower-intensity bortezomib plus thalidomide and prednisone (VTP), followed by one of two types of maintenance therapy for up to 3 years. With both induction regimens, bortezomib was given once a week after the first cycle rather than in the typical twice-weekly schedule.
Both of the less-intensive regimens led to response rates of more than 80 percent. In addition, 36 patients in the VTP group (28 percent) and 26 in the VMP group (20 percent) had complete remission. The regimens were associated with fewer cases of severe (grade 3 or higher) peripheral neuropathy and gastrointestinal symptoms than had been seen in a similar study known as the VISTA trial, in which more intensive-dosing of bortezomib was used.
“This is an important study that immediately affects clinical practice and provides important answers about how new agents such as bortezomib can be incorporated effectively in the overall treatment strategy,” wrote Dr. Vincent Rajkumar of the Mayo Clinic in an accompanying editorial. “Although the trial was undertaken in newly diagnosed patients, the findings might also be of value in relapsed and refractory disease,” he added.
The regimen “could be a platform for further refinement of an optimized treatment for elderly patients with multiple myeloma through use of lenalidomide instead of thalidomide and by reducing adverse effects through early intervention and prophylactic measures,” Dr. Maria-Victoria Mateos of the University Hospital of Salamanca and her colleagues concluded.
Lower-dose Treatments for Early-stage Hodgkin Lymphoma Do Not Compromise Results
In a phase III trial, patients with early-stage, low-risk Hodgkin lymphoma who received lower doses of chemotherapy and/or radiotherapy had clinical outcomes that were no worse than those of patients who received higher doses. The results of the study, which tested strategies to reduce the toxic effects of treatment while maintaining efficacy, appeared August 12 in the New England Journal of Medicine.
Dr. Andreas Engert of the University Hospital of Köln, Germany, and his colleagues from the German Hodgkin Study Group studied 1,190 patients newly diagnosed with stage I or II Hodgkin lymphoma and no clinical risk factors (including advanced age, previous treatment for Hodgkin lymphoma, or concurrent disease) who had been assigned to one of four groups. Two groups received four cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) and either 30 Gy or 20 Gy of involved-field radiotherapy (IFRT). The other two groups received only two cycles of ABVD chemotherapy, with one getting the higher and the other the lower amount of IFRT.
After 7.5 years, 96.6 percent of all patients had a complete remission and 8-year survival was 94.5 percent. Patients who received two rounds of chemotherapy did not fare worse than those who received four rounds; similarly, those who received 20 Gy of IFRT did not fare worse than those who received 30 Gy.
However, half of all patients getting the higher dose of chemotherapy reported serious adverse events—including infections, hair loss, anemia, and other blood disorders—compared with one-third of patients who received the lower dose. Six of the seven treatment-related deaths were in patients who received the higher dose of chemotherapy. Serious toxic effects from radiation were about three times more likely with the higher than the lower dose of radiation.
Although this trial did not include a no-radiotherapy comparison group, some experts believe that, given the long life expectancy of Hodgkin lymphoma patients with early-stage favorable disease, radiation therapy should be avoided when possible to minimize the risk of second cancers. “I would recommend that physicians evaluate patients after two cycles of ABVD chemotherapy with PET imaging and possibly avoid radiotherapy altogether, unless there is a compelling reason to use radiotherapy,” said Dr. Richard Little, senior investigator in the Clinical Investigation Branch in NCI’s Division of Cancer Treatment and Diagnosis.
Chemotherapy Affects Brain Structure of Breast Cancer Patients
A new study has provided some of the strongest direct evidence to date that chemotherapy has physical effects on areas of the brain that, when altered, could result in the array of cognitive symptoms that is often called “chemobrain.” The study was published online August 6 in Breast Cancer Research and Treatment.
In a small study of women with breast cancer, researchers from the Indiana University School of Medicine used MRI scans to show that chemotherapy was associated with a decrease in the density of brain gray matter. The affected areas include those involved in memory and in the ability to process information. Although several other studies have shown similar changes in these areas of the brain, this was the first study to follow women prospectively and to compare scans before and after chemotherapy.
“The alterations in gray matter density observed in the [chemotherapy] group are… consistent with the pattern of cognitive complaints and impairment found in neurocognitive studies,” wrote Dr. Andrew J. Saykin and colleagues.
The study included 17 women with breast cancer who underwent chemotherapy after surgery, 12 women with breast cancer who did not receive chemotherapy after surgery, and a control group of 18 healthy women. The initial MRI scans, performed shortly after surgery in the participants with cancer, showed no notable differences in gray matter density among the three groups. One month after completion of chemotherapy, however, MRI scans revealed notable decreases in gray matter density in women with breast cancer, as well as changes in gray matter density in women who received surgery only, although the changes for these women were not as great. No changes were seen in women in the control group. After 1 year, women treated with chemotherapy had recovered gray matter losses in some regions, but other deficits persisted.
Exactly how chemotherapy may be causing these changes is unclear, said study co-author Dr. Brenna McDonald. “However, the finding that the changes appear to resolve naturally to some degree in the first year after chemotherapy is completed is a very positive one,” she wrote in an e-mail message. Because of the limited follow-up in the study, she continued, it’s unclear how much further recovery may occur naturally. A number of studies have shown that such cognitive effects can persist for many years, she added. Additional studies are investigating whether other therapies, such as tamoxifen, may have similar effects on brain structure.
For more information on this topic, see: “Delving Into Possible Mechanisms for Chemobrain.”
Consuming High Levels of Red Meat and Fat May Increase Liver Cancer Risk
A recent prospective study found that higher consumption of red meat or saturated fat was associated with increased risks of both death from chronic liver disease (CLD) and incidence of liver cancer, while eating white meat was associated with decreased risks for both outcomes. The results were published online August 20 in the Journal of the National Cancer Institute.
Researchers analyzed data from nearly 500,000 men and women participating in the NIH-AARP Diet and Health Study. Participants whose self-reported levels of red meat intake were in the highest 20 percent were 2.6 times more likely to die from CLD and 74 percent more likely to develop hepatocellular carcinoma (HCC), the most common type of liver cancer, than participants in the lowest 20 percent of red meat intake.
In contrast, participants in the top 20 percent of self-reported white meat intake were half as likely to die from CLD or develop HCC as those in the lowest 20 percent of white meat intake. And whereas high fat consumption was associated with increased risks for both CLD and HCC, eating saturated fat was associated with the highest risk: those in the top 20 percent of saturated fat intake had 3.5 times the risk for CLD and nearly twice the risk for HCC as those in the lowest 20 percent.
The researchers adjusted for alcohol use, diabetes, obesity, and other dietary and lifestyle factors in their analyses to avoid confounding by these risk factors. Although they noted that residual confounding could still exist, it is unlikely because risk estimates for participants who reported abstaining from alcohol, whose BMI was in the healthy range, and who did not report a diagnosis of diabetes were similar to those in the total population.
A number of plausible mechanisms could underlie a causal association between red meat, CLD death, and HCC risk, the research team noted, including exposure to saturated fat, iron, and carcinogens formed from high-temperature cooking, such as heterocyclic amines and polycyclic aromatic hydrocarbons. However, in this study, although saturated fat was associated with both endpoints and heme iron was associated with CLD death, neither specific heterocyclic amines nor high-temperature cooking methods (other than pan-frying) was associated with CLD death or HCC risk. The mechanism by which white meat might reduce cancer risk is not clear.
“While these results are provocative, few studies have investigated these associations,” said study author Dr. Neal Freedman of NCI’s Division of Cancer Epidemiology and Genetics. “Though red meat and saturated fat have been associated with cancer at other sites, additional studies of HCC and CLD are needed. If we see similar results in other populations, dietary change may be an effective strategy to reduce the incidence of HCC and CLD.”
The researchers did not know participants’ history of hepatitis B and C infections, which is the main cause of HCC in most populations. The association between these viruses and meat and fat in the diet should be examined for HCC and CLD, Dr. Freeman noted.
Cancer Patients Leaving Hospice Early Boost Medicare Expenditures
An analysis of hospice patients with terminal cancer indicates that those who disenrolled from hospice care had higher rates of hospitalization, were more likely to die in a hospital, and incurred higher Medicare expenditures between hospice enrollment and death than patients who continued hospice care until death. The researchers adjusted for a number of factors, including the number of days from hospice enrollment until death, and found that total Medicare expenditures were $2,475 higher, on average, among the patients who disenrolled from hospice. The analysis was published online in the Journal of Clinical Oncology August 30.
Dr. Melissa Carlson of Mount Sinai School of Medicine and her colleagues analyzed the linked SEER-Medicare database for 90,826 hospice patients age 66 or older who died with a primary diagnosis of cancer between 1998 and 2002. The average patient age at death was 78.5 years, and 86 percent were non-Hispanic whites.
Of the 10.9 percent of patients (9,936) who disenrolled from a hospice program, 25 percent were hospitalized within 48 hours and 57 percent died within 30 days. Nearly 40 percent of patients who disenrolled from hospice subsequently re-enrolled. The researchers could not evaluate the causes or consequences of this pattern, nor did they have data on the reasons for disenrollment. The extra Medicare expenditures came primarily from hospitalizations and physician visits.
“Forty percent of Medicare’s total expenditures for hospice users with cancer were accounted for by only 5 percent of hospice users with cancer,” wrote the authors, “and a primary correlate of higher Medicare expenditures was whether a patient disenrolled from hospice.”
More than a million Medicare beneficiaries are currently receiving hospice care, and about one third of them have a cancer diagnosis. With annual Medicare hospice payments of over $11 billion, policymakers are considering tightening the criteria for eligibility for the Medicare hospice benefit, the authors noted. They suggested that examining why patients disenroll from hospice—including the rates of disenrollment from specific hospice programs—may lead to effective ways to reduce Medicare expenditures without restricting access to the hospice benefit.
The authors also proposed that the use of outpatient palliative care teams that can provide symptom control and end-of-life planning may be an effective way to help patients who disenroll from hospice avoid hospitalization while maintaining contact with an oncology clinic.
A Conversation With
Inside NCI: A Conversation with Dr. Crystal Mackall about Pediatric Oncology
The chief of NCI’s Pediatric Oncology Branch talks about the research in her lab at NCI and areas where pediatric cancer researchers are poised to make major advances.
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This is the fifth article in a series of stories related to cancer survivorship. Look for the symbol on the left in an upcoming issue for the next article in the series.
Palliative Care Improves Survival, Quality of Life in Advanced Lung Cancer
Results from the first randomized clinical trial of its kind have revealed a surprising and welcome benefit of early palliative care for patients with advanced lung cancer—longer median survival. Although several researchers said that the finding needs to be confirmed in other trials of patients with other cancer types, they were cautiously optimistic that the trial results could influence oncologists’ perceptions and use of palliative care. The results were published online August 19 in the New England Journal of Medicine.
Patients in the trial who received palliative care early in the course of their cancer treatments also reported better of quality of life and were less likely to be depressed than those who did not automatically receive such care. But the finding that received the most attention was the improved survival, a noteworthy result for patients with this notoriously difficult-to-treat disease.
The extent of the survival improvement was just short of 3 months, which is equivalent to what is commonly seen with standard first-line chemotherapy, according to the research team led by Dr. Jennifer Temel of Massachusetts General Hospital (MGH) and Harvard Medical School. While pleased with the results, Dr. Temel acknowledged in an interview that the findings have to be considered within the context of the study, which was conducted in a single large medical center with a strong palliative care program.
“Most big academic medical centers and larger community hospitals now have palliative care services. In larger hospitals, the rate [of such programs] is around 80 percent,” she said. “In smaller hospitals, they may not have access to these palliative care resources.”
In an accompanying editorial, Drs. Diane Meier and Amy Kelley, of the Department of Geriatrics and Palliative Medicine at Mount Sinai School of Medicine, acknowledged the trial’s limitations but argued that the findings stand to challenge the “prevailing notion of palliative care.” Until this point, palliative care has typically been seen “as the alternative to life-prolonging or curative care—what we do when there is nothing more that we can do—rather than as a simultaneously delivered adjunct to disease-focused treatment.”
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The Design and the Results
More than 150 patients at MGH who were newly diagnosed with advanced non-small cell lung cancer (NSCLC) were enrolled in the trial and randomly assigned to receive standard care for the disease or standard care plus early palliative care services.
Within 3 weeks of enrolling in the trial, patients in the palliative care group met with a palliative care team. Such teams can include specially trained physicians and nurses, social workers, and clergy members, although in this trial, Dr. Temel noted, the team included only physicians and nurse practitioners. Patients then met monthly with the palliative care team and had additional consultations as needed. Patients in the standard care group or their clinicians could also request palliative care services.
The 2.7-month improvement in median survival came as somewhat of a surprise, said Dr. Temel, noting that overall survival was 11.6 months for patients in the palliative care group compared with just less than 9 months in the standard care group. But there is a strong rationale for why early palliative care can have a significant clinical impact.
“We gave [patients] the tools to make sound decisions about their medical care,” she said. When it comes to discussions and debates about palliative and hospice care, she continued, “instead of talking about ‘rationing’ care, we should be talking about better educating patients so they can make more appropriate decisions about their care.”
For example, the survival rates were better despite the fact that more patients in the standard care group received aggressive care at the end of life, which was defined as chemotherapy within 2 weeks of death or 3 days or less in hospice prior to death. However, Dr. Temel stressed that she believes the survival benefit is most likely a result of the improvements in quality of life and depression. Although patient decisions on end-of-life care “probably contributed” to the survival benefit, she said, “the survival benefit was seen early in time, so it could not all be accounted for by less aggressive end-of-life care.”
For Dr. Christian Sinclair, a staff clinician at Kansas City Hospice and Palliative Care, an outpatient facility in Kansas City, MO, the improved survival was also unexpected, but for a different reason. “Palliative care can be used early, at the time of diagnosis, but so often it’s used during symptom crises in the middle to late stages of advanced disease,” he said. “So I’m surprised just because I haven’t seen a lot of early palliative care.”
Because good palliative care “can diminish or alleviate a lot of the physical and psychological symptoms associated with cancer and its treatment, it might follow that survival can be improved,” said Dr. Ann O’Mara of NCI’s Division of Cancer Prevention, who oversees a large portfolio of NCI-funded palliative care research. Often, when patients enter hospice programs, she continued, their disease status will improve. “And there is a lot of overlap in the kinds of services provided in palliative care and hospice, particularly in terms of aggressive symptom management, so it’s not surprising that patients receiving palliative care would see similar improvements,” she said.
Although it’s unlikely that a single study will dramatically change how palliative care is used in oncology, Dr. O’Mara believes that similar studies will only help to increase the visibility and acceptance of palliative care. But that doesn’t change what the research team accomplished in this trial, she continued, particularly given the patient population. “I applaud [the researchers] for having chosen patients with advanced lung cancer,” she said, “because their symptom burden is quite severe.”
She acknowledged that the outcome may be different for patients treated at smaller community hospitals, many of which don’t have staff with the expertise to deliver comprehensive palliative care of the type used in the MGH trial. “It’s not just about delivering pain or nausea medication; it also requires managing family, financial, and psychosocial issues. Palliative care is very complex,” she explained.
There are a number of obstacles to wider adoption of palliative care, said Dr. Sinclair, but a big part of the problem still traces back to the clinic. “There’s a high level of cultural resistance to earlier palliative care,” he said. While he acknowledged that data showing the impact of palliative care on patient outcomes are limited, in his experience, he said, “there’s still the stigma that it’s primarily for late disease.”
Dr. Temel and her colleagues are planning similar trials for patients with hard-to-treat cancers such as esophageal and pancreatic cancer. In the meantime, she hopes that the trial results will reinforce that palliative care and quality oncology care “are not an either/or proposition; they are not mutually exclusive. It’s feasible to provide both at same time, and it’s also beneficial for the patient.”
For more information, see: Palliative Care in Cancer, “Growing Pains: Palliative Care Making Gains,” Coping with Cancer: Supportive and Palliative Care, and the March 23, 2010 issue of the NCI Cancer Bulletin, which had several articles on the subject.
Autophagy: The Strange Dining Habits of Cancer Cells
Many cancer cells lead a difficult existence. Those mired deep in the core of a tumor, for example, have limited access to oxygen, growth factors, and nutrients from the blood vessels that feed the tumor. But when things get tough, the tough start eating. In these most dire of situations, many cancer cells will engage in an act of self-cannibalism called autophagy, gobbling up regular meals of cytoplasmic parts and degrading them into macromolecules that they recycle into other components that they need to survive. (View a video of cancer cells consuming themselves through autophagy online.)
Funding for autophagy-related research from NCI’s Division of Cancer Biology (DCB) has increased dramatically over the past several years. As a result of the emerging science in this area of research, DCB is planning an invitation-only workshop to bring together leaders in the field. The workshop will focus on how autophagy affects cancer cells, particularly its role in allowing the cells to maintain homeostasis at all stages of cancer development and growth.
“Autophagy research is an emerging area of interest within DCB,” said Dr. Barbara Spalholz, chief of DCB’s Cancer Cell Biology Branch. “We expect that the interaction between cancer and cell biologists at the workshop will highlight the importance of autophagy in cancer, identify potential preventive strategies, and reveal novel therapeutic targets.”
Normal cells rely on autophagy to maintain a balance between the synthesis and degradation of proteins and organelles during development or in times of stress. Cancer cells rely on this process as well, not just to survive in the inhospitable environment of a tumor, but also to ward off the effects of chemotherapy and radiation. “Pretty much every therapeutic regimen out there is inducing this pathway” in cancer cells, explained Dr. John Cleveland of The Scripps Research Institute in Jupiter, FL. Activation of autophagy, he continued, “is an intrinsic cell-survival mechanism that cancer cells turn on to recoup essential building blocks when they’re being poisoned or irradiated.”
A greater understanding of autophagy’s role in cancer has led some researchers to investigate whether blocking autophagy can make cancer treatments more effective, cutting off what amounts to an important escape route. The work is in its earliest stages, with the first human trials of autophagy inhibitors launched only in the last several years. But if successful, researchers believe the process could work for many cancer types as a way to help eradicate primary tumors and help prevent or eliminate metastases. (With a similar goal in mind, researchers are actively studying a process known as glycolysis, which is another source of nutrients for cancer cells.)
Survive and Resist
Autophagy is a process of capture and transfer. Beginning with some form of stress that causes the cell to ramp up its self-eating machinery, a double-membraned pouch, called an autophagosome, begins engulfing old or unneeded components, such as proteins and organelles, from the cell’s cytoplasm. The autophagosome then fuses with lysosomes, another type of membrane-bound structure replete with digestive enzymes, to form autolysosomes, which degrade the captured items into components (such as amino acids, fatty acids, and nucleotides) that the cell can reuse.
At the Cancer Institute of New Jersey, Dr. Eileen White and colleagues are among the leading research groups trying to better define the role of autophagy in cancer and determine whether interfering with this process could be used to treat cancer. In 2006, they were among the first to demonstrate that cancer cells from deep within a tumor had significantly elevated levels of autophagy, and that “it was supporting survival in that hypoxic environment,” she said.
In their continued research, the team has found a consistent pattern. “When you stress tumor cells,” Dr. White explained, “they start eating themselves, getting smaller and smaller and smaller, and at some point they stop dividing and just sit there; they are essentially dormant.” But once the stress is removed, in as little as 24 hours the cells can reinstate normal metabolic behavior and begin proliferating again. “As long as they can do that, and avoid being killed by stress or therapy, then that is the inherent problem,” Dr. White said.
A number of studies support the role of autophagy in treatment resistance, including resistance to targeted therapies. Spanish researchers reported last year, for example, that HER2-positive breast cancer cells that were resistant to trastuzumab (Herceptin) had significantly elevated autophagy activity (based on the levels of certain proteins involved in the autophagy process). Treating the same cells with an autophagy inhibitor led to reduced cell proliferation, and adding trastuzumab on top of autophagy inhibition restored the cells’ sensitivity to trastuzumab.
Although autophagy may be able to kill cells, in tumor cells its survival-promoting abilities appear to trump any propensity it may have to induce death, explained Dr. Ravi Amaravadi from the University of Pennsylvania Abramson Cancer Center, who is involved in several early-phase clinical trials testing autophagy inhibition. But based on what’s been seen in lab-based studies, he cautioned, there may be substantial differences in the autophagy activity in different cancer types, or even from tumor to tumor. Nevertheless, the available evidence suggests that autophagy “seems to be a process that could be important in many cancers,” he said.
When Dr. Herbert Zeh and his colleagues at the University of Pittsburgh Medical Center Cancer Centers started investigating autophagy in pancreatic cancer, one of the deadliest and most treatment-resistant cancer types, they began to consider the disease from a different perspective. “We thought, maybe it’s not a disease of unchecked cell proliferation,” he said. “What if the real problem is that the cells just forgot how to die the right way?” Dr. Zeh is the principal investigator of a phase I/II trial testing autophagy inhibition in patients with stage II or III pancreatic cancer.
By combining treatments that inhibit autophagy with traditional therapies that go after rapidly dividing cells, they hypothesize, cancer cells can be forced to undergo apoptosis, the most common form of cell suicide. “It’s a novel concept because we’re not just trying to make tumor cells die,” Dr. Zeh said. “We’re trying to ensure that they do it in the appropriate way.”
Looking Ahead for the Best Recipe
A number of clinical trials testing autophagy inhibition are actively recruiting patients with a variety of cancers, including breast, colorectal, myeloma, and chronic lymphocytic leukemia. All of the trials are using an off-patent drug called hydroxychloroquine, or HCQ, which can interfere with the autophagy process and is already used to treat several conditions, including malaria and rheumatoid arthritis. In most trials, HCQ is being combined with other therapies.
HCQ is thought to work by altering a lysosome’s internal pH, explained Dr. White, derailing the vesicle’s ability to degrade its contents and complete the recycling process. “We’re not sure if it’s the best [autophagy inhibitor], but it’s being used in patients already,” she continued, which can speed its clinical development and more quickly show whether autophagy inhibition improves patient outcomes.
Data from the largest trial to date involving HCQ—in patients with newly diagnosed glioblastoma multiforme—were presented at the American Society of Clinical Oncology annual meeting earlier this year. In the multi-institutional phase I/II trial, HCQ was combined with temozolomide and radiation therapy. Although some serious toxic effects were seen at the highest dose tested, Dr. Amaravadi said, at a lower dose, these effects waned and there was strong evidence of autophagy inhibition.
While much more work needs to be done on many fronts—such as better understanding the genetics of autophagy and identifying and validating robust biomarkers that measure the extent of autophagic behavior in a cell—the available evidence, Dr. Amaravadi believes, “suggests that there is potential for this drug.” But, he stressed, there is no evidence yet to support adding HCQ to any cancer regimens in hopes of improving outcomes.
A number of pharmaceutical companies are investigating autophagy inhibitors, Dr. Cleveland said, but the work is preliminary. As a potential therapeutic target, he continued, the autophagy pathway has significant promise, but it has potential pitfalls. Autophagy, for example, appears to have the ability to prevent healthy cells from becoming cancerous, by allowing them to degrade junk that might otherwise induce DNA damage and drive a cell toward malignancy. The same pathway also helps the immune system recognize potential threats, so disrupting it could, in theory, inhibit the body’s ability to mount an immune response against cancer.
“There are a lot of unknowns about autophagy,” Dr. Cleveland said. “It has different functions in different kinds of contexts…so our studies have to be carefully done. Being smart about how to deliver these drugs will be very important.”
Featured Clinical Trial
Comparing Post-transplant Therapies for Multiple Myeloma Patients
Name of the Trial
Stem Cell Transplant with Lenalidomide Maintenance in Patients with Multiple Myeloma (BMT-CTN-0702). See the protocol summary.
Dr. Amrita Y. Krishnan, Dr. George Somlo, and Dr. Edward Allen Stadtmauer, Blood and Marrow Transplant Clinical Trials Network
Why This Trial Is Important
Multiple myeloma is a cancer in which the body produces too many plasma cells, which are white blood cells that produce proteins called immunoglobulins. The plasma cells in multiple myeloma are abnormal and secrete excess amounts of immunoglobulin protein, which can be deposited in the kidneys and lead to kidney failure. In addition, the plasma cells can stimulate bone cells known as osteoclasts, which break down bone tissue, leading to increased bone fractures. Treatment with high-dose chemotherapy followed by transplantation of the patient’s own blood-forming stem cells (known as autologous stem cell transplantation) is a cornerstone of multiple myeloma therapy for eligible patients. Although this treatment often produces remission, it is not a cure, and most patients eventually relapse.
A number of advances in multiple myeloma treatment are helping to extend the lives of patients with this disease. Several research groups have demonstrated that a second round of chemotherapy and autologous stem cell transplantation can improve the likelihood of a near-complete response and extend progression-free survival. It has also been reported that maintenance therapy with the drugs thalidomide or lenalidomide can improve survival. And, a number of studies have suggested that combination chemotherapy that includes the drugs bortezomib, lenalidomide, and dexamethasone as either initial treatment or treatment for relapsed disease can induce high remission rates in both newly diagnosed patients and those with relapsed disease.
In this trial, patients age 70 or younger with multiple myeloma will be randomly assigned to treatment with one of three regimens after receiving high-dose melphalan chemotherapy and autologous stem cell transplantation: 1) a second round of melphalan chemotherapy and stem cell transplantation, followed by maintenance therapy with lenalidomide; 2) consolidation therapy with lenalidomide, bortezomib, and dexamethasone, followed by lenalidomide maintenance therapy; or 3) lenalidomide maintenance therapy alone. All patients will receive lenalidomide maintenance therapy for 3 years or until disease progression or unacceptable toxicity occurs. Doctors will monitor the patients for progression-free survival, response rates, event-free survival, overall survival, and side effects of treatment.
“The current therapies we have for multiple myeloma are great at producing remission, but they are not curative, so the challenge is maintaining those remissions,” said Dr. Krishnan. “This trial very logically builds upon the last 10 or 15 years of experience both in transplants for myeloma as well as the use of these new drugs bortezomib and lenalidomide in improving outcomes of the disease.”
“Transplants are still relevant in multiple myeloma treatment,” Dr. Somlo said. “The question here is what is the best way to sequence therapy involving a transplant—is it better to do one or two transplants in conjunction with lenalidomide maintenance therapy, and can novel therapies take the place of a [second] transplant?”
“We feel that all three of these strategies are good strategies for multiple myeloma treatment, but our hope is that one will rise above the others,” Dr. Krishnan added.
For More Information
NCAB Meeting Begins Today
The National Cancer Advisory Board (NCAB) meets September 7–8 in Building 31 on the NIH main campus in Bethesda, MD. NCI Director Dr. Harold Varmus will open the meeting with his first NCI Director’s Report. The agenda is now available, and the meeting will be broadcast live online. An archived videocast of the meeting will be available a few days after the meeting.
New Grants Awarded for Biomarker Discovery and Validation
NCI’s Early Detection Research Network (EDRN) announced 32 new 5-year grants to researchers across the country for the discovery and validation of biological markers that signal the earliest stages of cancer. The awards fund:
- 20 Biomarker Developmental Laboratories responsible for development and characterization of new biomarkers or refinement of existing biomarkers
- Eight Clinical Validation Centers that conduct clinical research on the validation of biomarkers in early cancer detection and risk assessment, and serve as resource centers by participating in collaborative biomarker validation studies
- Three Biomarker Reference Laboratories that serve as a resource for clinical and laboratory validation of biomarkers
- A Data Management and Coordinating Center that supports statistical and computational analyses, informatics infrastructure, and the coordination of network-wide meetings and conferences
The EDRN also elected Dr. Ian Thompson of the University of Texas Health Science Center as chair and Dr. Joshua LaBaer of Arizona State University as co-chair.
Since its creation in 2000, the EDRN has developed more than 127 biomarkers; five validation studies have been launched and three completed; and the EDRN has prepared markers for prevalidation and validation studies. More than 600 publications, 28 patents, and 14 licenses have been generated from research by EDRN scientists. The EDRN established clear milestones for continuing or discontinuing the development process for new biomarkers. Based on statistical criteria, performance characteristics of biomarkers, and anticipated clinical use, more than 100 biomarkers have been stopped from further development due to their lack of performance.
“The new grantees bring with them a wealth of expertise and resources in the areas of basic science, clinical science, public health, statistics, epidemiology, informatics, and translational research, and they employ a variety of discovery platforms, including genomics, proteomics, epigenomics, and imaging,” said Dr. Sudhir Srivastava, who heads the EDRN program.
Federal Committee Will Establish Breast Cancer Research Agenda
A newly formed advisory committee will develop and coordinate a strategic federal research agenda on environmental and genetic factors related to breast cancer. The National Institute of Environmental Health Sciences (NIEHS), in collaboration with NCI, established the Interagency Breast Cancer and Environmental Research Coordinating Committee (IBCERCC) to review all breast cancer research efforts conducted or supported by federal agencies.
The committee will develop recommendations for the secretary of HHS, NIH, and other federal agencies, to improve existing research programs related to breast cancer. Additionally, the IBCERCC will create a comprehensive plan to expand opportunities for collaborative, multidisciplinary research, and develop a summary of advances in federal breast cancer research.
The IBCERCC comprises 19 voting members, including representatives of federal agencies; non-federal scientists, physicians, and other health professionals from clinical, basic, and public health sciences; and advocates for individuals with breast cancer. A list of committee members can be found online.
The IBCERCC will hold its first meeting September 30–October 1 in the Washington, DC, area.
Glasgow Named DCCPS Deputy Director
Dr. Russell Glasgow was named deputy director of dissemination and implementation science in NCI’s Division of Cancer Control and Population Sciences (DCCPS). Dr. Glasgow will provide leadership on numerous research projects to close the gap between research discovery and program delivery in public health, clinical practice, and health policy. As deputy director, Dr. Glasgow will also be responsible for guiding some of NCI’s research dissemination tools, such as Cancer Control P.L.A.N.E.T, the Cancer Trends Progress Report, and State Cancer Profiles.
Dr. Glasgow earned his B.A. degree in psychology from the University of Iowa. He earned his M.S. and Ph.D. degrees in clinical psychology from the University of Oregon, Eugene. Dr. Glasgow is a behavioral scientist specializing in the design and evaluation of practical and generalizable behavior change interventions, especially using interactive technologies, for use in health care, worksite, and community settings. He has more than 30 years of experience in academia and has been the recipient of key awards and honors in his field, including the Society of Behavioral Medicine’s Distinguished Scientist Award and the American Diabetes Association’s Behavioral Medicine and Psychology Council Lectureship for Distinguished Contributions.
Most recently, Dr. Glasgow was a senior scientist with the Kaiser Permanente Institute for Health Research.
Groundbreaking Ceremony Held for NCI’s Future Satellite Campus
The September 1 groundbreaking ceremony for NCI’s future satellite campus and buildings in the Shady Grove area of Montgomery County, MD, drew a large crowd and featured remarks by NCI Director Dr. Harold Varmus, Maryland Governor Martin O’Malley, and U.S. Senator Ben Cardin, among others. The buildings are scheduled to open in 2013 and will house nearly 2,100 staff from many of NCI’s divisions, offices, and centers. The campus will allow for anticipated growth in NCI’s programs and personnel.
“We’ll be bringing staff from four different locations into one consolidated space,” said Dr. Varmus, who biked to the event and stood out among the attendees in his bicycle shorts and shirt. “We’re going to have environmentally friendly facilities, with accommodations for bike commuters like me.”
Dr. Varmus thanked the NCI employees who have worked with the developers and architects to design the new campus. “Their hard work in helping the planning process is very beneficial to accomplishing our mission,” he said.
New Brochure on Cancer Genomics Available
The Cancer Genome Atlas (TCGA) has developed an easy-to-read guide titled Cancer Genomics: What Does It Mean for You? The brochure describes the genomic basis of cancer, the work of TCGA, and how genomics research advances medicine.
TCGA is a joint initiative between NCI and the National Human Genome Research Institute. The comprehensive and coordinated effort is intended to accelerate the understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing. TCGA is mapping the genomic changes in 20 cancers to yield comprehensive and publicly accessible data for use by the cancer research community to discover new ways to better diagnose, treat, and prevent cancer.