Blog Archives


View the complete “Breakthrough Therapy Designation: Three Years Later” infographic.

As the U.S. Senate discusses the 21st Century Cures Act, which promises to accelerate the discovery and development of cures in the country, we look at the success of another program with the same goal: breakthrough therapy designation. Three years after its introduction by the U.S. Food and Drug Administration (FDA), this program is exceeding expectations.

“We never envisioned the breakthrough designation to be so robustly implemented as it has been,” said Jeff Allen, executive director at Friends of Cancer Research, a Washington, D.C. advocacy organization that helped to develop the program. “It’s wonderful to see how widely the FDA has been using it because it means patients are getting access to more treatment options sooner.”

In 2012, the FDA introduced the designation to speed the development of new therapies that could significantly improve the treatment of serious medical conditions. It does so by providing developers with regular interactions with FDA staff at all levels, a rolling review and a shortened review timeline.

Since then, the FDA has received 330 requests for a breakthrough designation and has granted it to 99 of those requests, including a chimeric antigen receptor T-cell therapy that is the focus of a collaboration between Celgene and Juno Therapeutics.

Breakthrough Therapy Designation: More Designations Granted Than Expected

“I don’t think anyone would have expected close to 100 designations in a little more than three years,” Allen said. “We’re already starting to see a number of approvals coming from products that have received the designation.”

Already, the program has provided patients with access to 26 new treatment options up to three years sooner than the standard approval process. And 16 of those were first-time approvals for novel therapies, which represent a new or different approach to attacking a particular disease. Others were approvals for existing medicines to treat different diseases.

Breakthrough Therapy Designation: More Approvals Than Expected

The diversity of therapeutics areas that the program has involved has also been a pleasant surprise. While cancer therapies received many of the designations, as expected, rare inherited disorders, infectious diseases and cardiovascular diseases also benefited.

Breakthrough Therapy Deisgnation: More Diversity Than Expected

The program’s success comes down to the all-hands-on-deck approach by the FDA and its industry partners, according to Allen. “While many focus on how the designation has changed the culture at the FDA, it’s a very intensive process for the sponsors as well,” Allen said. “They have to meet the deadlines as rapidly as the FDA is advancing their internal processes.”

Some have voiced worries about safety and efficacy data from accelerated clinical trials and the strain on resources for the FDA and sponsors, but Allen does not share those concerns.

Thankfully for the patients that will benefit from these therapies, a lot of hard work is going into this program.

“Having had a hand in writing the law, we explicitly did not alter the standards that have been in place for decades,” Allen said. “From a legal standpoint, there’s nothing adjusted in terms of the levels of evidence needed to demonstrate efficacy and safety.”

The program is only applied to therapeutic areas of unmet medical needs for serious and life-threatening diseases. The alternatives for these patients are limited, so making new treatment options available as quickly as possible while still maintaining confidence in the therapy is important.

While the program is resource-intensive, the FDA and sponsors have both shown committed efforts to prioritizing these much-needed therapies and expediting their development. “It requires a lot of careful planning and a lot of collaboration,” said Allen. “Thankfully for the patients that will benefit from these therapies, a lot of hard work is going into this program.”

Additional resources may be coming to more broadly implement programs such as the breakthrough designation. For instance, the 21st Century Cures Act would continue to modernize the clinical trials process and increase FDA funding by $550 million over 5 years.  Following months of legislative and advocacy work, the U.S. House of Representatives passed their version of the bill in July. Now it’s the Senate’s turn to show they are equally committed to providing new treatment options for patients quickly and safely by passing this legislation.

Many cancer survivors live in fear, knowing that the disease may return. Some cancer cells may survive treatment and can go on to form another tumor, delivering a particularly emotional blow to any patient.

“Some therapies seem to be very good at shrinking tumors, but they leave some cells behind,” said Samuel Levy, vice president of Genomic Sciences at Quanticel Pharmaceuticals, a company that is leveraging single-cell genomics to study individual tumor cells. That’s because therapies generally attack specific behaviors of tumor cells, but as Levy points out, “Not every cell in the tumor is doing the exact same thing.”

Pockets of tumor cells may behave differently because of genetic alterations or environmental factors. By identifying these different sub-groups, researchers may one day identify characteristics of these cells called biomarkers that predict which treatments or treatment combinations will ensure that no cancer cell is left behind in a patient. That, however, requires a relatively novel approach: analyzing cells one by one.

Some cancer cells may survive treatment.

Traditionally, cells have been analyzed in bulk—partly because of the assumption that cells in a certain population behaved the same and partly because it was simply easier (in fact, possible at all) to do. When the human genome was first sequenced, it wasn’t the genetic information from any one cell but rather an average genome from thousands—if not millions—of cells. So the most popular sequence ended up in the final product.

I could list a whole host of diseases—autoimmune diseases for instance—where characterizing the behavior and characteristics of single cells may have great value.

But with this bulk approach, it’s easy to miss the rare sub-groups such as cancer stem cells, which researchers believe may be responsible for forming the tumor in the first place. From a clinical perspective, if a therapy eliminates all the different sub-groups within a patient’s tumor, it could be a very effective treatment options for that cancer patient.

Since the human genome was first sequenced, scientists have worked hard to improve the techniques used to amplify DNA into larger quantities and to analyze the genetic material. “The analysis techniques of the past simply required more material than we could pull out of a single cell,” Levy said. “So we had to focus first on optimizing the chemistry until we could actually analyze RNA and DNA from a single cell and trust the results.”

Next, researchers needed the capability to sequence thousands of individual cells quickly and accurately. While a range of single-cell isolation techniques have been refined over the past few years, the Quanticel team has developed their own because they saw limitations with regard to throughput and accuracy in previous approaches.

Today, their platform consists of a robotic arm manned with a camera that identifies single cells on a dish. Then the arm gently sucks up and moves the cell into another plate that keeps the cells separate, known as a microwell plate. The image-and-vacuum approach is gentler and more accurate than other techniques.

The Quanticel platform leverages a robotic arm manned with a camera to identify a single cell, suck it up and move it into a microwell plate on the left.

The Quanticel platform leverages a robotic arm manned with a camera to identify a single cell, suck it up and move it into a microwell plate on the left.

“In our approach, we’re not forcing cells into water-in-oil droplets, or handling with multiple micropipettes so there’s less damage to the cells,” Levy said. This could lead to inaccurate or just plain wrong results from any analysis of those cells. “And because we take before-and-after photos, we can guarantee close to 100 percent accuracy in the capture and delivery process.”

Once the single cells are deposited in the microwell plate, researchers can analyze them. Besides single-cell DNA sequencing and gene expression analysis (determining which genes are turned “on” or “off” in a given cell), it won’t be long before researchers can look at the epigenetics (the 3D wrapping of DNA that helps determine whether genes are on or off) and protein profile of single cells.

Recognizing the potential of single-cell analysis to improve cancer treatment and identify new therapeutic targets, Celgene entered into a strategic alliance with Quanticel Pharmaceuticals in 2011 and acquired the company in 2015.

Cancer is just the starting point; single-cell analyses could be valuable in other diseases in which different sub-groups of cells are to blame. “I could list a whole host of diseases—autoimmune diseases for instance—where characterizing the behavior and characteristics of single cells may have great value,” Levy said.

It’s not rare for a patient to be told they have ulcerative colitis only to later find out that they instead have Crohn’s disease.

“It’s difficult for doctors to make a proper diagnosis sometimes because Crohn’s can look very similar to ulcerative colitis,” Dr. Giovanni Monteleone, a gastroenterologist at the University of Rome Tor Vergata, said.

Shared characteristics include diarrhea and abdominal pain caused by inflammation of the digestive tract, but the location of this inflammation differs. In ulcerative colitis, inflammation only affects the large intestine, starting with the rectum—which is located in the lower left abdomen. Meanwhile, Crohn’s disease most commonly involves the terminal ileum—located in the lower right abdomen—although it can affect the entire gastrointestinal tract as well.

Crohn's Disease vs. Ulcerative Colitis

And while ulcerative colitis works its way from the rectum through the colon continuously, Crohn’s disease can cause patches of inflammation surrounded by healthy spots. That patterning can only be identified through a colonoscopy to view the inner lining of the large intestine. Even with this invasive test, about 10 percent of cases are still unclear.

Genetic studies are no help in the matter. “The genetic alterations associated with these diseases are common to both,” Monteleone said. “So we have no genetic diagnostic test to single out a colitis or Crohn’s diagnosis.”

What’s left, then, is simply time. “In those cases, the patient will eventually be diagnosed with one disease or the other as evidence mounts,” Dr. Guillermo Rossiter, senior director of Inflammation and Immunology R&D at Celgene, said.

We have a long way to go in terms of helping the most patients with medical therapies.

For instance, some patients develop anal fistula and fissures—areas of tunneling and painful cracks in the skin around the anus. “That’s a sign that we’re dealing with Crohn’s disease and not colitis,” said Dr. Faten Aberra, a gastroenterologist at the University of Pennsylvania and a committee member at the Crohn’s & Colitis Foundation of America.

At this year’s Annual Scientific Meeting of the American College of Gastroenterology (ACG) in Honolulu, researchers are discussing ways to improve both the diagnosis and treatment of these diseases.

Today, for instance, scientists are looking at how antibodies in a patient’s blood and urine can be used to differentiate these diseases. At ACG, researchers will discuss how symptoms outside the digestive tract can be used to tell these diseases apart.

With the proper diagnosis, doctors can then select the best treatment, from medical options—such as steroids, immunosuppressants and biologics—to more severe surgical procedures to remove diseased sections of the bowels. While up to 75 percent of ulcerative colitis patients will respond to medications, 70 percent of Crohn’s disease patients will undergo surgery.

Even the medical treatment options are far from ideal. “Steroids, immunosuppressants and biologics both have unattractive safety profiles, and patients often become less responsive to biologics over time,” Rossiter said.

New ways to treat inflammatory bowel diseases will of course also be a topic of conversation at ACG. Although medical and surgical treatment can help ease some of the symptoms, none targets the root causes. And there are no cures.

“We need something else to improve the quality of life of these patients,” Monteleone said. “These are nasty conditions that affect their lives; they stay home for long times, cannot work, cannot spend time with their relatives because of their quality of life and hospitalizations.”

Patients have reasons to be hopeful, though, as new treatment options are being developed. And the recent recognition of both Crohn’s and ulcerative colitis as orphan diseases by the U.S. Food and Drug Administration should help expedite the development of several therapies currently in clinical trials.

“We have a long way to go in terms of helping the most patients with medical therapies,” Aberra said. “We can get some patients into remission, but some do not respond at all; we still need to figure out which patients will respond to which medicine.”

Health care leaders are gathered today in Boston for The Economist’s Health Care Forum to discuss progress in cancer care and how to pay for the innovations that may one day cure this diverse set of diseases. If the recent hepatitis C example is any indication, it’s clear today’s health care system isn’t financially prepared for a cure.

The treatment of hepatitis C experienced a massive breakthrough in late 2013, when the FDA approved two novel therapies for the disease. Despite high cure rates with the new options, state Medicaid programs and private health plans have been denying patients access to the treatments for financial reasons.  Yet financial analyses suggest the therapy offers substantial savings over the long-term.

“It’s a paradoxical situation,” Soeren Mattke, senior scientist at the RAND Corporation, said. “You have a therapy with undisputed value, but a payer can’t pay for it because of their cash flow problems.”

Health Care Political Cartoon: Financing Cures

Their short-term cash flow issues are preventing the economy — and patients — from reaping the lifelong financial benefits. While a curative therapy has a reported price tag of $84,000, the alternative is ongoing supportive therapy, at nearly $10,000 per year. In just nine years, then, the novel therapy would pay for itself. And after 25 years, the cost of supportive therapy would reach an estimated $242,000, several times the cost of a cure.

New Treatments Have Long Term Benefits

But today’s health systems were not designed to recognize such long-term cost-savings. Private insurers are not guaranteed to realize them, since their members can change health plans yearly. And more cash-constrained programs like Medicaid and the U.K.’s National Health System are up against strict annual budgets that don’t lend themselves to future-looking decisions.

What health needs is a way to finance those early upfront costs over the long-term. “Treatment costs can be stretched over time, making therapies more affordable for payers,” Mattke said. “It’s been kind of an accident that no one has thought of financing treatments before.”

Treatment costs can be stretched over time, making therapies more affordable for payers. It’s been kind of an accident that no one has thought of financing treatments before.

This happens every day in housing and education. When we purchase a house or put ourselves through college, we don’t pay for it all upfront. Without credit markets, we would have fewer homes and college diplomas, both of which provide lifelong value for their owners.

Even in health care, examples exist. Medical equipment manufacturers offer health care facilities financing options to lower upfront costs.

Payments could even be linked to real-world performance to reduce the risks associated with new technologies, since clinical trials don’t always mimic the real world performance of a drug. “You don’t want to be stuck paying for something that isn’t working,” Tomas Philipson, Daniel Levin Professor of Public Policy at the University of Chicago, said. “Tying payments to performance is harder to do administratively but not impossible.”

Returning to the problem that private payers face, of patients’ moving from one insurer to another, Mattke noted that it’s not an insurmountable challenge. “It’s only a technicality,” he said. “When you move, you sell your mortgage, right? It’s all about money flow, and that can always be managed.”

And yet resistance to such financing innovation remains high. Private insurers and Medicaid have found it easier to ration therapies, but we’re beginning to see a backlash. Earlier this month, health experts urged the White House that Medicaid should provide patients with better access to new hepatitis C therapies.

The hepatitis example was a wake-up call for health care payers, Philipson said. “New innovations are coming to market, and we’re going to run into this situation more and more,” he said. “If we don’t solve these cash flow problems, there’s going to be less innovation.”


While most myeloma patients experience remissions lasting less than three years, a select few have no signs or symptoms for 10 years or more. Research suggests that lasting success may be due to immune system differences that promote disease suppression.

“The hematology community is coming to the realization that a key element in the way forward is to better understand and treat the immune aspects of myeloma,” Dr. Brian Durie, a multiple myeloma specialist at the Cedars-Sinai Medical Center, said. “We need a better understanding of what causes relapse, and we need to develop new therapies that overcome that resistance. We need to remember these obstacles when we are developing new treatments.”

Among the promising results presented at ASH last year were several on immunomodulating therapies, including two phase I studies of anti-CD38 antibodies. Antibody-based therapies target molecules on cancer cells, making them more visible to both the patient’s immune system and other cancer treatments.

Another area of interest in immunotherapy for multiple myeloma is genetically modifying a patient’s own immune cells to target and destroy the cancer cells. One such therapy is known as chimeric antigen receptor (CAR) T-cell therapy. The promising results of several CAR T-cell therapy clinical trials in myeloma, as well as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia and acute myelogenous leukemia, were also presented at ASH in 2014.

Recognizing the potential of immunotherapy in multiple myeloma, Celgene has established several strategic collaborations to leverage these advances in immunotherapy over the past few years. In 2013, Celgene began collaborating with bluebird bio and the Baylor College of Medicine to discover, develop and commercialize antibodies for B cell-mediated blood cancers.

This spring, Celgene announced a collaboration with AstraZeneca/MedImmune Limited to research a pathway that tumor cells hijack to evade the immune system. By targeting this pathway for inhibition, the aim is to improve the ability of the patients’ immune cells to attack blood cancer cells, including myeloma cells.

More recently, Celgene and Juno Therapeutics, Inc. agreed on a long-term collaborative partnership to bring CAR T-cell therapies and T cell receptor technologies to market for cancer patients.

While the results from preliminary studies of these immunotherapy approaches are promising, whether they will improve patient outcomes in the long run remains to be seen. “We’re now exploring whether it’s possible to get rid of every myeloma cell and effectively cure patients with these new therapies,” Durie said. “We’re focusing on looking for residual disease to determine whether we need to continuously modulate the immune system in these patients.”

In the past, a cancer diagnosis meant a death sentence to patients, but today, cancer patients have new hope as innovative therapies are being developed and approved. That’s the message of “Cancer: The Emperor of All Maladies,” a three-part six-hour documentary from executive producer Ken Burns, which airs on PBS March 30 to April 1, 2015.

But if health insurers continue to make cancer patients pay more for these therapies, those treatments might not be affordable options. Today, 48 percent of cancer patients say they paid more for health care over the past year, and treatment copays have been one of the primary drivers of those rising costs, according to a recent survey conducted by the Cancer Support Community.

“Some cancer patients are facing a significant economic burden because their insurance simply isn’t working for them,” Joel Beetsch, vice president of Global Patient Advocacy at Celgene, said. “The insurance landscape has fallen behind the pace of science. We all need to do our part to grant access to innovative therapies so the patient is always at the center of our actions.”

More than 30 percent of cancer patients reported being financially affected by their cancer care costs in a 2010 survey of over 2,100 cancer patients.

Those financial hardships negatively affected how patients rated their physical and mental states as well as overall satisfaction in social activities and relationships. In fact, financial hardship was the single strongest predictor of quality of life in cancer patients, according to an analysis of the survey results.

Specialty tiers, step therapy and other utilization management policies used by insurers that focus primarily on cost-savings can be detrimental to patients.

“We as a health care ecosystem continue to focus on the needs of cancer patients, and restricting access is not serving the best interests of our patients,” Beetsch said.

Instead of focusing on what is best for those they insure by providing affordable access to the new targeted therapies highlighted in the documentary, some insurers are raising costs for patients instead.

Health insurance plans sold through the Affordable Care Act marketplace are requiring patients to pay more for some medicines used to treat cancer. The proportion of Silver plans—the most popular plans purchased—that place all molecular targeted inhibitors, a type of innovative targeted cancer therapy, in specialty tiers jumped from 34 percent in 2014 to 47 percent in 2015. And since drugs on specialty tiers can force cancer patients to pay as much as half the cost, this increase can have devastating effects on more and more patients.

Insurers- increasingly place cancer therapies in specialty tiers.

“Specialty tiers, step therapy and other utilization management policies used by insurers that focus primarily on cost-savings can be detrimental to patients,” Beetsch said. “These policies must follow clinical guidelines approved by the medical community to ensure a focus on the patient’s health.”

Since cancer is not one disease but hundreds of different diseases, the one-size-fits-all approach to treatment promoted by some insurance plans will not be effective.

“Individuals must be treated in ways that are tailored to their individual disease,” Dr. Andrew L. Kung, chief pediatric oncology at the NewYork-Presbyterian/Columbia University Medical Center, said at a press briefing on the “Cancer: The Emperor of All Maladies” documentary held at Columbia University last week.

Restricting or delaying access to the right therapies increases the risk that the patient’s disease will worsen. Some states are taking action to increase access to medicines that can improve patient health and actually reduce health care spending, and hopefully the documentary will help raise awareness of these efforts and the innovative cancer research from leading oncologists.

“My hope is that everyone who watches this documentary will understand that we know more about cancer than ever before, innovation is driving the science forward, and access to that innovation will improve the lives of the patients we are all working to serve,” Beetsch said.

The first medicine based on antisense technology was approved by the FDA in 1998. With scarcely a follower in the years since, many in the industry have questioned the potential of these treatments. Recent developments, however, suggest they may be on the rise again.

In 2013, the FDA approved a second antisense therapy—this one designed to treat a genetic defect that leads to high cholesterol.



And now, more than 40 antisense therapies are in clinical trials for diseases such as cancer, diabetes and neurodegenerative diseases; over 20 of those therapies are in advanced stages of development.

“There’s really a nice potential for antisense therapies to be able to fix, modify or even eliminate disease that is caused by genetic mutation,” Scott Smith, global head of the Celgene Inflammation and Immunology franchise, said. “And there is antisense research being done in asthma, arthritis and other inflammatory diseases.”

Antisense therapies target molecules called messenger RNA (mRNA)—the intermediary between a gene and the protein it codes for. If the DNA molecules that make up the genome can be envisioned as a twisted ladder (the famous “double helix”), with steps consisting of partnered nucleotide pairs, RNA resembles that ladder cut down the middle lengthwise. This single-stranded, unpaired structure is essential to the production of proteins from a given gene.



Although the theory behind antisense dates back to the 1970s, the technology only became practical in the 1990s, when the human genome was mapped, lending researchers the gene sequences they’d need to design an antisense molecule. With the right sequence, antisense therapies are meant to bind to a disease-associated mRNA, and thereby block production of the relevant dysfunctional, or simply overabundant, protein.

But their single-stranded nature leaves antisense molecules vulnerable to enzymes that can break them down, creating obstacles for scientists looking to turn them into therapies. As a result, researchers have been working on improving their life-span, distribution and binding power, often through chemical modifications.

At the University of Rome Tor Vergata, Professor Giovanni Monteleone is leading the quest for an antisense therapy for inflammatory diseases. His mission has been to overcome some of the hurdles these therapies have faced.

“It’s difficult for the antisense molecule to reach its target organs at high concentrations,” Monteleone said. “This is one reason why many such therapies did not work in the past. In the end, we believe it’s a question of administration rather than of something special about the technology.”

I think there is a lot of hope for antisense therapies in the future, but it does require some different thinking.

Designing a new administration method has been a focus for Monteleone and others interested in this technology platform.

“If you give the drugs orally, they get degraded—broken down—before getting to the target tissue,” Smith said. “And if you give them intravenously, they are circulating in the whole body and not necessarily hitting the target tissue, which can lead to side effects.”

One new possibility researchers are exploring is to administer an antisense therapy topically. That way, the entire body is not exposed to potential off-target consequences that could lead to side effects. And a topical formulation would allow specific, targeted application to the disease area.

Only clinical trials will tell us whether the promise of these therapies will bear out. Monteleone and Smith, along with others at Celgene, are optimistic. New findings from clinical trials examining an antisense therapy for Crohn’s disease were recently published in the March 19 issue of The New England Journal of Medicine. Additional findings are also expected to be presented at Digestive Disease Week (DDW) 2015 in Washington DC on May 16-19.

“I think there is a lot of hope for antisense therapies in the future, but it does require some different thinking,” Smith said. “As an industry, we need to find a more eloquent way to deliver the drug to diseased cells. If some of the delivery problems can be overcome, there’s tremendous potential for these drugs.”

Although breast cancer survival rates are improving on the whole, those for women diagnosed with the triple-negative form remain significantly lower. In large part, that’s because triple-negative breast cancer (TNBC) doesn’t respond to many of the more modern, targeted treatments.

But results of trials of combination therapies, which attack different aspects of the disease, are showing promise. At Celgene, we are committed to  helping improve the lives of patients with TNBC.

About 10 percent of breast cancer cases are triple-negative. While 93 percent of women with other types of breast cancer survive five years after diagnosis, only 77 percent of those TNBC can say the same, according to a 2007 study of 50,000 women with breast cancer.

“With all the progress that’s been made in treating certain types of breast cancer, triple-negative metastatic breast cancer unfortunately remains especially challenging,” Denise Yardley, senior investigator at Sarah Cannon Research Institute Breast Cancer Research Program, said. “That’s due in part to the genetics of the tumors, in part to where the metastases tend to occur, and in part because the disease is so aggressive.”

Indeed, TNBC is one of the most aggressive types of cancer. Women diagnosed with TNBC are four times more likely to have that cancer spread, or metastasize, to other organs within five years than patients with other types of cancer. Most often, TNBC tends to spread to vital organs such as the brain and lungs.

In a study published in Clinical Cancer Research in 2007, researchers found that the median time to metastatic recurrences in TNBC patients was just 2.6 years, while the median time for patients with other breast cancers was 5.0 years. In addition, the survival time from diagnosis of distance metastatic TNBC was just 9 months compared with 22 months for other cancers.

Some of the most effective breast cancer treatments today target proteins on the surface of breast cancer cells, such as human epidermal growth factor receptor 2 (HER2), estrogen receptors and progesterone receptors. Because the growth of TNBC cells isn’t supported by the presence of too many HER2 receptors, or by progesterone or estrogen hormones, these therapies are less effective.

Clearly, different approaches to treating this particularly aggressive form of breast cancer are required. One strategy that has received significant attention lately is a combination of therapies.

At the 2013 San Antonio Breast Cancer Symposium, researchers from Northwestern University presented promising data from a clinical trial of a combination of chemotherapies that showed improved outcomes for women with TNBC. After being treated with the combination therapy, 43 percent of women in the study were tumor-free. Historically, only 30 percent of women with TNBC are tumor-free after treatment.

“Triple-negative breast cancer tends to be very aggressive, and because it is aggressive it metastasizes very fast,” said Virginia Kaklamani, director of translational breast cancer research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and lead researcher of the study, said in a statement. “We don’t have many good treatments for it, which is why the results of our study is such good news.”

The results of combination therapy trials for TNBC are promising, although more effective treatments are still needed. Trials of different combination therapies are ongoing, so patients with TNBC should consider enrolling in trials and should always discuss all their treatment options with their doctors.

Researchers at New York University (NYU) School of Medicine may have figured out how ravenous pancreatic tumor cells feed themselves, according to a study published in the prestigious scientific journal Nature. Identifying this nutritional mechanism could open new doors for cancer treatments.

In many cancers, including pancreatic, a mutated version of a protein called Ras helps drive tumor cell growth and cancer progression. These Ras-mutated cells need extra nutrients to finance their accelerated growth, but until recently scientists didn’t fully understand how they met their food requirements.

In the Nature study, led by Cosimo Commisso, a postdoctoral fellow in the Department of Biochemistry and Molecular Pharmacology at NYU School of Medicine, the researchers showed that cancer cells with a specific Ras mutation known as KRAS use a feeding method called macropinocytosis. This mechanism allows the cells to devour an abundant natural protein called albumin. The tumor cells then dismantle the albumin for amino acids, which are necessary for the cancer cells’ growth.

During macropinocytosis, a large fluid-filled sac called a macropinosome is pinched off from the cell membrane and brought to the interior of the cell, where its contents, including nutrients, can be used by the cell machinery.

Commisso and colleagues found that pancreatic cancer cells had more macropinosomes than did normal cells. And pancreatic tumors in mice stopped growing and sometimes even shrank when the researchers used a chemical to block macropinocytosis. “A big mystery is how certain tumors meet their excessive nutrient demands,” Dr. Commisso said. “We believe they accomplish this by macropinocytosis.”

The findings suggest that the process of macropinocytosis is necessary for KRAS cancer cells to thrive. If so, blocking the process may offer a new way to kill off cancer cells. “This work offers up a completely different way to target cancer metabolism,” said Dafna Bar-Sagi, PhD, senior vice president and vice dean for Science, chief scientific officer and professor, Department of Biochemistry and Molecular Pharmacology, at NYU Langone Medical Center, who was lead investigator on the study. “It’s exciting to think that we can cause the demise of some cancer cells simply by blocking this nutrient delivery process.”

Alternatively, researchers might leverage this uptake mechanism as a way to get tumor cells to take up anti-cancer drugs, by fooling them into devouring chemotherapies or novel treatments along with albumin.

It has long been assumed that we’re stuck with the genes we’re born with—for better or worse. But epigenetics, the dialing up and down of genes by environmental factors, is altering that view.

The study of epigenetics is the study of how information coded by genes is translated and expressed by cells, and it looks at how inherited traits are altered by environmental conditions without changing the actual DNA sequence.

Exactly how the environment influences genes is still being unraveled. Lifestyle choices and other factors appear to alter the molecules that surround DNA, affecting how tightly it is packed and thus how active or inactive certain genes are. The packing is controlled by several families of enzymes that add or remove tiny chemical “tags” on the DNA.

The exciting thing about epigenetic changes, unlike genetic mutations, is that they can be reversed. And that makes it attractive to researchers hoping to cure diseases of all kinds. By playing with the tagging enzymes, troublesome genes that give rise to cancers can be reset to a normal state. “It’s easy to make inhibitors of enzymes,” Scott Armstrong, oncologist at Memorial Sloan-Kettering Cancer Center in New York, recently told Nature. “Everyone sees this as a potential opportunity.”

Targeted therapies activate or deactivate parts of the chromatin with the aim of slowing or stopping a disease. Therapies such as this can also be used in combination with more traditional treatments such as chemotherapy.

While fewer than half a dozen epigenetic medications are on the market today, their potential is on the rise. Celgene has two therapies that target epigenetic alterations and is looking to develop more. To that end, Celgene partnered with Cambridge, Mass.-based Epizyme, a biopharmaceutical company focused on epigenetics, in April 2012.

The companies are looking to identify therapies to treat a rare blood cancer called mixed lineage leukemia (MLL). Although the patient population is not large, those with this form of leukemia have few options. And that makes it the perfect arena for Celgene.

In 2006, pitcher Jon Lester of the Boston Red Sox was undergoing chemotherapy for anaplastic large cell lymphoma, a potentially fatal cancer of the immune system, yet seven years later he won two 2013 W­­orld Series games.

Like Lester, many of the more than 70,000 people diagnosed with lymphoma each year survive because of advancements in chemotherapy and other treatments. However, most people don’t realize that this cancer is actually a  large group of distinct diseases. Which therapies they receive and how well they will respond to treatment depend on the type of lymphoma they develop.

Lymphoma, the most common form of blood cancer, occurs when the immune system produces too many of the cells called lymphocytes, which normally guard the body against viruses and bacteria. These cells multiply normally in the course of an infection, leading to swollen lymph nodes, such as in mumps or mono, but after the infection has subsided, the cells die off and the lymph nodes return to normal size. When these lymphocytes become malignant, they multiply continuously and lymph nodes become larger and larger even in the absence of an infection.  Hodgkin’s lymphoma, one of the many subtypes of lymphoma, is a remarkable treatment success story. The vast majority of patients are cured with chemotherapy and or radiation therapy.  Patients have a more than 80 percent chance of cure even when the cancer has widely spread throughout the body.

Hodgkin’s lymphoma is characterized by the presence of an abnormal cell called the Reed-Sternberg. All other lymphomas—those that do not have Reed-Sternberg cells—are lumped into a category called non-Hodgkin lymphoma (NHL).

There are more than 30 different types of NHL. Some forms are treated differently than others. For example, anaplastic large cell lymphoma, the type of lymphoma that Jon Lester was diagnosed with, often responds well to a chemotherapy regimen called CHOP, which includes four drugs:  cyclophosphamide, doxorubicin, vincristine and prednisone. CHOP also works against other NHL sub-types that fall within the same category as anaplastic large cell lymphoma, known as peripheral T cell lymphomas.

The most common type of NHL, diffuse large B cell lymphoma (DLBCL), is also treatable and potentially curable. This fast-growing lymphoma  accounts for about one third of NHL cases. For this lymphoma, it is typical for lymph nodes to double in size every month, and patients often present within a few months of having noted an enlarged lymph node. The typical first line treatment is a modified version of CHOP, known as R-CHOP, that adds a “targeted therapy” called rituximab which is  a monoclonal antibody, that homes directly to the cancer cells and promotes their destruction.  Over 90 percent of patients with localized, early stage DLBCL will be cured with a combination of R-CHOP and radiation therapy and approximately 50 percent of patients with advanced stage DLBCL will be cured with R-CHOP. Unfortunately for those patients who are not cured by R-CHOP there are less attractive second line therapies, including chemotherapy or high dose chemotherapy followed by autologous stem cell rescue, also known as bone marrow transplant. Many fewer can be cured at that point and the majority of these patients will not survive their disease.

The second most common subtype of NHL, follicular lymphoma (FL), grows slowly, with lymph nodes doubling in size approximately every six to 12 months, and patients often get diagnosed a year or later after they first noted an enlarged lymph node. Many patients may not require treatment initially and can just be observed. A small fraction never require treatment, however, eventually, the vast majority of  patients will require therapy which is typically rituximab combined with a chemotherapy. Unlike DLBCL, patients with FL are rarely if ever cured but may live many years  because of the slow growth of the tumor cells and the ability to treat with multiple therapies. Eventually, however, most patients will die of their disease and in about 25 percent of them their FL will transform to DLBCL which is typically not responsive to therapy in this setting.

Another type of NHL that responds to chemotherapy is Burkitt’s lymphoma. Doctors first noticed this cancer in children in Africa, but it also strikes people infected with human immunodeficiency virus (HIV), organ transplant recipients, and others. Chemotherapy combinations cure about 50 percent of patients, meaning there are many who need other choices. This lymphoma is very rapidly growing, and lymph nodes double in size within a few days to a few weeks. While it is rapidly growing, it is curable in many patients when diagnosed early.

Mantle cell lymphoma (MCL) only accounts for about five percent of the cases of NHL but it is a very aggressive type of lymphoma  and is typically diagnosed in very advanced stages of the disease. Treatments like R-CHOP have improved the prognosis for patients, who now survive for five to seven years on average, but the disease recurs in nearly all patients and cures are extremely rare.  Continued scientific advancements  are providing  additional options for patients

The picture however is continuing to improve for all of the lymphomas with the continued research and development of exciting therapies that specifically target the cancer cells, and agents that modify the immune system. These new therapies include monoclonal antibodies that target directly to the cancer cells and kill the cancer cells by a variety of immune mechanisms, monoclonal antibodies that are “packaged” with toxic chemicals that target directly to the cancer cells to deliver these toxic agents, and tyrosine kinase inhibitors that are small molecules that can be given orally and target different growth receptors in cancer cells and very effectively kill the cancer cells, and other agents to stimulate the immune system. This is perhaps the most exciting era in lymphoma history where basic science discoveries are becoming available to lymphoma patients with the hope of  improving their survival and  quality of life.

Multiple myeloma (MM) is the second most commonly diagnosed blood cancer, after non-Hodgkin lymphoma, yet few people know much about this deadly disease. Approximately 22,000 Americans were diagnosed with MM in 2013. In the United States, nearly 74,000 have MM, and an estimated 10,700 will die from the disease this year. Globally, it’s estimated that 103,000 people were diagnosed with MM in 2008, which equates to 12 percent of all blood cancers diagnosed, according to Cancer Research UK.

“Myeloma is important because it’s increasing in incidence,” Brian G.M. Durie, MD, chairman and co-founder of the International Myeloma Foundation, said at the American Society of Hematology (ASH) Annual Meeting in New Orleans in December 2013. “There are more patients around the world being diagnosed with myeloma, and for some reason it’s being diagnosed in patients who are younger.”

The reason behind this increase is unclear. What we do know is that MM is a cancer in which plasma cells—an important part of the immune system—become immortal and eventually replicate uncontrollably and accumulate in the bone marrow, the soft tissue at the center of the bones. The cancer cells grow out of control, crowding out normal cells.

The signs and symptoms of multiple myeloma at early stages of the disease are subtle. But as the disease progresses it can cause effects such as bone destruction, anemia (a lack of red blood cells) or even kidney failure. Many people with MM experience debilitating bone pain and fractures that require radiation or surgery. Bone fractures can be particularly dangerous when they occur in the spinal column, causing the vertebrae to collapse or compress, damaging the spinal cord. In some cases, paralysis can occur. Patients may also experience weight loss, numbness or weakness in the legs and repeated infections such as pneumonia, shingles or sinusitis.

While the cause of multiple myeloma is unknown, several risk factors increase the odds of developing it, including radiation exposure and even farming. MM is twice as common in African Americans compared with Caucasians and is significantly more common in patients who have a close relative with the disease. However, most patients with MM have no known risk factors other than age. On average, MM patients are 70 years old at diagnosis.

There is currently no cure for multiple myeloma, but medical advances are helping make progress on this front. Since the introduction of novel, innovative therapies in the 1990s, survival times have improved by an impressive 300 percent—from a median survival of 2.5 years after diagnosis in 1997 to more than 10 years in 2012. Between 2000 and 2009, the United States saw a 73 percent increase in the number of myeloma survivors. As survivorship increases, researchers are hoping they can do even better, by making myeloma a chronic condition like other incurable diseases such as diabetes and hypertension. “We are able to discuss the idea that we are attempting to cure myeloma,” Dr. Durie said at ASH.

In the interim, a lot of headway has been made in improving the prognosis for patients with MM, but there is still a need for earlier diagnosis and new treatment options.

“The treatment of myeloma is at a unique crossroads, as the work that has been done has created a positive foundation for patient outcomes,” Mohamad Hussein, MD, vice president of Global Scientific Affairs, Multiple Myeloma for Celgene, said. “We also have the opportunity through our commitment to a new understanding of the disease to get closer in the coming years to our goal of turning this incurable cancer into a chronic, manageable condition.”

Impressive numbers such as these are yet another reason why we must continue to support medical innovation. They are proof that even progressive improvements can add up to make real differences in people’s lives.

Posted on by

Chemotherapy is a foundational treatment that still plays a vital role in treating cancer. While the advent of targeted treatments and immunotherapy has excited the masses, chemotherapy is aiming to keep pace. More than one hundred chemotherapy treatments are in use today, many of them used in combination with other drugs or treatments.

In the last decade, researchers have been devising ways to increase the uptake and concentration of chemotherapy in the tumor as well as new ways of combining treatments in hopes of improving their effectiveness and limiting some side effects.

“Chemotherapy has dramatically improved in the last decade,” George R. Simon, MD, FACP, FCCP, director of thoracic oncology at the Fox Chase Cancer Center in Philadelphia, told WebMD. “There has been a dramatic change in our ability to minimize side effects over the last few decades. Modern chemotherapy drugs are more effective and generally less toxic.”

Since 1990, the cancer death rates have been declining yearly in the United States, meaning survival rates for cancer patients are better than they were three or four decades ago. Approximately half of this improvement is due to treatment progress, with a large portion of that due to chemotherapy being included in many regimens.

Decades ago, the discovery of chemotherapy changed the approach to cancer treatment. Whether it was a derivative of tree bark or a man-made chemical compound, chemotherapy was found primarily to prevent cells from multiplying by interfering with the DNA-copying process used by all replicating cells. Most chemotherapies developed before 1990 were not targeted toward the cancer itself and could therefore damage healthy cells in addition to cancer cells. Hair follicles, for example, are rapidly replicating cells, which is why patients undergoing chemotherapy often lose their hair.

Chemotherapy was initially used as a supplement to other methods of treatment, such as surgery to remove the tumor and radiation to kill it. But whereas surgery and radiation are localized treatments that affect small areas of the body, chemotherapy affects the entire body.

Over the last thirty years, many scientific advances have occurred that significantly enhanced our understanding of how cancer develops and how cancer cells differ from healthy cells, which has led to the identification of specific treatment targets. Newer therapies typically aim for targets that are specific to cancer cells and do not occur, or are rare, in healthy cells.

Recent advances in chemotherapy have made it more suitable for certain cancers. As chemotherapy continues to evolve, some of the newer iterations have succeeded where older chemotherapies have not.

Scientists are still working continuously to develop better treatment options—including more advanced forms of chemotherapy—to control cancer, with the ultimate goal of a cure. According to the American Cancer Society, recent research includes new classes of chemotherapy, novel combinations of chemotherapy medications, and new routes of administering treatment. Some of the more exciting approaches involve nanotechnology and liposomal therapy.

No matter the form, chemotherapy remains a crucial part of the treatment plan for thousands of patients with various early- and late-stage cancers. In the age of targeted therapies based on gene mutations, receptors on cancer cells or the body’s immune response, the role of chemotherapy is still pertinent. Chemotherapy can shrink tumors to make some patients eligible for other treatment options, such as surgery or radiation. For others, chemotherapy can be used when the effects of targeted treatments begin to wane. Whether used alone or in combination with next-generation treatments, chemotherapy will remain a mainstay of cancer therapy for the foreseeable future.

Posted on by

Possibly the only thing more frightening than being diagnosed with cancer is learning you have a form of the disease you’ve never heard of. That’s exactly what Robin Roberts, host of “Good Morning America” felt in 2012, at the age of 51, when she was diagnosed with a rare form of blood cancer. “It is something called MDS—myelodysplastic syndromes,” she announced to her viewers, admitting that she didn’t know what exactly it was at the time. “If you’re going… what? I was doing the same thing.”

MDS is a type of cancer in which the bone marrow does not make enough healthy blood cells, and instead abnormal cells take over the bone marrow or blood. In healthy people, the bone marrow contains stem cells (immature cells) that eventually become mature, functional blood cells. They may become red blood cells to carry oxygen, white blood cells to fight infections, or platelets, which stop bleeding by forming clots.

But in patients with MDS, the young blood cells do not mature correctly and instead die in either the bone marrow or the blood. As a result, there are fewer healthy blood cells, which can lead to infections, anemia (a lack of healthy red blood cells that carry oxygen throughout the body) or heavy bleeding. There are eight different types of MDS that can be diagnosed by identifying specific changes to the cells in the bone marrow and blood.

Certain risk factors increase the chance of developing MDS, including being male and older than 60, as well as having been exposed to tobacco, chemicals such as pesticides or heavy metals like mercury and lead. A person who has received radiation or chemotherapy is also at increased risk.

While symptoms are rare in early stages of the illness, over time patients can suffer from shortness of breath, easy bruising, exhaustion, frequent infections and tiny red spots under the skin. The risk of severe infections is especially serious. A recent study at the Cleveland Clinic reported that 100 out of 500 patients with MDS had had at least one infection that required hospitalization.

A patient’s outlook, or prognosis, often depends on several factors, including the number of blood cell types affected, prior radiation or chemotherapy, history of anemia, changes in the structure of the chromosomes, the amount of abnormal cells in the bone marrow, and the age and overall health of the patient.

Current treatment options for MDS include antibiotics to prevent or treat infections, transfusions, erythropoiesis-stimulating agents (which tell the body to make more red blood cells), immunosuppressive therapy (which weakens the immune system), chemotherapy, disease-modifying therapies and bone marrow transplants, which currently offer the only chance for a true cure.

John Huber, executive director of the Aplastic Anemia and MDS International Foundation, acknowledges that bone marrow transplants would be an ideal fix if only it worked for everyone. “If the transplant works, you’re cured,” he said. “But bone marrow transplants are not 100 percent for every patient.”  In fact, the rate of success is only about 20 to 40 percent.

That’s partly because the patient needs to find a donor with marrow very similar to his or her own. Roberts was fortunate that her older sister was the right bone marrow match, as siblings have roughly a one in four chance of matching.

The TV anchor, who had previously survived breast cancer after undergoing chemotherapy a few years before, learned she had MDS the same day ”Good Morning America” beat its rival “The Today Show” in ratings for the first time in 16 years. And while undergoing tests before the transplant, Roberts learned that she would be interviewing President Barack Obama the next day, a high point in her already very successful career.

These positives helped motivate Roberts. “I’m like everyone who faces some life altering situation,” she said on the episode of her announcement. “It’s about focusing on the fight and not the fright.”

For many patients, a bone marrow transplant isn’t an option, perhaps due to their age, other health-related issues, or the lack of a matching donor. In that case, other options are needed. New disease-modifying therapies are helping to improve quality of life for many patients with MDS. “Therapies and treatments can allow patients to live longer,” Huber said, and he expects even more options for MDS patients in the near future. “Exciting research is being done. That’s where the hope is.”