New designer compound treats heart failure by targeting cell nucleus.

Cell paper highlights entirely new approach to heart protection, addressing major unmet need

Researchers from Case Western Reserve University School of Medicine and Dana-Farber Cancer Institute have made a fundamental discovery relevant to the understanding and treatment of heart failure – a leading cause of death worldwide. The team discovered a new molecular pathway responsible for causing heart failure and showed that a first-in-class prototype drug, JQ1, blocks this pathway to protect the heart from damage.

In contrast to standard therapies for heart failure, JQ1 works directly within the cell’s command center, or nucleus, to prevent damaging stress responses. This groundbreaking research lays the foundation for an entirely new way of treating a diseased heart. The study is published in the August 1 issue of Cell.

“As a practicing cardiologist, it is clear that current heart failure drugs fall alarmingly short for countless patients. Our discovery heralds a brand new class of drugs which work within the cell nucleus and offers promise to millions suffering from this common and lethal disease,” said Saptarsi Haldar, MD, senior author on the paper, assistant professor of medicine at Case Western Reserve and cardiologist at University Hospitals Case Medical Center.

Heart failure occurs when the organ’s pumping capacity cannot meet the body’s needs. Existing drugs, most of which block hormones such as adrenaline at the cell’s outer surface, have improved patient survival. Unfortunately, several clinical studies have demonstrated that heart failure patients taking these hormone-blocking drugs still succumb to high rates of hospitalization and death. Leveraging a new approach, the research team turned their attention from the cell’s periphery to the nucleus – the very place that unleashes sweeping damage-control responses which, if left unchecked, ultimately destroy the heart.

The team found that a new family of genes, called BET bromodomains, cause heart failure because they drive hyperactive stress responses in the nucleus. Prior research linking BET bromodomains to cancer prompted the laboratory of James Bradner, MD, the paper’s senior author and a researcher at Dana-Farber, to develop a direct-acting BET inhibitor, called JQ1. In models of cancer, JQ1 functions to turn off key cancer-causing genes occasionally prompting cancer cells to “forget” they are cancer. In models of heart failure, JQ1 silences genetic actions causing enlargement of and damage to the heart – even in the face of overwhelming stress.

“While it’s been known for many years that the nucleus goes awry in heart failure, potential therapeutic targets residing in this part of the cell are often dubbed as ‘undruggable’ given their lack of pharmacological accessibility,” said Jonathan Brown, MD, cardiologist at Brigham and Women’s Hospital and co-first author on the paper. “Our work with JQ1 in pre-clinical models shows that this can be achieved successfully and safely.”

The team led by principal investigators Haldar and Bradner studied mice who develop classic features of human heart failure, including massively enlarged hearts that are full of scar tissue and have poor pumping function.

For one month, the team administered a single daily dose of JQ1 to the sick mice. The treated mice were protected from precipitous declines in heart function in a matter of days. Animals who received the compound saw a 60 percent improvement, as compared to an untreated control group.

“Remarkably, at the end of the experiment, the hearts of many JQ1 treated mice appeared healthy and vigorous, despite being exposed to persistent and severe stress,” said Priti Anand, a researcher in Haldar’s lab and co-first author on the paper. “We knew we were on to something big the first time we saw this striking response.”

This collaboration started when Haldar read Bradner’s landmark 2010 Nature paper describing the creation of JQ1 and its ability to transform cancer cells into healthy ones. Following an open-source approach to drug development, Bradner elected to make JQ1’s chemical recipe publicly available to accelerate the creation of new treatments for patients. This synergistic approach to discovery opened the door for Haldar to work with Bradner to probe the role of BET bromodomains in the heart.

“So much has been learned from this molecule,” noted Bradner. “The fundamental similarity between the biology of cancer cell growth and heart enlargement following extraordinary stress connects these mature fields of study in new and exciting ways, of immediate relevance to drug development. This study best exemplifies the power of open-source approaches to drug discovery.”

In the coming months, the team will test JQ1 in preclinical models of heart failure and other cardiovascular conditions. With the jumpstart offered by Bradner’s creation of JQ1, the research team hopes to one day move to clinical trials.


Bone Marrow Transplantation (BMT) in Myelodysplastic Syndromes: To BMT or Not to BMT—That Is the Question.

Those who treat patients with myelodysplastic syndromes (MDS) have been forced to become comfortable with a rather uncomfortable truth. MDS is a bone marrow failure syndrome that represents the most commonly diagnosed myeloid malignancy and predominantly affects older adults, with a median age at diagnosis of 71 years.1,2 The only cure for MDS is hematopoietic stem-cell transplantation (HSCT). For a variety of reasons, including patient comorbidities, availability of related or matched donors, related donor comorbidities, physician and patient preference, and treatment-related adverse events, transplantation is only considered in approximately 5% of patients with MDS.2 Thus, even when we offer disease-modifying therapies such as azacitidine, decitabine, and lenalidomide, we are ultimately palliating 95% of our patients.36Despite this, patients often perceive these drugs to have curative potential in this setting, but cure is unfortunately not possible with these agents.7

How do we change this paradigm? Although some factors, such as patient comorbidities and availability of donors, are largely immutable, others factors have improved, making HSCT more appealing. One such advance is reduced-intensity conditioning transplantation, which greatly reduces the toxicity of the preparative regimen without compromising efficacy, and in so doing has raised the age for potentially eligible transplantation candidates into the eighth decade.8 Another modifiable area is in identifying patients for whom the risk-benefit analysis for transplantation is more favorable compared with managing the disease with palliative intent. This, in turn, could affect patient and physician preferences.

In the article that accompanies this editorial, Koreth et al9 report on a Markov decision analysis exploring the role of reduced-intensity allogeneic HSCT in older patients with MDS. This statistical technique relies on assumptions, which themselves are based on best estimates of outcome given in previously published studies, to play out scenarios of what would happen in real life to a given patient if he or she decided to undergo HSCT early, at or near diagnosis, or instead to pursue supportive care, growth factor, or disease-modifying therapy. Although this approach is not perfect, it does allow for sensitivity analyses in which assumptions can be changed to see if the same conclusion holds, and it is the best substitute available in the absence of prospective, randomized studies. This is also not the first time some of these investigators have tackled this question, or this methodology. In 2004, Cutler et al10 published a decision analysis of patients with MDS treated with myeloablative conditioning transplantation. Given this conditioning regimen, patients were younger (with a median age of 40.4 years), and given the timing at which this analysis was conducted, a paucity of individual patient data were available to appropriately reflect nontransplantation treatment approaches. So, although the results of the study by Cutler et al make clinical sense, namely, that early transplantation provides maximal quality-adjusted survival in higher-risk patients with MDS (those falling into intermediate-2 and high-risk categories of the International Prognostic Scoring System [IPSS]), these conclusions have always given treating doctors pause because the participants did not reflect the full spectrum of patients with MDS who are seen in everyday clinical practice.

The analysis by Koreth et al9 addresses these shortcomings. Now, given the nonmyeloablative preparative regimen, the median age of the 132 patients undergoing transplantation gleaned from the Center for International Blood and Marrow Transplant Research, Dana-Farber Cancer Institute, and Fred Hutchinson Cancer Research Center data sets is 64 years—closer to what we see in clinic. Patients who did not undergo transplantation included 132 with lower-risk disease (IPSS low and intermediate-1) receiving best supportive care; 91 anemic or transfusion-dependent patients receiving erythropoiesis-stimulating agents; and 164 higher-risk patients with MDS receiving azacitidine or decitabine. Patients being treated with lenalidomide, immunosuppressive approaches, or drug combinations were not included. Primary end points of the model were life expectancy (LE) and quality-adjusted life expectancy, an end point adjusted for quality of life, the values of which were derived from studies in which patients may not reflect those included in the current analysis. The authors tried to keep the assumptions used in an already complicated model to a minimum, and in so doing ignored some real-life scenarios, such as a patient initially in the nontransplantation arm deciding at a later time to undergo transplantation. That being said, the results suggest that for lower-risk patients with MDS, median LE for those avoiding HSCT was approximately double that of those undergoing HSCT, at 77 versus 38 months. For higher-risk patients, a more modest advantage was seen for early HSCT, with a median LE of 36 months, versus 28 months for nontransplantation approaches. Interestingly, in the Kaplan-Meier survival curve, that advantage starts to become apparent only after 40 months of follow-up, when the therapy-related adverse effects of HSCT have been realized.

In a separate article accompanying this editorial, Voso et al11 report on a validation of the revised IPSS (IPSS-R) in a cohort of 380 patients with MDS who were registered in the Gruppo Romano Mielodisplasie and diagnosed over a 10-year period. The IPSS-R was developed to improve on what have been regarded as shortcomings of the classic IPSS, including both an underrepresentation and relative discounting of the importance of cytogenetic abnormalities, sensitivity to degrees of cytopenias, and weight given to blast percentage.12,13 The authors found that the IPSS-R was able to predict leukemia-free and overall survival in their population and that it was able to make these predictions better than the classic IPSS and WHO prognostic scoring system. This is not in itself novel—the initial publication of the IPSS-R included validation in a separate cohort from the Medical University of Vienna and demonstrated improved discriminatory capacity compared with the classic IPSS. However, this article does advance the field in showing the ability of the IPSS-R to retain its predictive abilities in a small cohort of patients treated with disease-modifying agents—a group not included in the development or validation of the IPSS-R previously. It remains to be seen whether the IPSS-R remains robust in larger cohorts of treated patients, or whether additional revisions to the IPSS-R may be required for treated patients as a group or for specific therapies. This task (determining whether further revisions are needed) is already being initiated by the International Working Group.

How can we apply these two publications to the next patient with an MDS who walks into clinic? In practice, the IPSS and IPSS-R are used both to predict survival and to help determine therapeutic approach. A patient falling into lower-risk categories is much more likely to be treated with erythropoiesis-stimulating agents, lenalidomide, immunosuppressants, or supportive care, whereas a higher-risk patient should be considered for hypomethylating agents or HSCT. The article by Voso et al11 helps refine our definition of lower and higher risk and starts to substantiate it in treated patients, whereas the article by Koreth et al9 adds further support to pursuing HSCT in higher-risk patients at presentation—as defined by the IPSS, not the IPSS-R. What remains are questions regarding the best approach for patients in the IPSS-R intermediate-risk category, who are neither lower nor higher risk, and the need to validate these approaches prospectively, given that our best data for most MDS management principles remain circumstantial. Unfortunately, there’s the rub.

Source: JCO


Use of the Word “Cure” in Oncology.

Purpose: Use of the word “cure” in cancer care reflects a balance of physician and patient optimism, realism, medico-legal concerns, and even superstition. This study surveyed a group of oncology specialists regarding the frequency and determinants of using the word cure.

Methods: Oncology clinicians at the Dana-Farber Cancer Institute (n = 180) were invited to complete a survey regarding the word cure in cancer care. Participants completed a 19-question survey regarding how commonly their patients are cured, how often they use the word cure in their practice, and details about its use. Three case scenarios were presented to elicit participants’ views.

Results: Of the 117 participants (65%) who provided responses, 81% were hesitant to tell a patient that they are cured, and 63% would never tell a patient that they are cured. Only 7% felt that greater than 75% of their patients are, or will be, cured. The participating clinicians reported that only 34% of patients ask if they are cured. For 20-year survivors of testicular cancer, large-cell lymphoma, and estrogen receptor–positive breast cancer, 84%, 76%, and 48% of clinicians, respectively, believed that the patients were cured, and 35%, 43%, and 56% recommended annual oncology follow-up of the patients. Twenty-three percent of oncology clinicians believed that patients should never be discharged from the cancer center.

Conclusion: Oncology clinicians report that patients are hesitant to ask whether they are cured, and the clinicians are hesitant to tell patients they are cured. Annual oncology follow-up was frequently endorsed, even after 20 years in remission.

Source: JOP

Scientists find mutation driving pediatric brain tumors.

A type of low-grade but sometimes lethal brain tumor in children has been found, in many cases, to contain an unusual mutation that may help to classify, diagnose and guide the treatment of the tumors, report scientists at Dana-Farber Cancer Institute.

The researchers led a study of pediatric low-grade gliomas, samples of which were collected through an international consortium organized by brain tumor specialists at Dana-Farber/Children’s Hospital Cancer Center. Their findings are being published online by the Proceedings of the National Academy of Sciences (PNAS) the week of April 29.

Low-grade gliomas are the most common type of pediatric brain tumors, diagnosed in about 1,000 young patients annually in the United States. There are about 30 distinct types of these tumors, which arise from specialized cells called glia in the brain. Low-grade gliomas are generally slow-growing, said Keith Ligon, MD, PhD, a senior author of the study, but they behave unpredictably and can be life-threatening.

The investigators focused on diffuse low-grade gliomas, so-called because they lack a tumor mass but spread throughout the brain. As a result, diffuse gliomas often recur after surgery and are more likely to evolve into lethal glioblastomas than are non-diffuse low-grade tumors. “Many of these patients do well, but it’s hard to generalize, as the tumors are difficult to diagnose and study because without better tools pathologists can’t name them consistently,” explained Ligon, who in addition to being a researcher is also a neuropathologist. The research was undertaken in hopes of identifying a common genetic alteration that could be used to better define and design treatments for them.

The researchers analyzed DNA from 45 tissue samples collected from seven institutions in collaboration with Rameen Beroukhim, MD, PhD, a Dana-Farber genome biologist and co- senior author of the study. They looked for mutations caused by extra or missing copies of DNA code in the tumor genomes.

One alteration stood out: a gene called MYBL1, a transcription factor important for controlling other genes, was rearranged and missing a part of its genetic message in nearly 30 percent of the diffuse tumors categorized as grade 2 in terms of aggressiveness. The scientists went on to show that the mutated version of MYBL1 can cause tumors in mice. Previously MYBL1 was not known to cause cancer, but a closely related gene, MYB, is one of the oldest “proto-oncogenes” — a normal gene that can become a cancer-causing gene.

“The creation of these truncated genes, reminiscent in structure of the viral oncogene, is a potential driver for this type of tumor,” said Lori Ramkissoon, PhD, co-first author along with Peleg Horowitz, MD, PhD, a neurosurgery resident, both of Dana-Farber. “It gives us something to follow up on and investigate the function of this gene. It may lead to a specific test for diagnosing these tumors, and we will also try to determine whether patients who have this mutation do better or worse than those lacking the mutation.”

The paper’s other authors include investigators and clinicians from Dana-Farber; the Broad Institute; Brigham and Women’s Hospital; Boston Children’s Hospital; Stanford University School of Medicine; Children’s Cancer Hospital, Cairo, Egypt; University of Texas South Western Medical Center, Dallas; Hospital for Sick Children, Toronto; Children’s National Medical Center, Washington; Johns Hopkins University School of Medicine; and the University of Calgary.

Source: Dana-Farber/Children’s Hospital Cancer Center


Targeting cancers’ ‘addiction’ to cell-cycle proteins shuts down tumors in mice.

In what they say is a promising and highly selective treatment strategy, scientists at Dana-Farber Cancer Institute have safely shut down breast cancer and a form of leukemia in mice by targeting abnormal proteins to which the cancers are “addicted,” according to a new study.

Even though the investigators genetically silenced the proteins or blocked them with a drug in normal as well as cancerous tissues, the animals remained healthy, they report in the Oct. 16 issue of the journal Cancer Cell.

The experiments targeted two related proteins, cyclin D1 and cyclin D3, that control cells’ growth cycle. Many types of cancer have abnormal amounts of the proteins, spurring the cells to grow too rapidly and form tumors. Peter Sicinski, MD, PhD, the paper’s senior author, said that the new results show that the cancers’ addiction to these proteins is an Achilles’ heel that can be safely targeted with an inhibitor drug that halts cancer growth or causes cancer cells to die.

Based on the results, the Dana-Farber scientists are planning a clinical trial, using an experimental cyclin-inhibiting drug called PD0332991 that has already been tested in a form of lymphoma.

“It was impressive to find that you could target a single cyclin protein and completely clear the leukemia and the mouse remained healthy,” said Yoon Jong Choi, PhD, the study’s lead author. “We’re excited because we think this approach is very promising” as a potential treatment for some cancer types, she added.

Some of the experimental mice had been engineered to develop a type of breast cancer driven by the ErbB2 oncogene. Others were modified to develop a type of T-cell acute lymphoblastic leukemia (T-ALL) that is driven by an abnormal pathway known as Notch1. In one experiment, human T-ALL cells were infused into mice that then developed the disease.

Blocking cyclin D1 in the mice drove the breast cancer cells into a kind of permanent retirement called senescence, an irreversible halt to their growth cycle. Inhibiting cyclin D3 in the T-ALL leukemia mice caused the cancer cells to self-destruct — a programmed death process called apoptosis.

In addition to these tests with mouse cancers, the scientists found that the cyclin-D-inhibiting drug had similar effects on human blood cancer cells in the laboratory.

Cyclin proteins act as “checkpoint” guards to control cell’s cycle of rest, growth and division. The D-cyclins determine when a cell begins making DNA in preparation for dividing to form new cells. In many types of cancer, an excess of cyclins allows cells to grow too fast and form tumors. Abnormal cyclins D1, D2 and D3 are found in breast, lung, endometrial, pancreatic, and testicular cancers and in multiple myeloma and other blood cancers.

In a key report in Nature in 2001, Sicinski showed that mice engineered to lack cyclin D1 were resistant to developing breast cancer. It wasn’t known for many years, however, whether knocking out cyclin D1 could halt an established cancer, or if breast cancer needed the protein long-term.

Also unknown was whether normal cells could get along without cyclin D1: If not, treating cancer by targeting the protein might be too dangerous.

To test these questions, Choi and her Dana-Farber colleagues developed a strain of mice with cyclin D proteins that could be inactivated at any time by treating the mice with the drug tamoxifen.

“By generating these ‘conditional’ knockout mice, we could address these questions for the first time,” said Choi. The effect was global, affecting all the body cells, not just those that were cancerous. When the cyclin D proteins were turned off using this technique, the addicted cancer cells shut down while normal cells were unaffected.

The authors say the results show that blocking cyclin D “represents a highly selective anticancer strategy that specifically targets cancer cells without significantly affecting normal tissues.”

Other authors of the report include Xiaoyu Li, MD, PhD, a co-first author, and Harald von Boehmer, MD, PhD, of Dana-Farber, and Andrew L. Kung, MD, PhD, formerly at Dana-Farber and now at Columbia University.

Source: Dana-Farber cancer institute.



Dana-Farber compounds or creates medication tailored for individual patients.

News of unclean facilities and lax safety standards at the New England Compounding Center in Framingham has cast a public spotlight on compounding — a critical, but not widely known, sector of the pharmaceutical industry. To learn more about compounding, its role in cancer treatment, and its use at Dana-Farber, DFCI Online spoke recently with Sylvia Bartel, RPh, MHP, the Institute’s vice president of Pharmacy Services.


What is pharmaceutical compounding?

It’s the preparation of sterile products used to treat patients intravenously. Such medications could be chemotherapy agents, antiemetics (which prevent nausea and vomiting), support medications, or vaccines.

Does Dana-Farber’s pharmacy do compounding?

Yes. The dose of chemotherapy a patient receives is based on his or her height, weight, and individual health circumstances. Because those factors vary from patient to patient and visit to visit, we prepare patient-specific doses on-site.

What are the main types of medications compounded here?

In general, they’re chemotherapy agents and biotherapies (drugs that stimulate the body’s immune system defenses) that treat a patient’s cancer. We also prepare antiemetics, as well as intravenous fluid solutions that could contain potassium or magnesium to prevent the depletion of these nutrients in patients receiving chemotherapy.

Does Dana-Farber use products from the New England Compounding Center?

The only products we’ve purchased from the New England Compounding Center are two topical solutions (agents applied to tissue) used in gynecologic procedures.

What is done to ensure the safety of products compounded here?

We have numerous safeguards to ensure the proper preparation of sterile products. We train and monitor our staff in correct preparation techniques. We routinely test staff members’ sterile technique and the work environment for microbial growth. We’ve implemented a series of quality-control checks and report regularly to the Institute’s Infection Control Committee.

What specific safety precautions are in place?

We follow USP 797, a set of regulations developed by the United States Pharmacopeial Convention, a scientific organization that sets standards for the purity of medicines. The standards govern the preparation of sterile products in “clean rooms” where dust and foreign matter is kept below certain levels. Products are prepared within biological safety cabinets within the clean rooms. Before entering a clean room, the staff washes their hands and put on special clothing, much like that used in an operating room. Clean rooms undergo specific cleaning procedures on a daily, weekly, and monthly basis, and we routinely test surfaces from to ensure there is no microbial growth.

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Source: Dana-Farber cancer institute.

Researchers identify three subtypes of high-grade serous ovarian cancer.

Findings may indicate how patients will respond to treatment

New research led by Dana-Farber Cancer Institute scientists may soon enable doctors to determine which patients with high-grade serous ovarian cancer (HGSOC) – the most common cancer of the ovary – are most likely to benefit from a certain class of drugs.

Using technology able to pick out abnormalities in single units of the genetic code, the researchers sorted tumor samples from HGSOC patients into three subtypes based on the extent of a particular kind of genetic damage within the cells. Patients in the subtype with the highest levels of damage – representing one-third to one-half of all HGSOC patients – were the slowest to develop resistance to platinum chemotherapy treatment such as carboplatin. Overall, these patients lived longer without having their disease worsen than more did patients in the two other groups.

“Our findings suggest that, for the first time, we can determine which patients have the best chance of responding to specific categories of drugs for high-grade serous ovarian cancer,” says Dana-Farber’s Ursula Matulonis, MD, one of the senior authors of the study, which has been published online by the journal Clinical Cancer Research. “For this disease, one of the most difficult to treat of all gynecologic cancers, the study is an important step forward.”

J. Dirk Iglehart, MD, of Dana-Farber and Brigham and Women’s Hospital, is the paper’s other senior author, and Zhigang Wang, MD, PhD, of Dana-Farber, is the first author.

HGSOC cells have a high degree of “genomic instability,” their nuclei littered with large numbers of extra or missing chromosomes or chromosome fragments. One of the consequences of this havoc is a process known as loss of heterozygosity (LOH). LOH occurs in cells that lack the usual complement of two normal copies of each gene, having instead a normal and mutant copy of certain genes. When the normal gene in these mismatched pairs becomes inactive or mutated, the cell has no normal copy of the gene left – and is said to have lost heterozygosity.

In the study, investigators used single nucleotide polymorphism (SNP) arrays – technology that reads the elements of the genetic code one by one – to probe HGSOC tissue samples for instances of LOH. The samples tested fell neatly into three groups based on the patterns of LOH within them.

One of these groups was distinguished by a high level of LOH and a deleted segment of chromosome 13. When researchers reviewed the medical records of patients in this group, they found the patients were slow to develop resistance to chemotherapy drugs.

“Patients with the greatest burden of LOH had the longest progression-free survival – the period of time after treatment when their disease is not advancing,” says Wang. “This is the group which stands to derive the most from treatment with certain classes of drugs.”

LOH hampers cancer cells’ ability to survive, rendering the cells particularly dependent on proteins that repair damaged chromosomes. Drugs that target those repair proteins, including a class of agents known as PARP inhibitors, may be especially effective against HGSOC cells with high levels of LOH, the study authors assert.

The authors also found that LOH patterns in HGSOC were similar to those in triple-negative breast cancer, a form of breast cancer also characterized by a high level of chromosomal instability. The discovery suggests that agents effective in treating HGSOC might be effective against this type of breast cancer as well, the authors claim.




Lung Cancer Genome Surveys Find Many Potential Drug Targets.

Five new studies have identified genetic and epigenetic alterations in hundreds of lung tumors, including many changes that could be targeted by drugs that are already available or in clinical testing.

The reports, all published this month, included genomic information on more than 400 lung tumors. In addition to confirming genetic alterations previously tied to lung cancer, the studies identified other changes that may play a role in the disease. (Links to the study abstracts appear in the sidebar below.)

“These five papers are the first major salvo of genome-wide studies using all of the newest technologies to analyze a large number of lung cancers,” said Dr. John Minna, a clinician and lung cancer researcher at the University of Texas Southwestern Medical Center, who co-authored one of the studies.

Collectively, the studies covered the main forms of the disease—lung adenocarcinomas, squamous cell cancers of the lung, and small cell lung cancers.

Although preliminary, the findings could be used to develop molecular markers for identifying patients who are candidates for certain targeted drugs. At the same time, researchers in the lab can now evaluate the newly discovered changes to identify novel potential therapeutic targets.

“All of these studies say that lung cancers are genomically complex and genomically diverse,” said Dr. Matthew Meyerson of Harvard Medical School and the Dana-Farber Cancer Institute, who co-led several of the studies, including a large-scale analysis of squamous cell lung cancer by The Cancer Genome Atlas (TCGA) Research Network.

Some genes, Dr. Meyerson noted, were inactivated through different mechanisms in different tumors. He cautioned that little is known about alterations in DNA sequences that do not encode genes, which is most of the human genome.

Squamous Cell Tumors

The TCGA investigators sequenced the genomes or exomes (the protein-coding regions of DNA) of tumor samples from 178 patients with squamous cell lung cancer. In more than half of the tumors examined, the researchers found a change to a gene or a signaling pathway that is targeted by a drug that exists or is in development. The findings were reported in Nature on September 9.

“This gives us an enormous opportunity for progress in this disease,” said Dr. Meyerson.

The TCGA model integrates genomic data for squamous cell lung cancers with clinical information, when available, and with other tumor characteristics, such as gene expression, epigenetic changes to cells, and alterations in the number of gene copies.

“The framework for these five studies was built on a convergence of new technologies and the need to better understand the biology of lung cancers as it relates to new therapies for our patients,” said Dr. Paul Paik, who treats patients with lung cancer at Memorial Sloan-Kettering Cancer Center and was part of the clinical team involved in TCGA.

Small studies (for example, here and here) have provided hints that certain signaling pathways are important in squamous cell lung cancers, leading to new trials of targeted drugs. “Now, with the publication of the TCGA study, we know that squamous cell lung cancers have a myriad of potentially targetable changes,” Dr. Paik noted.

An unexpected finding was the presence of mutations in the EGFR gene in about 1 percent of squamous cell tumors. These tumors might respond to available drugs that block signals through the EGFR pathway.

The researchers also found evidence of genetic changes that may help lung cancer cells evade surveillance by the immune system.

The Five Studies

Testing Lung Tumors

Any therapeutic targets to emerge from the new reports would need to be incorporated into molecular tests that can identify candidates for certain drugs. A leader in this work is the Lung Cancer Mutation Consortium, which has been building knowledge of the mutations associated with the disease and testing for these changes.

Many patients with lung adenocarcinomas have benefited from targeted drugs. Crizotinib (Xalkori), for instance, has elicited some dramatic responses in patients whose tumors harbor a particular gene fusion. Some medical centers now routinely test tumors before selecting treatment for patients with lung adenocarcinomas.

“If you look at lung cancer as a whole, the big therapeutic targets were first identified in adenocarcinomas,” Dr. Minna explained. “Now there are new targeted therapies that could make an impact on squamous cell lung cancer.”

At Memorial Sloan-Kettering, all patients with squamous cell lung cancer have their tumors tested for drug targets using various techniques, including DNA sequencing. Among 28 of these patients evaluated recently, more than 60 percent had tumors that contained a potential target.

Dr. Paik noted that his group will use the TCGA results to expand their testing. “In a sense, the future potential of this new work is being realized now,” he said. “That’s pretty exciting.”

Small Cell Lung Cancer

Two new reports describe genetic changes in small cell lung cancers, which tend to be aggressive and about which little has been known. The research teams conducted exome or whole-genome sequencing on a total of 82 samples of such tumors.

“This study gave us a host of new targets to explore,” said Dr. Charles Rudin of the Johns Hopkins Kimmel Cancer Center, who led one study. The next steps will be to validate which targets are driving the growth of tumors and are “druggable,” he added.

The researchers found that a gene called SOX2, which plays a role in normal development, may contribute to some small cell lung cancers, as well as other cancers, and could be targeted.

Small cell lung cancers have been challenging to study because most are not treated surgically, so tumor samples are rare. What’s more, these tumors have high rates of genetic mutations due to tobacco smoke, yet only some mutations are driving the disease, noted Dr. Roman Thomas of the University of Cologne in Germany, who led the other study.

Using statistical “filters,” his group found that genes involved in modifying histone proteins, which help package DNA within a cell, were frequently mutated in the disease.

“These cancers are extraordinarily complex, so as researchers our steps forward are incremental—but, still, they are steps,” Dr. Thomas noted. “No one would have imagined that lung cancer would be the prototypical disease for targeted medicine.”

Comparing Tumors in Smokers and Nonsmokers

Non-small cell lung cancers were the focus of two additional studies, which appeared in Cell. One group sequenced the exomes or genomes of 183 tumor samples, and the other conducted whole-genome sequencing of tumor tissues from 17 smokers and nonsmokers.

“We found a substantially lower number of mutations in the genomes of tumors from nonsmokers compared to the smokers,” said Dr. Ramaswamy Govindan of the Washington University School of Medicine in St. Louis, MO, who led the study. Five study participants who had never smoked had a mutation that could be targeted by an existing drug.

All these studies show how diverse and how complicated the cancer genome is. But we now have a panoramic view of the genomic landscape, and this is important for moving forward in this disease.

—Dr. Ramaswamy Govindan

In all, the study authors found 54 genes with potentially targetable alterations in the 17 patients.

“The days of large clinical trials for lung cancer are over,” Dr. Govindan said, noting that patients need to be selected for specific treatments based on the characteristics of their tumors. “We also need to develop clinical trials that move targeted therapies to earlier stages of lung cancer, where we have a better chance of a cure.”

Future clinical trials, he predicted, would look for relatively large effects of drugs in selected patients. Dr. Minna agreed, saying, “If the effects are not there, we will move on to the next target and the next drug.”

The new results are really a teaser for what’s coming. TCGA plans to sequence a total of 500 adenocarcinomas and 500 squamous cells tumors. These results could help shed light on issues such as epigenetic changes in lung cancer, mechanisms of drug resistance, and how tumors are influenced by the surrounding tumor microenvironment.

“All these studies published back to back show how diverse and how complicated the cancer genome is,” Dr. Govindan said. “But we now have a panoramic view of the genomic landscape, and this is important for moving forward in this disease.”

Dr. Minna added, “After treating thousands of patients with lung cancer and not doing too well, I am very excited about the new results.”

Source: NCI

Researchers Use Gene Deletions to Find Cancer Treatment Targets.

Chromosomal damage that can transform healthy cells into cancer cells may also create weaknesses that can be exploited to kill the cancer cells, a new study suggests. The idea, called “collateral vulnerability,” could be used to identify new targets for drug therapy in multiple cancers, according to researchers from the Dana-Farber Cancer Institute and the University of Texas MD Anderson Cancer Center. The study was published August 16 in Nature.

Directly targeting genetic mutations that drive cancer with drugs is difficult, particularly in the case of mutations that delete tumor suppressor genes. Using data on the brain cancer glioblastoma multiforme (GBM) from The Cancer Genome Atlas (TCGA) initiative, the research team identified a number of “collateral” or “passenger” gene deletions that occurred during chromosomal damage that resulted in the loss of tumor suppressor genes.

The researchers next looked for passenger gene deletions that met two criteria: the deleted genes were involved in functions vital to cell survival, and the deleted genes were closely related to existing genes that perform similar functions. This loss of redundancy caused by passenger gene deletions can potentially be exploited to selectively kill tumor cells, the authors explained.

One gene that met these criteria is ENO1. ENO1 produces enolase 1, an enzyme that plays a central role in a process cells use to make energy. Human cells have a closely related gene (ENO2) that produces the enzyme enolase 2, which acts as a back-up for enolase 1 in brain tissue. Brain cells normally have a high level of enolase 1 activity and a small amount of enolase 2 activity. In some patients with GBM, however, the tumor cells lack enolase 1 activity because ENO1 was deleted when a tumor suppressor gene was deleted. This lack of enolase 1 activity could make these tumor cells more vulnerable to enolase inhibition.

This idea was tested using two targeting strategies. First, in GBM cell lines that lacked ENO1, the investigators showed that silencing ENO2 gene expression with a short hairpin RNA (a short RNA sequence that blocks the production of enolase 2 protein from ENO2 messenger RNA) sharply reduced cell growth, and tumors failed to form in mice injected with the treated cells.

The second approach involved a drug that targets the enolase 1 and enolase 2 proteins. Treatment of GBM cell lines lacking ENO1 with the drug caused the cancer cells to die because of the low overall enolase levels in these cells. But drug treatment had little effect on normal brain cells or GBM cells that had ENO1, since these cells have high levels of ENO1 gene expression and are, therefore, less sensitive to the drug.

The collateral vulnerability concept is similar in some respects to the idea of synthetic lethality, which uses genetic mutations in cancer-associated genes to identify other potential cellular vulnerabilities, explained the study’s co-lead author, Dr. Florian Muller of MD Anderson.

There are many more passenger gene deletions than tumor suppressor gene deletions, “and some of these passenger-deleted genes perform functions critical for cell survival,” Dr. Muller continued. “So, by expanding the concept to passenger genes, we vastly expand the possibility of finding these relationships, and, in the case of essential-redundant gene pairs like ENO1 and ENO2, we also provide a rational, knowledge-based method of drug-target discovery.”

The researchers are extending their work to other passenger gene deletions in GBM, Dr. Muller said.

This research was supported in part by the National Institutes of Health (CA95616-10 and CA009361).

Also in the Journals: Youth Tobacco Use Dropped between 2000 and 2011

Tobacco use and cigarette smoking fell among middle and high school students between 2000 and 2011, according to data from the National Youth Tobacco Survey, a school-based, self-administered questionnaire given to students in grades 6 through 12. Researchers from the Centers for Disease Control and Prevention published the findings last month in Morbidity and Mortality Weekly Report.

Percentage of U.S. Middle and High School Students Using Tobacco

Middle School Students

High School Students





Current Tobacco Use





Current Smoked Tobacco Use





Current Cigarette Use





Source: NCI






Tumor microenvironment helps skin cancer cells resist drug treatment .

Neighboring non-cancer cells may contribute to drug resistance

One of cancer’s most frightening characteristics is its ability to return after treatment. In the case of many forms of cancer, including the skin cancer known as melanoma, tailored drugs can eradicate cancer cells in the lab, but often produce only partial, temporary responses in patients. One of the burning questions in the field of cancer research has been and remains: how does cancer evade drug treatment?

New research by a team from Dana-Farber Cancer Institute, the Broad Institute and Massachusetts General Hospital suggests that some of the answers to this question do not lie in cancer cells themselves. To find the answers, scientists are looking beyond tumor cells, studying the interplay between cancer cells and their healthy counterparts. The research team has found that normal cells that reside within the tumor, part of the tumor microenvironment, may supply factors that help cancer cells grow and survive despite the presence of anti-cancer drugs. These findings appear online this week in a paper published in Nature.

“Historically, researchers would go to great lengths to pluck out tumor cells from a sample and discard the rest of the tissue,” said senior author Todd Golub, MD, the Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber Cancer Institute, pediatric oncologist at Dana-Farber/Children’s Hospital Cancer Center, and director of the Broad’s Cancer Program. Golub is also a professor at Harvard Medical School and an investigator at Howard Hughes Medical Institute. “But what we’re finding now is that those non-tumor cells that make up the microenvironment may be an important source of drug resistance.”

To investigate how the tumor microenvironment may contribute to drug resistance, the researchers designed experiments in which cancer cells were grown in the same wells (miniscule test tubes no larger than a pencil eraser) along with normal cells. These co-cultured cells were then treated with anti-cancer drugs. When grown alone, such cancer cells died in the presence of many of these targeted agents, but when grown together with normal cells, cancer cells developed resistance to more than half of the 23 agents tested.

These observations reflect what clinicians often see in patients with cancers such as melanoma. In the case of melanoma, targeted therapies have been developed against a specific, common mutation in a gene known as BRAF. While some patients’ tumors show an overwhelming response to BRAF inhibitors and seem to disappear, other patients’ tumors only respond by slightly decreasing in size. The failure to shrink tumors at the outset suggests that those tumors possess some level of innate resistance — the ability to evade drugs from the beginning of treatment.

“Even though recent advanced in targeted therapy have caused tremendous excitement in melanoma, the fact remains that drug resistance eventually develops in nearly all metastatic melanomas treated with RAF inhibitors, and in some cases is present at the outset of treatment,” said Levi A. Garraway, MD, PhD, an associate professor at Dana-Farber and Harvard Medical School and a senior associate member of the Broad Institute. “There are many different types of mechanisms that tumors may hijack to circumvent the effects of therapy…no single experimental approach can capture all of these potential mechanisms. Thus, the application of complementary approaches can offer considerable synergy in terms of discovering the full spectrum of clinically relevant resistance mechanisms.”

Scientists have uncovered resistance mechanisms that cancer cells develop over time – genetic changes in specific genes that may give cancer the ability to overcome the effects of a drug with time – but these acquired resistance mechanisms do not explain the innate resistance seen in many tumors.

“We can take cancer cells out of a melanoma patient, put them on a dish, and most times they will turn out to be extremely sensitive to the targeted agents, but that’s not what we see in patients,” said Ravid Straussman, MD, PhD, a postdoctoral fellow at the Broad Institute and first author of the Nature paper. “Why do we get just a partial response in most patients? We set out to dissect this question, and the next logical step was to think beyond cancer cells.”

After completing systematic, high-throughput screens of more than 40 cancer cell lines, the researchers chose to focus on melanoma, looking at whether factors normal cells secrete help cancer cells resist treatment. They measured more than 500 secreted factors and found that the factor most closely linked to BRAF inhibitor drug resistance was hepatocyte growth factor (HGF). HGF interacts with the MET receptor, abnormal activation of which has been tied to tumor growth in previous studies but never to drug resistance in melanoma.

In addition to studying cells in the lab, the research team sought to replicate their findings in samples from cancer patients. Keith Flaherty, MD, director of developmental therapeutics at Massachusetts General Hospital Cancer Center and an associate professor at Harvard Medical School, and his lab provided 34 patient samples for study. The team measured levels of HGF in these samples and saw a relationship between how much HGF was present and the amount of tumor shrinkage patients experienced. For example, tumors in patients with high levels of HGF shrank less than those in patients with low HGF levels.

“To try to explore in patient samples what factors in the microenvironment are not only present but functionally important in drug resistance would have been largely impossible. Coming up with candidates in the lab and then exploring relevance in humans in a targeted way is the only tractable approach,” said Flaherty. “By taking this high-throughput screening, hypothesis-generating approach, we could then follow up by looking at patient samples. In a case like melanoma, where you already have a targeted therapy available, it puts you on good footing to narrow in on specific factors that may be at play in drug resistance.”

Several HGF/MET inhibitors are in clinical development or are FDA-approved for other indications, making clinical trials combining these inhibitors with BRAF inhibitors feasible in the future. In addition, researchers could follow the same approach taken by the team to screen other drugs currently in development, identifying mechanisms of resistance and ways to counter them even before treatment begins.

“Drug resistance should no longer surprise us,” said Golub. “We’re thinking about how to do this – how to systematically dissect resistance – much earlier in the drug development process so that by the time a new drug enters the clinic, we have a good sense of what the likely mechanisms of resistance will be and have a strategy to combat them.”

Source: Dana Faber cancer Institute.