University of Texas Southwestern Medical Center

The cancer stem cell discovery which sheds light on regrowth.

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When different kinds of cancer are tackled, tumors may shrink in reaction to treatments including chemotherapy, but there is often the possibility of them springing back.

Some scientists believe that regrowth occurs because chemotherapy fails to eradicate a small number of cells, known in the field tentatively as ‘cancer stem cells’. It may be the case that these kinds of cells perform the same function in all cancers that create solid tumor masses.

The suspicion of stem cell cancer cells has long been an aspect of research in the field, but the hypothesis has remained controversial — mainly due to the artificial environments that most studies have taken place in, where human cells are transplanted into mice.

Now, studies on three different kinds of cancerous tumor has suggested a key reason why certain types of cells play a part in regrowth – stem cells that fuel the cancer and are not killed by standard therapies.

Published in the journals Nature and Science, the new studies conducted by three independent teams of researchers believe that this discovery may be a breakthrough in the field of cancer research.

Conducting tests on mice, so-called tumor stem cells were identified in the brain, skin and gut. In one case, researchers were able to prove that treating glioblastoma — a fatal brain tumor — with chemotherapy left behind these kinds of cells, and eventually this sparked regrowth.

Luis F. Parada, a molecular geneticist hailing from the University of Texas Southwestern Medical Center in Dallas, and author of one of the studies, said:

“Everything has a soft underbelly once you understand it well. With all the modern molecular techniques and modern approaches we have, we should be able to find their soft underbelly.”

Each study used color markers to detect when tumor cells divided in the mouse hosts. By doing so, the researchers were able to detect which cells did not replicate — and whether old cells can fuel regrowth, or it has to be stem cell subsets.

Robert Weinberg, a biology professor at MIT who was not involved in the new studies said:

“What these three papers have done, through elegant strategies, is demonstrate, indeed there are cancer stem cells. It makes it more and more difficult for people to doubt the existence of cancer stem cells.”

Source: Smart planet

 

 

Potential New Class of Drugs Blocks Nerve Cell Death.

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Diseases that progressively destroy nerve cells in the brain or spinal cord, such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), are devastating conditions with no cures.

Now, a team that includes a University of Iowa researcher has identified a new class of small molecules, called the P7C3 series, which block cell death in animal models of these forms of neurodegenerative disease. The P7C3 series could be a starting point for developing drugs that might help treat patients with these diseases. These findings are reported in two new studies published the week of Oct. 1 in PNAS Early Edition.

“We believe that our strategy for identifying and testing these molecules in animal models of disease gives us a rational way to develop a new class of neuroprotective drugs, for which there is a great, unmet need,” says Andrew Pieper, M.D., Ph.D., associate professor of psychiatry at the UI Carver College of Medicine, and senior author of the two studies.

About six years ago, Pieper, then at the University of Texas Southwestern Medical Center, and his colleagues screened thousands of compounds in living mice in search of small, drug-like molecules that could boost production of neurons in a region of the brain called the hippocampus. They found one compound that appeared to be particularly successful and called it P7C3.

“We were interested in the hippocampus because new neurons are born there every day. But, this neurogenesis is dampened by certain diseases and also by normal aging,” Pieper explains. “We were looking for small drug-like molecules that might enhance production of new neurons and help maintain proper functioning in the hippocampus.”

However, when the researchers looked more closely at P7C3, they found that it worked by protecting the newborn neurons from cell death. That finding prompted them to ask whether P7C3 might also protect existing, mature neurons in other regions of the nervous system from dying as well, as occurs in neurodegenerative disease.

Using mouse and worm models of PD and a mouse model of ALS, the research team has now shown that P7C3 and a related, more active compound, P7C3A20, do in fact potently protect the neurons that normally are destroyed by these diseases. Their studies also showed that protection of the neurons correlates with improvement of some disease symptoms, including maintaining normal movement in PD worms, and coordination and strength in ALS mice.

Of mice and worms

In the ALS mouse model, a highly active variant of the original P7C3 molecule, known as P7C3A20, which the investigators synthesized, largely prevented death of the nerve cells within the spinal cord that are normally destroyed by this disease. The P7C3 molecule also worked, but was not as effective at protecting neurons in this model.

As cell survival increased in the ALS model, coordination and strength of the mice improved as well. Mice that were given P7C3A20 were able to stay on a rotating rod much longer than untreated animals or animals that received the less active compounds. Animals receiving P7C3A20 also performed better in analysis of their walking gait, which typically worsens in these animals as the disease progresses.

In PD, dopamine-producing neurons necessary for normal movement are gradually destroyed. In patients, loss of these brain cells leads to tremors, stiffness, and difficulty walking. The study again showed that P7C3 protects these neurons from cell death and the more active analogue, P7C3A20, provided even greater protection.

The two compounds also potently blocked cell death of dopaminergic neurons in a C. elegans worm model of PD. Moreover, reduced cell death in this model was associated with improved movement in the worms.

Healthy C. elegans worms have a very characteristic swimming motion. This movement is disrupted in the PD worm. Hector De Jesus-Cortes, a graduate student of neuroscience at UT Southwestern Medical Center and lead author of the Parkinson’s study, videotaped and analyzed the PD worms’ mobility with and without treatment. Normal swimming was almost completely preserved with P7C3A20, and was also fairly well preserved with P7C3.

Tweaking the molecule

The research team compared the activity of several new P7C3-related compounds that they synthesized, in both the hippocampal neurogenesis screen and the mouse model of PD.

“Every variation of our P7C3 molecule that works in the neurogenesis assay also works in the PD model,” Pieper says. “As we continue to refine the molecule, our hope is that the results from the neurogenesis assay will accurately predict the neuroprotective potency of the compound, and thus aid in more rapidly optimizing a new neuroprotective agent.”

The team plans to continue tweaking the structure of the P7C3 molecule to improve its neuroprotective ability while eliminating potential side effects.

“Our hope is that this work will form the basis for designing a neuroprotective drug that could eventually help patients,” Pieper says.

http://www.sciencedaily.com

 

 

 

Lung Cancer Genome Surveys Find Many Potential Drug Targets.

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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

New Drug Improves Survival in Patients with Advanced Lung Cancer.

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Patients with advanced lung cancer who received the drug bavituximab lived twice as long as trial participants who did not receive the drug. These results , from a phase II trial, were presented at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology. Peregrine Pharmaceuticals, Inc., the drug’s manufacturer, sponsored the trial.

Bavituximab is a monoclonal antibody that targets a molecule called phosphatidylserine (PS) that is found in the membranes of cells throughout the body, including those that line blood vessels. In normal cells, PS is restricted to the inside of cell membranes, where it is inaccessible to antibodies. Under certain conditions, like those found in the stressful tumor microenvironment, PS moves to the outer surface of the cell membrane, explained the study’s principal investigator, Dr. David Gerber of the University of Texas Southwestern Medical Center. In the case of tumor blood vessels, this means that PS is exposed and accessible to antibodies in the blood.

Laboratory studies have shown that bavituximab can trigger the destruction of tumor blood vessels. The drug may also work by harnessing the immune system. Tumors supplied by blood vessels with exposed PS can evade an immune response. That’s because exposed PS normally marks cells that are in the process of dying, so the immune system ignores them. The researchers hoped to learn whether bavituximab, by binding to PS, would signal to the immune system to attack tumor blood vessels with exposed PS, explained Dr. Gerber.

In the double-blind, placebo-controlled trial, the researchers randomly assigned 117 patients to one of three treatment groups: docetaxel (Taxotere) plus placebo, docetaxel plus a low dose of bavituximab, or docetaxel plus a higher dose of bavituximab. All patients had previously received initial chemotherapy. The trial was unblinded 18 months after the first patient was enrolled.

The results showed differences in tumor shrinkage (15 and 18 percent of patients in the low and high bavituximab groups had their tumors shrink, versus 8 percent of those receiving docetaxel plus placebo) and progression-free survival (about 4.5 months in the two bavituximab arms, versus 3 months with docetaxel plus placebo).

The greatest differences were for overall survival; patients receiving docetaxel plus placebo lived an average of 5.6 months from the start of treatment, whereas patients receiving docetaxel plus the low or high dose of bavituximab lived for an average of 11 and 13 months, respectively.

These survival differences are not likely due to differences in treatment received after the trial, Dr. Gerber noted. Seeing a larger improvement in overall survival than in progression-free survival is unusual for drugs that target cancer cells directly, he added. Because the improvement in survival with bavituximab “is persistent and most pronounced after a few months,” that suggests that the therapeutic benefit may be caused, at least in part, by an immune response, he said.

The researchers are planning a phase III trial of bavituximab in a larger group of lung cancer patients. Bavituximab is also being tested in combination with other treatments in patients with breast, rectal, liver, and prostate cancer.

Source: NCI