Experimental Drug Targets Breast Cancer Stem Cells

Main Category: Breast Cancer
Also Included In: Stem Cell Research
Article Date: 09 Dec 2011 - 1:00 PST

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In a novel therapeutic approach to treating breast cancer, Loyola University Medical Center researchers are reporting positive results from a clinical trial of a drug that targets tumor stem cells.

Existing cancer drugs are effective in killing mature cancer cells. But a handful of cancer stem cells are resistant to such drugs. They survive and go on to develop into new tumor cells.

A pilot study at Loyola found that an experimental drug known as a "notch inhibitor" appears to block this process by turning off key genes. Kathy Albain, MD, who led the study, presented findings during the 2011 CTRC-AACR San Antonio Breast Cancer Symposium.

Albain collaborated with scientists from Loyola, University of Mississippi Cancer Center, Baylor Breast Center and Merck Oncology.

"Our results suggest a potential role that notch inhibitors could play in optimizing existing therapies and in overcoming resistance to cancer drugs," Albain said.

The so-called notch protein promotes tumor growth and survival. The protein is present on the surface of cancer stem cells. The protein latches on to other cells, and the resulting "molecular handshake" activates various genes in the stem cells. Activating these genes, in effect, makes the stem cells resistant to common cancer drugs.

The study included 20 patients who finished all therapy. The women all had early-stage, estrogen-receptor-positive breast cancer.

Prior to surgery, the patients received one of two commonly used drugs, tamoxifen or letrozole. These drugs work by blocking estrogen stimulation of breast cancer cells. In addition to tamoxifen or letrozole, patients also received the experimental notch-inhibitor drug, MK-0752.

Following treatment with the notch inhibitor, patients underwent biopsies to provide tumor specimens. Researchers found that the drug turned off the key genes that in effect would have kept the tumor stem cells resistant to conventional drugs.

"The notch inhibitor appears to be doing what it is intended to do," said Clodia Osipo, PhD, a breast cancer scientist in Loyola's Cardinal Bernardin Cancer Center.

There were minimal side effects from either the notch inhibitor or the estrogen-blocking drugs. One patient experienced puffy eyes and coughing and four patients experienced facial acne. No patients experienced diarrhea or surgical complications

The purpose of the study was to determine how well the notch inhibitor is tolerated and how it affects the expression of critical genes in cancer stem cells. The next step is to determine how effective the drug would be in treating breast cancer.

Researchers proposed a randomized clinical trial, in which patients who received estrogen-blocking drugs before surgery would be compared to patients who received estrogen-blocking drugs plus a notch inhibitor.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our breast cancer section for the latest news on this subject. Clinical trial costs were funded by Swim Across America, an annual event in which swimmers raise money for the Cardinal Bernardin Cancer Center. Merck Oncology supplied the drugs and provided additional support.
Albain is a professor in the Department of Medicine, Division of Hematology/Oncology at Loyola University Chicago Stritch School of Medicine.
Co-authors of the study are Cheryl Czerlanis, Andrei Zlobin, Kyle R. Covington, Prabha Rajan, Constantine Godellas, Davide Bova, Shelly S. Lo, Patricia Robinson, Sharfi Sarker, Ellen R. Gaynor, Richard Cooper, Gerard Aranha, Kathy Czaplicki, Barbara Busby, Paola Rizzo, Tim Demuth, Patrick Stiff, Suzanne Fuqua and Lucio Miele.
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A Novel Strategy For Fighting Cancer Targets Secondary Tumors

Main Category: Cancer / Oncology
Article Date: 09 Dec 2011 - 0:00 PST

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The proliferation of metastases is often the main cause of complications and death from cancer. For the first time, researchers are looking very closely at the development of these metastases themselves, instead of focusing on the "primary" cancers from which they originated. In doing so, a team from the Swiss Center for Experimental Cancer Research (ISREC), at EPFL, was able to isolate a protein that plays a major role in metastasis development, and showed that the formation of secondary cancers could be prevented by blocking this protein. Their results were published December 7, 2011, in the advance online edition of the journal Nature and will open the door to new therapeutic options for treating late stage cancers.

A vital protein for metastases

The researchers already knew that cancer cells spread widely throughout the body once a malignant tumor is established. These cells don't always result in a secondary cancer, however. It turns out that all cancer cells aren't created equal: only some of them, known as "cancer stem cells," can initiate metastases. And in order to do this, they must settle into a spot - a niche - that is conducive for their development.

The ISREC team was able to show that several conditions are necessary for cancer to propagate. "In particular, we were able to isolate a protein, periostin, in the niches where metastases develop," explains Joerg Huelsken, holder of the EPFL Debiopharm Chair in Signal Transduction in Oncogenesis. "Without this protein, the cancer stem cell cannot initiate metastasis; instead, it disappears or remains dormant."

Minimal side effects in mice

Periostin exists naturally as part of the extracellular matrix, and has been shown to play a role in fetal development. In adults, it is only active in specific organs - the mammary glands, bones, skin and intestine. This research appears to prove that it plays an essential role in the environment that a cancer stem cell needs in order to develop a metastasis. Mice that were bred to lack this protein are resistant to metastasis formation. "We developed an antibody that adheres to this protein, making it inoperative, and we are hoping in this way to be able to block the process of metastasis formation," says Huelsken.

These experiments that blocked the periostin protein resulted in very few side effects in the mice. "This doesn't necessarily mean the same will hold true in humans," the researcher cautions. "We're not even sure that we'll be able to find an equivalent antibody that will work in humans."

This discovery is nonetheless very encouraging, especially since we now know that malignant tumors tend to spread more quickly than was previously believed. Preventing the development of metastases would thus appear to be an important therapeutic option that could limit the deleterious effects of cancers.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Animal Study Offers Insights Into Possible Drug Targets To Improve Memory As We Age

Main Category: Neurology / Neuroscience
Also Included In: Seniors / Aging;  Alzheimer's / Dementia
Article Date: 09 Dec 2011 - 2:00 PST

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Drugs that affect the levels of an important brain protein involved in learning and memory reverse cellular changes in the brain seen during aging, according to an animal study in The Journal of Neuroscience. The findings could one day aid in the development of new drugs that enhance cognitive function in older adults.

Aging-related memory loss is associated with the gradual deterioration of the structure and function of synapses (the connections between brain cells) in brain regions critical to learning and memory, such as the hippocampus. Recent studies suggested that histone acetylation, a chemical process that controls whether genes are turned on, affects this process. Specifically, it affects brain cells' ability to alter the strength and structure of their connections for information storage, a process known as synaptic plasticity, which is a cellular signature of memory.

In the current study, Cui-Wei Xie, PhD, of the University of California, Los Angeles, and colleagues found that compared with younger rats, hippocampi from older rats have less brain-derived neurotrophic factor (BDNF) - a protein that promotes synaptic plasticity - and less histone acetylation of the Bdnf gene. By treating the hippocampal tissue from older animals with a drug that increased histone acetylation, they were able to restore BDNF production and synaptic plasticity to levels found in younger animals.

"These findings shed light on why synapses become less efficient and more vulnerable to impairment during aging," said Xie, who led the study. "Such knowledge could help develop new drugs for cognitive aging and aging-related neurodegenerative diseases, such as Alzheimer's disease," she added.

The researchers also found that treating the hippocampal tissue from older animals with a different drug that activates a BDNF receptor also reversed the synaptic plasticity deficit in the older rats. Because histone acetylation is important in many functions throughout the body, these findings offer a potential pathway to treat aging-related synaptic plasticity deficits without interfering with histone acetylation.

"It appears that lifelong shifts in gene regulation steadily deprive the brain of a key growth factor and cause a collapse of the 'machinery' supporting memory, cognition, and the viability of neurons," said Gary Lynch, PhD, a synaptic plasticity expert at the University of California, Irvine. "The very good news suggested by this study is that it may be possible to reverse these effects."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our neurology / neuroscience section for the latest news on this subject. The research was supported by the National Institute on Aging and UCLA Older Americans Independence Center.
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Promising Multiple Sclerosis Treatment Targets Immune Cells To Increase Neuroprotection

Main Category: Multiple Sclerosis
Article Date: 08 Dec 2011 - 0:00 PST

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Laquinimod is an orally available synthetic compound that has been successfully evaluated in phase II/III clinical studies for the treatment of relapsing-remitting multiple sclerosis (RRMS). The mechanism of action of laquinimod has not been fully elucidated, but a study published in the January 2012 issue of The American Journal of Pathology suggests that laquinimod triggers immune cells within the central nervous system to produce and release brain-derived neurotrophic factor (BDNF), contributing to the repair or survival of neurons and thus limiting brain damage.

"Our data are indicative of a direct and sustained effect of laquinimod on the up-regulation of bioactive BDNF in patients with RRMS. Additionally, we demonstrate that laquinimod targets monocytes and skews the phagocyte population towards a regulatory phenotype, which in turn mediates immune modulation in vivo," explained Jan Thöne, MD, of the Department of Neurology at St. Josef-Hospital Bochum and Ruhr-University Bochum, Germany.

Neurotrophins, such as BDNF, are essential for the development and maintenance of neurons and axons in the central nervous system. Although BDNF is mainly produced by neurons, several types of immune cells also secrete BDNF, suggesting a role in neuroprotection.

To elucidate the mechanism of action of laquinimod, and to explore its potential neuroprotective capacity, the researchers evaluated levels of BDNF in the serum of RRMS patients treated with laquinimod in phase II clinical trials. A significant and robust BDNF increase occurred in 76% of the laquinimod-treated patients, with up to an 11-fold increase in BDNF serum levels observed in individual patients. BDNF elevation in individual patients was independent of relapse rate, and there was no correlation between BDNF levels and age, gender, or baseline disability. Yet, the source of serum BDNF subsequent to treatment remained questionable.

Experiments with animal models corroborated the findings in human patients. Experimental autoimmune encephalomyelitis (EAE; a model of MS) was induced in mice with a conditional BDNF deficiency in immune cells (LLF mice) and in wild-type (WT) control mice. Treatment with laquinimod resulted in a significant reduction in EAE incidence and disease severity in the WT mice. The effect of laquinimod was significantly reduced in the LLF-mice.

Further studies showed that WT mice treated with a suboptimal dose of laquinimod demonstrated a significant reduction in the inflammatory area and level of demyelination. These mice also displayed a reduction of macrophage infiltration and a significant preservation of axonal densities in comparison with laquinimod-treated LLF mice and controls. The data suggest a BDNF-dependent mechanism of action for laquinimod in autoimmune demyelination.

To investigate whether laquinimod-treated monocytes mediate immune modulation in vivo, laquinimod-stimulated monocytes were injected into WT mice at an early EAE disease stage. The mice showed less severe disease course than controls. Transfer of laquinimod-treated cells derived from LLF mice into WT mice with ongoing EAE did not influence disease course. The cells also secrete significantly less IL-10, an immunomodulatory cytokine that is associated with the generation of regulatory monocytes.

"Consistent with immunomodulatory properties, laquinimod skewed monocytes towards a regulatory phenotype and also acted via modulation of BDNF, which may contribute to neuroprotection in MS patients," said Dr. Thöne. "To date, selective targeting of monocytes has not been described for any other MS pipeline drug, highlighting an innovative mechanism of action of laquinimod."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our multiple sclerosis section for the latest news on this subject. The article is "Modulation of Autoimmune Demyelination by Laquinimod via Induction of Brain Derived Neurotrophic Factor," by J. Thöne, G. Ellrichmann, S. Seubert, I. Peruga, D-H. Lee, R. Conrad, L. Hayardeny, G. Comi, S. Wiese, R.A. Linker, R. Gold (doi: 10.1016/j.ajpath.2011.09.037). It will appear in The American Journal of Pathology, Volume 10, Issue 1 (January 2012) published by Elsevier.
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