Silencing a deadly conversation in breast cancer

ScienceDaily (June 2, 2011) — While it is already known that breast cancer cells create the conditions for their own survival by communicating their needs to the healthy cells that surround them, Australian researchers have identified a new way of turning off that cellular cross talk.

See Also:Health & MedicineBreast CancerCancerWomen's HealthColon CancerLung CancerOvarian CancerReferenceMetastasisBreast reconstructionBreast cancerBRCA1

They have shown that a molecule known as 'hedgehog' sits at the centre of the switchboard in breast cancer, transmitting biochemical signals between the cancer cells and healthy cells.

When this conversation is blocked -- or hedgehog is 'silenced' -- tumours shrink and stop their spread.

While the finding applies to all breast cancers, it is particularly relevant for women with basal breast cancer, for which there is no current targeted therapy.

The good news is that drugs for silencing hedgehog are already undergoing Phase 2 clinical trials in other cancer types.

Clinical Associate Professor Sandra O'Toole and Dr Alex Swarbrick, from Sydney's Garvan Institute of Medical Research, analysed breast tumour samples from a cohort of 279 women with advanced breast cancer, revealing that the higher the level of hedgehog, the more aggressive the cancer.

Having discovered high levels of hedgehog in some breast cancer patients, they went on to over-produce the protein in mouse models of basal breast cancer. Mice developed tumours that grew and spread through the body rapidly. When hedgehog was blocked, the tumour growth and spread were significantly slowed.

These findings are published in the journal Cancer Research, now online.

"We are hopeful that our findings will drive the progress of clinical trials for anti-hedgehog drugs in breast cancer," said Dr Alex Swarbrick.

"Finding an effective drug target for basal breast cancer is a very high priority. It is often referred to as 'triple negative disease', because it doesn't produce any of the oestrogen, progesterone or HER2 receptors, targets of the drugs tamoxifen and Herceptin, which are very effective in other breast cancers."

A/Prof O'Toole, also a pathologist at Sydney's Royal Prince Alfred Hospital, undertook the study as part of her PhD. "These findings may provide some hope to the many women who succumb to breast cancer each year, especially the basal sub-type, although obviously it is early days," she said.

"More work in animal models is needed to understand exactly how best to block this pathway."

"Our study demonstrates that starving breast cancer cells of hedgehog significantly slows their growth and spread."

Email or share this story:

Pleural mesothelioma: Combination therapy shows promise for rare, deadly cancer caused by asbestos

ScienceDaily (June 2, 2011) — Pleural mesothelioma patients who undergo lung-sparing surgery in combination with photodynamic therapy (PDT) show superior overall survival than patient treated using the conventional therapy of extrapleural pneumonectomy (EPP) (or en bloc removal of the lung and surrounding tissue) with PDT, indicates new research from the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania. The research is published in the June 2011 issue of the Annals of Thoracic Surgery.

See Also:Health & MedicineMesotheliomaWounds and HealingLung DiseaseDiseases and ConditionsLung CancerToday's HealthcareReferenceMesotheliomaLung cancerMetastasisGlioma

"Unlike patients who receive traditional lung sacrificing surgery for mesothelioma, the patients in our study who underwent lung sparing surgery and photodynamic therapy, a light-based cancer treatment, have experienced unusually long overall survival rates. The median survival for those patients had not been reached at over two years when the results were analyzed. That's unusual in this field, especially when the majority of those patients are older and have advanced cancer," said Joseph Friedberg, MD, co-director of the Penn Mesothelioma and Pleural Program and the thoracic surgeon who performed the operations cited in the study. "In addition to the overall survival statistics, the difference between having and not having a lung, both with respect to the risk of surgery and the ability to enjoy a normal life after surgery, is crucial for these patients."

Mesothelioma is one of the most aggressive and deadliest forms of cancer and is usually caused by exposure to asbestos. Exposure to asbestos typically precedes development of the cancer by anywhere from 10 -- 50 years, but once it occurs, the average survival rate following diagnosis is often only 9-12 months.

Although mesothelioma can occur in other locations like the abdomen, pleural mesothelioma is the most common form of the disease and accounts for roughly 70 percent of cases. This form originates in the pleura -- the membrane surrounding the lung and lining the chest -- where it starts off as a microscopic sheet of malignant cells that coats the interior of the chest and can grow to be several inches thick. The coating and enveloping nature of the cancer makes it impossible to completely remove it with surgery alone. As a result, the conventional surgery-based approach to treatment involves radical surgery that includes removing the lung, in combination with chemotherapy and whole chest radiation. Even with this aggressive treatment, the disease will recur in almost all patients.

The current study had two goals. The first was to determine if using a new combination of PDT and surgery would allow a less extensive surgical procedure to be used in lieu of an EPP. The second was to determine if, based on previous research from Penn with PDT, the treatment would have any positive effect on survival for patients.

Unlike radiation, which passes through the body, the PDT therapy used in the current study penetrates only a short distance which allows the lung to be preserved. The PDT treatment aims to eradicate the remaining microscopic disease trigger a patient's own immune system to help fight cancer. Penn is one of only two centers in the world where PDT is used to treat pleural mesothelioma.

In the study, 28 patients (19 men, 9 women) underwent surgical resection plus PDT for pleural mesothelioma. Patients were aged from 27 to 81 years. All patients were seen in a multidisciplinary setting and educated about the spectrum of treatment options available, including surgical intervention and its currently investigational status. Of the study group, 14 patients were treated by modified extrapleural pneumonectomy (MEPP) and 14 by radical pleurectomy (RP) and intraoperative PDT. Twenty-two of the 28 patients also received chemotherapy.

Demographics in the MEPP and RP cohorts were similar in age, sex, stage, nodal status, histology, and adjuvant treatments. Stage III/IV disease was present in 12 of 14 patients (86 percent) in both groups. The median overall survival for the patients who received the MEPP treatment was 8.4 months. At a follow-up 2.1 years after the end of treatment, a median survival rate for the patients who received a radical pleurectomy had not yet been reached. The results yielded by the radical pleurectomy and adjuvant PDT were superior to other studies of surgical treatment plans with patients of similar demographics.

"Our primary motivation in attempting the lung sparing surgery was preservation of quality of life, and we were hoping the survival results would at least be similar to the more traditional pneumonectomy approach," said Friedberg. "Although our pneumonectomy results were in line with what is often reported for similar patients having surgery-based treatments, we were completely caught off guard when the analysis revealed a significantly longer survival for the patients who retained both lungs."

Although all patients in the current study received the PDT therapy in combination with a different surgical technique, the researchers further note that the use of intraoperative PDT is the evident difference between the multimodal protocol used in the current study and other standard treatment options presently in use, and it seems worth speculating on any potential direct contributions of the PDT to the overall survival rates.

"Why this is happening is unclear and has emerged as the focus of our continuing research," said Friedberg. The possibility exists that the residual PDT-treated microscopic disease induced an autologous tumor vaccine effect or potentially enhanced the effect of adjuvant treatments.

"This study has limitations, as many mesothelioma studies do, but these results are very encouraging. The findings from our study are particularly notable because many of the patients in this study would often be excluded from surgery-based therapy because of their advanced age or unfavorable oncologic characteristics such as the large bulk of their cancers or the spread to the lymph nodes," said Dr. Friedberg. "Based on these results this lung-sparing technique, combined with photodynamic therapy, has become the backbone of our surgery-based treatment protocols."

A larger study investigating the efficacy of this multimodal approach is currently underway at Penn.

The Penn Mesothelioma and Pleural Program is a unique program that consists of a multidisciplinary team of dedicated specialists with a passion and expertise for treating patients with these difficult cancers. The Penn Program offers a true multidisciplinary approach, presenting patients with essentially all treatment options offered world wide and a number of treatments offered only at Penn.

Email or share this story:

Leucine deprivation proves deadly to malignant melanoma cells

ScienceDaily (May 16, 2011) — Whitehead Institute researchers have found that depriving human melanoma cells of the essential amino acid leucine can be lethal to the cells, suggesting a possible strategy for therapeutic intervention.

See Also:Health & MedicineSkin CancerBrain TumorStem CellsLymphomaDietary SupplementLung CancerReferenceEssential nutrientBiochemistryGlutamic acidCells of the stomach

The researchers observed the effect in melanoma cells with a mutation in the RAS/MEK signaling pathway -- the most common mutation found in the deadliest form of skin cancer.

Leucine is one of nine essential amino acids humans must ingest, as we are unable to synthesize them. These nine, along with 12 non-essential amino acids, are the building blocks of proteins used in muscle production and normal cell functions. Cellular amino acid levels and other nutrients are monitored by the mTOR pathway. Typically, when levels of one or more amino acids drop too low, the mTOR pathway is turned off, which activates a process called autophagy.

During autophagy, the cell attempts to boost amino acid levels by breaking down the cell's protein-based structures back into their amino acid components. This is similar to the entire body breaking down fat and muscle when it is on a diet. For a cell, autophagy is a short-term survival mechanism.

According to their paper published in the May 17 issue of Cancer Cell, researchers in the lab of Whitehead Institute Member David Sabatini found that melanoma cells with RAS/MEK pathway mutations short-circuit this chain of events.

"The odd thing is that if you remove this one essential amino acid, leucine, the melanoma cells don't activate autophagy," says Sabatini, who is also a professor of biology at MIT and a Howard Hughes Medical Institute (HHMI) investigator. "Because leucine is essential, they eventually die. Potentially, that could be used as a way of targeting the melanoma cells if one could mimic the lack of leucine."

When melanoma cells with RAS/MEK pathway mutations are deprived of leucine, mTOR does not sense it, so mTOR does not turn off, and autophagy never begins. Instead, the cells behave as if there were no nutrient shortage until they reach a metabolic crisis and die.

Although cells in a test tube can be deprived of leucine completely, removing leucine from a mouse or a human is almost impossible, due to large leucine reservoirs in muscles. To test how leucine deprivation works in an animal model, Joon-Ho Sheen, who is first author of the Cancer Cell paper, implanted human melanoma tumors with RAS/MEK pathway mutations into mice. He then fed the mice a leucine-free diet. Within a few days, the leucine concentration in the mice's blood dropped from about 110 micromoles to 60 or 70 micromoles. As the blood leucine levels dropped, so too did the leucine levels within the mice's cells. Still, the drop in leucine wasn't sufficient to kill the melanoma cells in vivo.

Sheen then gave the mice the drug chloroquine along with a leucine-free diet. Chloroquine, which is an anti-malaria drug, inhibits autophagy. With the one-two punch of chloroquine and a leucine-free diet, the melanoma cells died, significantly reducing tumor sizes compared with mice fed either a normal diet or a leucine-free diet without chloroquine.

For Sheen, these results raised more questions, particularly with regard to potential therapeutic applications.

"Thanks to the pioneering work by others in the autophagy field, we were able to show that leucine deprivation triggers apoptosis in melanoma cells. I think our work provides a framework, but there are many areas to fill in," says Sheen, who is a postdoctoral researcher in the Sabatini lab. "In practice, how can you deprive just leucine in humans? Maybe using some sort of enzyme that degrades leucine or a small molecule inhibitor that blocks leucine's uptake by cells. And we need a better way to target autophagy; chloroquine isn't very efficient at this. And those are just the immediate, foreseeable issues."

This research was supported by the National Institutes of Health (NIH), the U.S. Department of Defense (DoD), the Jane Coffin Childs Memorial Fund for Medical Research, and the American Brain Tumor Association.

David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

Email or share this story: