Treatment Information No comments yet

New cancer drug sabotages tumour’s escape route

By on February 28th, 2012

Some untreatable cancers could soon be held in check by an experimental drug that targets not only the tumour itself, but also how it evolves to spread through the body.

The new drug, Cabozantinib, or cabo for short, simultaneously neutralises two mechanisms cancers need to survive. First, it chokes each tumour’s blood supply by blocking a molecule on the surface of its blood vessels, called vascular endothelial growth factor receptor (VEGFR). There is evidence in animals that cancers can respond to this kind of attack by invading new tissues, where they may be able to generate secondary tumours. Importantly, cabo foils this strategy by blocking a second receptor called c-MET that would otherwise help cancer cells spread to new tissue.

Tumours confined

To test whether the drug works in practice, Donald McDonald of the University of California at San Francisco and colleagues bred mice to develop tumours, or inoculated them with human cancers. After 14 weeks, the mice were given daily doses of cabo. All the treated mice survived to the age of 20 weeks, when the experiment ended. None of the mice that received a placebo survived that long.

“The absence of metastasis, confinement of the tumour to a smooth and compact cell mass and survival beyond 20 weeks has to my knowledge never been observed before in this mouse model of cancer,” says Holger Gerhardt, who studies tumour blood vessel growth at Cancer Research UK in London.

The broader implication of McDonald’s research is that existing drugs which cut the blood supply to tumours could be improved by giving patients a second drug that blocks the c-MET receptor as well.

It may be that choking off the cancer’s blood supply makes them more aggressive and more likely to spread. If so, giving a c-MET blocker as well might make treatment more successful.

Philippe Bishop at Genentech in San Francisco says that Avastin – one of the current drugs that blocks blood supply – is already being tested in combination with onartuzumab, an antibody that blocks signalling by c-MET.

“An Avastin and onartuzumab combination is being studied in trials for advanced triple-negative breast cancer, metastatic colorectal cancer and advanced non-squamous non-small cell lung cancer,” he says.

Pain relief

Whether combining existing drugs with c-MET blockers works or not, cabo seems to be steaming ahead. Some 108 men with prostate cancer that had spread to their bones recently completed a three month course of cabo treatment. In 82 of them the cancerous lumps on their bone either shrank or vanished completely. The tumours grew in just three of them. “It was a stunning effect,” says Dana Aftab of Exelixis, the company in South San Francisco that is developing Cabo.

Two-thirds of the men who received the drug also said that their pain receded. Some of them stopped taking morphine. Three-quarters of the men also saw their primary cancers shrink.

Howard Scher at the Memorial Sloan Kettering Cancer Center in New York says that two larger trials are now under way. The aim of one trial involving 246 patients will be to reduce pain; the other, with 960 patients, will attempt to prolong survival.

Cabo has also performed well against a type of kidney cancer, and a variant of thyroid cancer for which there are few treatment options.

Patrick Schoffski at the Catholic University of Leuven (KUL) in Belgium, who has been involved in some of the cabo trials, says that the results have been unexpectedly promising. Normally, new drugs do not work when tried against different tumour types. “Nine out of 10 tumour types typically get ruled out within a year,” says Schoffski. The opposite happened with cabo, which generated promising responses in 12 out of 13 cancers tested.

As a result trial protocols had to be amended for cabo because it wasn’t ethical to withhold the drug from people who had benefited. “I’m not aware of this happening before in oncology,” says Schoffski.

Despite the progress, the company is keen to play down its potential. “We’ve always been very careful not to over-promise on anything,” says Aftab. Likewise, Exelixis’s chief medical officer, Gisela Schwab, warns that cabo only slows the cancer. “They are not cured, but their disease is being controlled,” she says.

There is also the possibility that cancers will evolve yet another way to overcome cabo’s double punch. For now, its benefits are causing quite a stir in the cancer community. “The details unravelled [so far] are truly impressive,” says Gerhardt. …source …more about cancer


Blogging No comments yet

Older Age Worsens Breast Cancer Prognosis

By on February 27th, 2012

Older age at diagnosis of postmenopausal, hormone receptor-positive breast cancer may independently worsen outcomes, researchers found.

Breast cancer-specific mortality was 25% higher for women 65 to 74, and 63% higher for women 75 or older, compared with those under 65 (both P<0.001) after adjustment for other factors within a randomized trial.

Recurrence of the disease also was more likely with older age, Cornelis J.H. van de Velde, MD, PhD, of Leiden University Medical Center in Leiden, the Netherlands, and colleagues reported.

These findings were "regardless of a higher risk of other-cause mortality and independent of tumor and treatment characteristics," they noted in the Feb. 8 issue of the Journal of the American Medical Association.

While the reason for the findings wasn't clear from the trial, "undertreatment, in particular undertreatment of either chemotherapy or radiotherapy, may explain age-specific outcome in this relatively healthy population," the group suggested.

The 9,766 women enrolled in the randomized TEAM (Tamoxifen Exemestane Adjuvant Multinational) trial all got surgery and endocrine therapy.

A prior analysis of this trial, which had no upper age limit, pointed to more frequent drug discontinuation and less subsequent therapy, including radiation, among the patients 75 or older.

Only 5% of the women 75 and older got adjuvant chemotherapy, whereas 48% of them had nodal involvement.

Van de Velde's analysis by age included 1,357 women 75 or older and 3,060 women ages 65 to 74, although the largest proportion of the women enrolled were under 65.

During a median of about five years of follow-up during the trial, the incidence of death from breast cancer was higher in the older age groups:

8.3% in patients ages 75 or older
6.3% in patients ages 65 to 74
5.7% in patients younger than 65 years
But all-cause mortality also was higher in the older groups due to competing causes of death, such that the proportion of deaths due to breast cancer declined with age, from 78% before age 65 to 36% at 75 and beyond (P<0.001).

Adjusting for competing mortality risk attenuated the breast cancer-specific mortality risk only slightly, to 22% higher at 65 to 74 and 50% higher at 75 plus compared with under 65. Controlling for comorbidity likewise had little impact.

Tumor size was larger at older age, but even in a sensitivity analysis stratifying by size in centimeters, older age consistently predicted worse breast cancer-specific mortality rates within each strata.

Risk of breast cancer relapse also tended to be higher at older ages in multivariable analysis, with a hazard ratio of 1.07 at ages 65 to 74 and 1.29 at ages 75 and older, compared with those younger than 65 (P=0.06 for trend).

That finding suggested that selective misclassification, with death more often attributed to breast cancer at older ages, wasn't likely a source of bias, van de Velde's group noted.

They cautioned, though, that the results might not generalize to all breast cancer patients because the trial included only estrogen and progesterone receptor-positive breast cancer in postmenopausal women.

Other limitations were lack of data on adherence to nonrandomized treatment and the possibility of residual confounding.

"These data underline the need for age-specific breast cancer studies in order to improve breast cancer outcome in patients of all ages," the researchers concluded.

The TEAM (Tamoxifen Exemestane Adjuvant Multinational) trial was supported by an unrestricted grant from Pfizer.

Van de Velde reported having received an institutional grant from Pfizer and being a member of the European Cancer Organization board.

Primary source: Journal of the American Medical Association Source reference: Van de Water W, et al "Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor–positive breast cancer" JAMA 2012; 307: 590-597. ...source …more about breast cancer


In-Depth Information No comments yet

How Cancer Cells Change Once They Spread To Distant Organs

By on February 24th, 2012

Oncologists have known that in order for cancer cells to spread, they must transform themselves so they can detach from a tumor and spread to a distant organ. Now, scientists at Weill Cornell Medical College have revealed critical steps in what happens next – how these cells reverse the process, morphing back into classical cancer that can now grow into a new tumor.

Their findings, now published online and in an upcoming issue of Cancer Research and funded through a National Cancer Institute grant to the Cornell Center on the Microenvironment and Metastasis and the Neuberger Berman Foundation, show that a single protein, versican, is key to this process in breast cancer, the tumor they studied. When researchers stopped versican from functioning in mice, breast cancer could not “seed” themselves into the lungs and form secondary tumors.

“Our findings both help us understand how breast cancer metastasizes to the lungs and ways to possibly prevent that deadly spread,” says the study’s senior investigator, Dr. Vivek Mittal, an associate professor of cell and developmental biology in cardiothoracic surgery and director of the Neuberger Berman Lung Cancer Laboratory at Weill Cornell Medical College.

“These are exciting insights into a poorly investigated area,” Dr. Mittal says. “There are no clinically approved drugs now that can effectively target metastatic lesions, which is why more than 90 percent of human cancer-related deaths come from spread of the disease from a primary tumor.”

“The results of this study are a critical step in deconstructing the process of metastases — which is critical to curing our patients,” says co-author Dr. Linda T. Vahdat, professor of medicine, chief of the Solid Tumor Service and director of the Breast Cancer Research Program at Weill Cornell. “As a direct result of this study, we are working on ways to interrupt the process by which tumors co-opt the infrastructure in our bodies to grow and spread.”

This important study starts to unravel the mechanistic basis of cancer metastases, not only in breast cancer but possibly in other types of cancer, says Dr. Nasser Altorki, the David B. Skinner Professor of Thoracic Surgery at Weill Cornell Medical College and director of the division of thoracic surgery at NewYork-Presbyterian/Weill Cornell. “The need for a prepared and receptive soil may be required for cancer cell seeding regardless of the primary cancer’s site of origin.”

The Seed and the Soil

Cancer researchers have believed that for a cancer to spread, its “seed” must find the right “soil” in a distant organ in order to thrive. And they have hypothesized that this seed is formed through a process known as epithelial-mesenchymal transition (EMT), in which cancer cells lose their sticky grip to other cells in a primary tumor and become more mobile, able to travel through the blood to a distant organ.

But what happens next is conjecture. Scientists have speculated that the cells undergo a reverse process, called mesenchymal-epithelial transition (MET), in which the cancer seeds morph back into epithelial cells that can make contact with tissue and integrate in the new organ. Little is known about MET compared to EMT.

In this study, Dr. Mittal, along with his colleagues at Weill Cornell, studied mouse models of spontaneous breast cancer development. They first discovered that primary breast tumors send a signal that forces bone-marrow-derived hematopoietic cells to move into the lungs of the mice. “This appears to be the soil the cancer seeds need,” says Dr. Mittal. The next question was obvious: What is it about the soil that helps the seed?

The team found that a subtype of these bone marrow cells expressed versican, which allowed the cancer cells, once they traveled to the lungs, to morph back into epithelial cells. “The primary tumor sets up the lung microenvironment to promote metastasis,” he says. “MET resulted not from properties within the cancer cell itself, but due to a unique crosstalk between the microenvironment and tumor cells in the lung.”

In their next experiment, the researchers blocked versican production by injecting small interfering RNAs (siRNAs) in the bone marrow that silenced the versican gene, which prevented MET and blocked tumor outgrowth in the lung.

Human Tumors Express Versican

Next, they investigated human breast metastases to the lung, utilizing lung samples obtained from breast cancer patients contributed by researchers at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. “We found versican was highly expressed in those lung tumors, which matched what we found in our mice,” Dr. Mittal says. “This all made sense to us, because versican has been linked to cancer progression, although no one knew why.

“This is the first study demonstrating the significance of MET in the formation of macrometastases in distant organs,” Dr. Mittal says. “Given the findings, we now have a potential strategy to stop cancer spread before it starts, or to shut it down if it has already occurred.” …source …more about cancer