Wednesday, May 28, 2008

Cancer Vaccine Target Pinpointed

Scientists may be one step closer to producing a specific targeted vaccine for killing cancer cells.

UK researchers have identified a unique protein, known as DNGR-1, on immune cells which they hope will help them harness the body's defences to attack a tumour. A vaccine designed to "home in" on the protein would then deliver a message to the immune system to attack the invading cancer. The research is published in the Journal of Clinical Investigation.

The protein is unique to a type of immune cell called a dendritic cell, which is responsible for triggering the body's defence system. Its job is to present pathogens or foreign molecules to other cells of the immune system, which in turn eliminate them.

The results of this research are an important step towards understanding how to create targeted cancer vaccines in the future. The team at Cancer Research UK's London Research Institute said scientists have been searching for proteins or "tags" on dendritic cells for over 30 years.

Dendritic cells are now recognized as the gatekeepers of the immune response, possessing a unique potential for acquisition of antigens at extremely low exposure levels and for efficient presentation of these in an immunogenic form to the naive T-cell system.

In theory a vaccine carrying a foreign molecule from a cancer cell could be targeted to the dendritic cells, which would then prompt the immune system to attack the "invading" cancer. The same approach could potentially be used for treating other diseases such as HIV or malaria.

Vaccines work by triggering an army of immune cells, called T cells, to attack potentially dangerous foreign molecules, like those found on pathogens. Dendritic cells are the messengers, telling the T cells who to attack. The vaccine will carry a sample of the offending molecule and deliver it to DNGR-1 on the dendritic cells, which in turn will present the molecule to the armies of T cells and instruct them to attack.

Although many vaccines have been tested in the clinical, few have proven successful so far. Part of the problem is locating the right target to effectively start the attack reaction over prolonged periods of time. The results based on a more targeted approach will be interesting.

Tuesday, May 20, 2008

Low levels of Vitamin D linked with poorer outcome in breast cancer

One of the most important abstracts at the forthcoming ASCO meeting suggests that vitamin D deficiency at the time of diagnosis is associated with a worse outcome in breast cancer. The results were reported in an analysis of 512 women treated in Toronto, Ontario.

Many of the women had low levels of vitamin D at the time they were diagnosed with breast cancer; some 37.5% had levels classified as "deficient," and only 24% had levels that were "sufficient". Is this a random or relevant finding?

After a median follow-up of 11.6 years, it was found that compared with women who had normal levels of vitamin D at diagnosis, the women with vitamin D deficiency were 94% more likely to experience metastasis and 73% more likely to die.

It is surprising to find vitamin D deficiency is so common in women diagnosed with breast cancer and that very low vitamin D levels adversely affect patient outcome. Although the data show an association, it is impossible say it is causal until the results are replicated.


ASCO 2008 Annual Meeting

Thursday, May 15, 2008

Chemical prevents cancer in the lab

While researching new ways to stop the progression of cancer, researchers at the University of Oklahoma Health Sciences Center have discovered a compound that has shown to prevent cancer in the laboratory.

The compound, which still faces several rounds of clinical trials, successfully prevented normal cells from turning into cancer cells and inhibited the ability of tumours to grow and form blood vessels. If successful tests continue, researchers eventually hope to create a daily pill that would be taken as a cancer preventive.

“This compound was effective against the 12 types of cancers that it was tested on,” said Doris Benbrook, Ph.D., principle investigator and researcher at the OU Cancer Institute. “Even more promising for health care is that it prevents the transformation of normal cells into cancer cells and is therefore now being developed by the National Cancer Institute as a cancer prevention drug.”

The concept behind the translational research is that certain patterns of molecular alterations can transform normal cells into cancer cells. Interfering with a subset of these alterations can prevent cancer or induce a natural form of cell death called apoptosis. Interfering with the development of blood vessels within tumours (angiogenesis) can prevent and treat cancer.

The synthetic compound, SHetA2, a Flex-Het drug, directly targets abnormalities in cancer cell components without damaging normal cells. The disruption causes cancer cells to die and keeps tumours from forming.

Flex-Hets or flexible heteroarotinoids are synthetic compounds that can change certain parts of a cell and affect its growth. Among the diseases and conditions being studied for treatment with Flex-Hets are polycystic kidney disease, kidney cancer and ovarian cancer.

Dr Benbrook and her research team have patented the Flex-Het discovery and hope to start clinical trials for the compound within 5 years. If the compound is found to be safe, it would be developed into a pill to be taken daily like a multi-vitamin to prevent cancer.

The compound could also potentially be used as maintenance therapy to prevent cancer from returning after traditional radiation and chemotherapy treatments, especially in cancers that are caught in later stages such as ovarian cancer where life expectancy can be as short as 6 months after treatment.


University of Oklahoma
Benbrook Laboratory

Wednesday, May 14, 2008

EGFR testing in lung cancer - which patients should receive kinase therapy?

Mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). As a result, the blocking of EGFR to treat non-small cell lung cancer is becoming increasingly common, but there is considerable debate about when to initiate therapy and how best to select patients.

Recently, results from the iTarget trial were reported for gefitinib/Tarceva (OSI, Genentech/Roche) in the first-line treatment of 34 patients with mutations. The investigators, from the Massachusetts General Hospital Cancer Center in Boston, reported an overall response rate of 55%. This is similar to reports from other investigators, although no patient with atypical mutations achieved a response. As previously reported, mutations were seen more frequently in females, lifetime nonsmokers, and patients with adenocarcinoma. A median progression-free survival of 9.2 months and an overall survival of 17.5 months was also observed. Patients were treated with gefitinib 250mg per day until progression or unacceptable toxicity.

An editorial by Frances Shepherd, published in the Journal of Clinical Oncology, suggested that it is highly likely that a panel of tests will be used in the to determine which patients are likely or not likely to benefit most from therapy. Dr. Shepherd argued that the unselected non-small cell lung cancer population is definitely not the appropriate comparator.

There have now been several publications in which the survival rates of patients with EGFR mutations treated with chemotherapy have been reported and their survival has been significantly longer than that of patients with wild-type EGFR and the median survival has not been reached at 2 years. According to Shepherd, this tells us that the studies of first-line EGFR tyrosine kinase inhibitor therapy in mutation-positive patients likely have all been published prematurely, with median follow-up times less than half the expected survival time of patients treated with chemotherapy.

"With this in mind, does the 17.5-month median survival in the Sequist et al., study really compare favourably to historical controls?"

The problem is, we still don't know which patient sub-types would ideally benefit most and would, therefore, see an improved response rate. Further trials are likely needed before this crucial question can be adequately answered.

Saturday, May 10, 2008

p53 gene and it's role in cancer

Ironically, death is critical to life.

Apoptosis is the programmed death of cells that are irretrievably damaged or at the end of their useful life. The process is essential for organisms to develop and survive by regenerating new cells. In cancer, this process goes awry because mutations allow cells to divide and proliferate uncontrollably rather than dying, so a tumour mass is formed.

Mutations can occur by addition, deletion or inactivation. Inactivation of p53, for example, can lead to the development of different types of cancer. Although scientists have long known that p53 inactivation plays a central role in the development of cancer, little was known about whether p53 inactivation played a role in maintaining cancers. It was also unclear whether switching p53 back on in tumour cells would have any therapeutic effect.

In 2007, researchers at the Howard Hughes Medical Institute demonstrated that inactivating the p53 gene is necessary for maintaining tumour survival. Conversely, reactivating the p53 gene in mice caused blood, bone and liver tumours to self destruct. The p53 protein is called the “guardian of the genome” because it triggers the suicide of cells with damaged DNA. Cancers can, however, mutate to circumvent p53 reactivation.

It is now known that in most cancer cases, the P53 gene is damaged or switched off, but Scottish researchers found they could reboot it. Biological compounds called tenovins were used to turn off certain enzymes which act as switches and control p53. The compounds were initially selected for study because they induced the required effect on whole cells as opposed to the use of purified proteins. The findings indicate that improved tenovin derivatives may have the potential to stop tumours and that their ability to switch on P53 contributes to this. Tenovins work by inhibiting sirtuins. This may facilitate further optimisation of the compounds in development for inactivating the cancer.

Note: GSK recently purchased Sirtris, a biotechnology company focused on sirtuin research

Saturday, May 3, 2008

Ovarian cancer - early detection via the fallopian tube?

New research recently reported at the American Association of Cancer Research suggests that fallopian tube cells rather than ovarian surface cells are the probable site of origin of most cases of ovarian serous carcinoma, the most common type of ovarian cancer. This finding may lead to earlier detection, as well as better treatment and perhaps even prevention of ovarian cancer.

There is no reliable early diagnostic test for ovarian cancer, so approximately 80 percent of cases are diagnosed at a very late stage. Thus when oncologists diagnose ovarian cancer, they often find massive invasive tumours on the surface of the ovary (usually the tumor does not invade the ovary). It is rare to find early pre-invasive in situ tumours, as with breast cancer.

Levanon and colleagues studied a group of women at very high risk for ovarian cancer due to family history who underwent removal of their fallopian tubes and ovaries as a preventive measure. When these women were closely evaluated, it was found that they had early cancerous growths, and these early growths were in the fallopian tube, not on the surface of the ovary. The growths were confined to a particular area within the fallopian tube called the fimbria, which is located close to the ovary.

The team's findings may change how pathologists examine fallopian tubes after surgical removal, with a new emphasis on the fimbria to measure the incidence of precursors and early cancers among women who carry BRCA mutations. Future studies may explore connections between specific genetic or environmental modifiers and the incidence of precursor lesions in the fimbria.

On PET scans and detecting cancer...

A national study appearing in today's Journal of Clinical Oncology (JCO) demonstrated the value of positron emission tomography (PET) scans for treating patients with ovarian, prostate, pancreatic and other types of cancers.

PET scans are commonly used for the diagnosis, staging and restaging of cancers as well as the monitoring of tumour response to treatment for Medicare patients with nine types of cancers covered by the Centers for Medicare and Medicaid Services (CMS): breast, cervical, colorectal, esophageal, head and neck, non-small-cell lung, thyroid, lymphoma and melanoma.

In making the positive PET reimbursement decision for these nine tumour types, CMS used the standard "that all evidence currently available must be adequate to conclude that the item or service is reasonable and necessary." Clinical oncology, however, deals with many more than nine tumour types, and some major human diseases, such as pancreatic, ovarian, and prostate cancers were not included; patients with these tumours and a variety of others were, therefore, potentially being denied the benefits of PET imaging.

By providing images of cancerous changes at the molecular level, PET scans for cancer have given physicians the ability to detect developments that can be undetectable with routine medical imaging and have become a powerful tool in fighting cancer.

The accompanying editorial by Dr Larson put it admirably. He noted that, "One can only hope that this approach by CMS will be expanded to other aspects of diagnostic imaging practice in oncology."