Cryoablation: A New Tool In The Oncologists Toolbox

Prostate cancer treatment, while generally quite successful when the cancer is caught at an early stage, isn't without its problems. In the short term, radiation therapy and surgery can damage closely associated nerve bundles and cause incontinence and impotence. In the long term, resistance to therapy can develop, limiting the treatment options available. A new treatment option pioneered by doctors at the Center for Safer Prostate Cancer Therapy in Orlando, USA is an effective solution to these problems.

Cryoablation (or cryotherapy) is a minimally invasive technique where a needle is inserted through the skin and into the prostate tumor, guided to the exact location with 3D imaging. Once the head of the needle is in place, a argon gas is circulated through the needle tip, reducing its temperature and freezing the surrounding tumor tissue. Freezing is a highly effective method of tumor killing as the formation of ice crystals within the cell spear through the membranes and simply destroy the whole cell structure, whereas radiation therapy relies on DNA damage and cell suicide, a process which tumors often grow resistant to. The treatment uses two freeze cycles with an intermediate thawing step to ensure cell kill.

The study at the center followed 120 men who had cryoablation. The patients were monitored for 12 years, after which 93% showed no signs of cancer recurrence, despite more than half of them initially being assessed as at high risk of cancer recurrence. Furthermore, in the 7% of patients whose cancer did return, it was located elsewhere in the prostate gland and further cryoablation was used successfully in treating those cases, resulting in 100% effective disease management. All patients retained full bladder control and only 15% experienced impotence.

The treatment isn't exclusive to prostate cancer, great success has also been seen in kidney cancer. Doctors at Johns Hopkins Hospital in Baltimore have tested it on 90 tumors in 84 patients and observing for 3 years (two years longer than is standard for kidney treatments). They have seen 100% efficacy on tumors of 4cm or less in size, close to 100% in tumors up to 7cm in size, and two of three 10cm tumors were successfully killed. 75% of kidney tumors are less than 4cm in size at the time of diagnosis so cryoablation is a very real option for the majority of cases. Indeed, the doctors argue that the procedure should become the gold standard, replacing the current surgery which involes several days in hospital with an outpatient procedure that preserves as much kidney as possible.

Data for both studies was presented at the Society of Interventional Radiology's 34th Annual Scientific Meeting.

Cancer Stem Cells

We begin life as a bundle of embryonic stem cells, which divide and differentiate until you have all the various cell types required to make the many tissues and organs of the human body. In adulthood some stem cells remain to maintain the body's diverse cell types during growth, injury and aging. These adult stem cells are less adaptable than the embryonic stem cells which can form any tissue type, adult stem cells exist in multiple sets each specialised for maintaining a particular tissue types. Tissues that have been identified to contain stem cells include bone marrow, blood, brain, muscle, skin and liver. Most other tissues are also likely to contain stem cells, but their number is tiny in comparison to the normal cell population and this makes their identification difficult.

In recent years it has become evident that cancers also have tiny populations of stem cells that produce the main body of the cancer. During cancer treatment, the chemotherapy drugs and radiation therapy are often highly successful in reducing the size of the tumor, and often the cancer seems to be totally cured. However, several months or years later, the cancer often returns. This could only happen if a population of cancer cells survived the therapy, that population is likely to be very small, small enough not to be seen by a surgeon or a radiographer, it could even be a single cell. These cells are thought to be the cancer stem cells, indeed it has been shown that the cancer stem cells are highly resistant to radiation death, and are often resistant to chemotherapy too.

It would seem to make sense that cancer originates from adult stem cells that have mutated to form cancer stem cells. Adult stem cells are constantly copying their DNA and dividing to produce a specialist cell and a replacement stem cell to maintain the stem cell population. They divide like this constantly throughout your whole life to maintain your body. Each time the DNA is replicated it is vulnerable to copying errors, and over a lifetime may acquire mutations in tumor suppressor genes, inactivating the genes that control cell growth.

If current chemotherapy drugs are not effective against the cancer stem cells, it is because the majority of cancer research to date has been performed using cancer cells which are more than likely the product of the stem cells, but not the stem cells themselves. This means the drugs have been developed to be effective against the body of the tumor, but may not be targeting the cancer stem cells that drive the growth. While destroying the main body of a tumor is still useful in alleviating the pain and problems of having large masses interfering with the organs, the cancer stem cells will also need to be targeted to achieve a true cure.

Much work is currently underway at research institutions around the globe to better identify these cancer stem cells, their genetics and molecular mechanisms. For example this week the pharmaceutical giant Eli Lilly began a collaboration between its Singaporean Centre for Drug Discovery and Singapore's National Neuroscience Institute and Institute for Clinical Sciences. This collaboration has the aim of utilising newly isolated brain tumor stem cells to discover new drugs that will be effective in targeting the stem cells that cause brain tumors.

Meanwhile in Cincinnati, researchers at the Cincinnati Children's Hospital Medical Centre have recently been exploring the involvement of cancer stem cells in neuroblastoma, a cancer of the nervous system. They are also experimenting with a potential virus therapy. This virus is a specially modified herpes virus that could target neuroblastoma stem cells and kill them by infection.

Efforts in recent decades have given us hundreds of chemotherapy drugs of varying effectiveness. But until now we have been measuring their success against the general tumor mass and not on the cancer stem cells. With greater understanding of the biology of cancer stem cells we will be able to target them specifically and ensure the whole tumor is treated. This should improve the survival of cancer patients and reduce the rates of relapse following therapy.

Immunotherapy - Switching Anti-Cancer Immunity Back On

The immune system is a powerful tool that protects us from being infected by the many bacteria, fungi and viruses that would otherwise find a warm wet nutrient rich wound an ideal place to colonise. But it also has a role in protecting us from our own cells. Immune surveillance is the body's way of keeping a check on cells that begin to divide uncontrollably. Such cells have mutated somehow and will be recognised as defective and destroyed by the immune system. Generally this works very well for most of our lives; unfortunately it applies the 'survival of the fittest' rule to cancer cells. The 'fittest' cancer cells being those that acquire the mutations enabling them to mutate faster than the immune system can recognise them, or those that acquire a mutation that causes some kind of immunosupression. Eventually the cancer evolves to a form that completely evades the immune system, usually by secreting a cocktail of chemical messengers that stop immune cells recognising them.

Many approaches are being tried in an effort to make the immune system recognise the cancer again and begin killing it. Cocktails of lab-grown tumor cell vaccines have had mixed success in trials, ongoing are Phase II trials by Onyvax whose therapy consists of three types of lab grown cancer cells, which are injected into patients with prostate cancer. The immune system will recognise these cells as totally foreign, and in the process should notice some cancer associated proteins which it had previously missed due to the immunosuppression by the cancer. Although this approach has shown some effectiveness in previous trials by extending patients lives by around 6 months, it only slows the cancer and never causes remission. This could be because this approach doesn't do anything to overcome the immune suppression by the cancer, there may very well be a well armed immune response ready to attack the cancer, but every time it gets close it is prevented from attacking.

Dendreon is another company with a prostate immunotherapy, this one uses lab-primed immune cells called Antigen Presenting Cells (APC) and injects them into patients, once in the patient the APCs 'teach' the patients immune system to attack the cancer. This approach is similar to the Onyvax approach, but is further in development, unusually it is in its 3rd Phase III clinical trial, ideally those should only happen once. It is clearly having an interesting effect on cancer, enough to continue investigations, but its not significant enough to bring it to market yet. Again, this therapy doesn't address the issue of immune suppression.

Cell Genesys had a vaccine very similar to Onyvax's, except it included an extra immune stimulatory factor in an attempt to overcome the immunosuppression with an even more powerful immune response. This attempt failed, their PhaseIII trial was terminated and the therapy abandoned. Things are beginning to look a bit bleak, I shall bring us onto some more promising therapies.

NovaRX have a therapy similar to that of Onyvax and Cell Genesys but for advanced lung cancer, it uses four sorts of cancer cell in its vaccine; crucially it also blocks a signal protein called TGF-β, which is an immunosuppressor secreted by the tumor cell. This approach seems to be highly effective, extending patients lives by years in a phase II study and is now in a PhaseIII study.

These types of therapies are important, because once a working therapy is produced for one cancer type, the same approach can be used for nearly all other types of cancer. In all of these trials however, the vaccines usually only work for a certain subpopulation of those tested. I wrote previously about the great variation in cancer between people and the need to personalise treatments using biomarkers. These companies will be monitoring patients and discovering biomarkers that will help optimise future treatments with their products.

One way to overcome the problem of treating unique cancers with general vaccines, is to make the vaccine unique to the patient. Antigenics have a vaccine which is tailored to each patient by taking a biopsy of the tumor, taking it to the lab and creating a personalised vaccine from it. This vaccine has been effective in prolonging survival in kidney cancer and melanoma has been approved for treating kidney cancer in Russia and has been submitted for approval in Europe.

I have presented a small selection of therapies here, a search of 'cancer vaccine' on clinicaltrials.gov provides a list of 303 clinical studies that are seeking patients, hundreds more have completed recruitment and are ongoing. So there is much more information to be gained in the not too distant future. Using this information the next generation of cancer vaccines are likely to incorporate several modes of action including blocking the immunosuppressive activity of the tumor, priming the immune system to attack, and boosting that attack with immunostimulators. Perhaps by doing this, we will be able to extend lives by decades rather than months and years.

A Little Help from Man's Best Friend

My last post suggested that some new drugs don't make it to market because the existing trials process doesn't provide critical information that can be used to optimise the trial design and reveal the true potential of the drugs being tested.

A change in the existing trial process would have serious legal and ethical issues to contend with, and so is unlikely to occur. It can however be supplemented in such a way that streamlines the process, more accurately determines the effect of a cancer drug and can reduce the time to market. That solution is dogs. These are not your typical animal experiments, such as the rat or mouse models of cancer, in which the animal often lacks a fully functional immune system and the cancer itself is a cross-species 'xenograft' implant. Its fairly easy to see how these models do not accurately represent the type of cancer that occurs naturally in the body, and that's where the dogs come in.

In the USA up to 6 million pet dogs are diagnosed with cancer every year. Canine cancer is surprisingly similar to human cancer. Dogs get the same types of cancers as humans, they are genetically similar to humans and crucially, large scale genomic analyses of canine tumors have shown that there are no differences in the genetic mechanisms of the cancer. The other similarities in canines include their size and the fact that they possess fully functioning immune systems. The similarity between dogs and humans is so close that most existing drugs can be used to treat equivalent diseases in both species.

Naturally dog owners are keen to pursue any therapies that may prevent the death of their pet. Fortunately they can, in the USA the National Cancer Institute operates a network of animal hospitals, fully equipped with state of the art imaging technologies to accurately diagnose and monitor canine cancer. Similar work is carried out at the Roslin Institute in Scotland. These centres are used to test new therapies on the plentiful supply of canine patients following Good Clinical Practice guidelines and central reporting of dangerous side effects not too dissimilar to those in place to protect human patients.

The canine trials can start providing detailed information on the mechanisms of the drugs action before even the Phase I trial in humans starts. Information such as genetic profiles for which the drug is ineffective or blood markers that can be used to determine successful responses in advance of significant tumor reduction. These can all be translated to human systems and used to better design the human trials. These types of biomarkers are not often discovered until around Phase II of human trials, and are usually validated during phase III. Having them in place for Phase I is very useful as they can be validated in the early phases and used to optimise the later more expensive and time consuming phases. For example selective enrolment of patients who have the genetic or biochemical profile compatible with the drug would make the trial more decisive, while freeing other patients to pursue other therapies with more likelihood of success for them. Another benefit is instead of waiting years to determine the survival of the patient and therefore whether the drug was effective, biomarkers that provide advanced indicators of survival could provide that information in months, drastically reducing the length of the trial and therefore the costs.

Comparative Oncology such as this has the potential to give us a much more detailed understanding of the drugs we are testing and should help bring more new drugs to market and quicker. Cancer is a complex and diverse disease that will not be overcome by a single therapy alone, we will need to use combinations of therapies specifically targetted to a patients personal disease to attack it from several fronts. Therefore understanding each cancer type and each drug as much as is technically possible will be critical in determining potential drug synergies and creating successful recipes for treatment.

The Increasing Use of Biomarkers in Cancer Research

Hello and welcome to my first 'SciBite'. Whilst looking for a subject to write my first post about I came across an article about prostate cancer and a particular type of androgen (male hormone) receptor. This article details the discovery of several variants of androgen receptor, and how the expression of one particular variant seems to be responsible for enabling prostate cells to grow even without the androgens they usually require.

This is important because current standard treatment for prostate cancer often involves disrupting this androgen signal, either by castration, or more commonly in the richer countries of the world, hormone therapy. Both of these methods are initially highly successful, often large decreases in the size of the tumor are observed, but frequently the cancer develops independence from the androgens that used to dictate its growth, and a new phase of the disease is entered.

The discovery of this variant androgen receptor sheds some light on the mechanism of the cancers evolution to this phase, but usefully it also provides a 'biomarker' to help consultants decide the best course of therapy to place their patient on. It is possible to test a biopsy of the tumor to establish if this variant receptor is present, if it is already present at a high level then hormone therapy may not be a very successful option and the patient may benefit from an alternative treatment. For patients who are undergoing hormone therapy, it may provide a useful guide as to how far along the tumor has got to becoming androgen independent, and enable a switch to another treatment before tumor growth becomes completely uncontrolled.

This is one good example of a current trend in cancer research and treatment: Identification and utilisation of biomarkers to better diagnose, monitor and treat cancer. Previously cancers have been categorised according to the organ or tissue of origin, and all cancers of that origin tended to be treated the same way. However, more recently new technologies such as gene expression profiling have shown that the genetics of tumors can differ greatly between patients, even if the tumors are in the same tissue. Furthermore it has exposed the fact that there can be large genetic differences even within a patients own cancer, primary tumors being significantly different to secondary tumors. The differences extend beyond the genomic level, as all changes at that level are translated into cellular changes, the up or downregulation of tumor specific proteins may be detectable in the blood as is the case with PSA in prostate cancer.

These differences go some way to explaining why cancer treatment has until now been so hit-and-miss. If cancers of the same tissue can be caused by completely different mechanisms, then it is unreasonable to expect one treatment to be successful with them all.

The advantage we gain from the genetic analyses available to us now is that we can see easily which genes are undergoing changes in the development of a cancer, and investigate them specifically. This will inevitably provide many new cancer biomarkers to help us understand the processes occurring within cancers, give us a clue about the prognosis for the patient and enable us to more precisely target specific processes in the tumor with proven drug combinations.

I recently heard a speaker at a lecture say something along these lines: "We don't need to develop any new cancer drugs, we already have a lot of those, we just don't fully understand how they work or who they will work for, and that is where we need to focus our efforts".