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Metastatic bone disease is currently incurable in a significant number of cancer patients worldwide. In order to improve patient outcomes, there is a need to increase funding to support research projects tackling this specific area. Although additional research will be required to bring the experimental bisphosphonate-MMP-2 inhibitors into clinical use, cancer patients do have options to access cutting-edge therapies. Joining a trial allows patients access to the newest therapies and/or therapy combinations available, while also helping inform treatment decisions and outcomes for future patients. There are currently seven different active prostate cancer trials ongoing in Ireland, including one investigating radium-223.
According to the National Cancer Registry Ireland, prostate cancer is one of the most frequently diagnosed cancers in men, second only to non-melanoma skin cancer, and the net five-year survival rate for patients is 90.6 per cent. Men who are diagnosed with an early-stage cancer or small tumour benefit from many available treatment options, a major one being to keep an eye on it, or undergo ‘active surveillance’. This involves regular six-month check-ups to monitor the prostate-specific antigen (PSA) levels in the blood and digital rectal exams to inspect the size of the prostate. Biopsies can also be scheduled if required.
While it may seem counterintuitive not to aggressively treat and immediately surgically remove all cancers, it is the best option for a significant number of prostate cancer patients. The decision to choose active surveillance as a treatment strategy involves both the patient and their care team carefully considering several factors. All therapeutic interventions cause side-effects and for prostate cancer, these can include infection, toxicity and erectile dysfunction. Therefore, the risk of cancer progression, tumour grade, age of the patient and quality of life play a significant role in treatment planning for low-risk patients.
If the cancer presents as a locally-advanced tumour, meaning it has spread outside of the prostate gland into nearby tissues, radiation therapy to control tumour growth and subsequent surgical intervention may be offered. Chemical therapies are also available and the standard of care in this regard is known as hormone therapy. Prostate cancer cells rely on hormones known as androgens to grow.
The main androgen in men is testosterone and androgen deprivation therapy (ADT) works to either prevent the body from producing testosterone or stop the action of testosterone in order to slow the growth of the tumour. Several anti-androgens are approved to treat prostate cancer, including abiraterone and enzalutamide, and these can sometimes be given with steroids such as prednisone to improve outcomes and reduce side-effects. Chemotherapeutic agents such as docetaxel can also be prescribed alongside hormone therapy to inhibit tumour growth. Rather than specifically targeting the hormone that stimulates the growth of the cancer cells, chemotherapies act by killing rapidly-dividing cells such as cancer cells and are thus helpful in slowing the growth of tumours.
While the aforementioned treatments are effective at controlling the growth of the cancer cells and slowing the progression of the tumour for a period of time, with prolonged treatment, resistance emerges. At this point the cancer is described as advanced or metastatic castrate resistant prostate cancer (mCRPC). Despite the positive outlook for the majority of prostate cancer patients, mCRPC remains an incurable disease and a significant healthcare burden predicted to cause approximately 250,000 deaths globally this year.
Seed and soil
At this point, it is important to consider the bigger question of what causes cancer cells to spread to and monopolise distant organs in the body. This question has plagued cancer biologists for generations. As far back as 1889, Dr Stephen Paget, while working as a surgeon in London, contemplated this quandary and coined his ‘seed and soil’ theory. After analysing the case histories of 735 patients who died from breast cancer, Dr Paget was inspired to align cancer spread (metastasis) with the seed dispersal strategies used by plants. Per this analogy for plants to spread, seeds are scattered indiscriminately away from the parent plant.
In order for the new plant to survive and thrive, it must land in a hospitable soil environment. Similarly for a cancer to spread, the cancer cells (or ‘seeds’) would enter the body’s circulatory system and become dispersed to distant organs of the body. If the environment (or soil) of the distant organ were irrelevant, then the location of cancer metastases would be randomly spread throughout the body. Dr Paget found this not to be the case and proposed that the properties of the secondary site or organ must contribute to the survival of the cancer.
This ‘seed and soil’ proposal was revolutionary at the time and thus, as often happens with unconventional ideas, was thoroughly ignored for about 100 years. However, the medical and scientific communities now acknowledge that certain cancers preferentially spread to particular organs and although the reasons for this are yet to be fully understood, research efforts and treatment regimens are seeking to harness this to improve patient outcomes. Moreover, great strides have been made in cancer treatment and a cancer diagnosis in 2017 is by no means a ‘death sentence’.
What makes mCRPC (along with multiple myeloma and metastatic breast cancer) a difficult disease to treat is that its ‘soil’ or organ of choice to spread to is the bone. In fact, approximately 90 per cent of the men who succumb to mCRPC display evidence of bone metastasis. Not only are these metastases currently incurable, they can cause significant patient discomfort by causing skeletal-related events (SREs).
This term encompasses the common complications associated with bone metastases that include bone pain, skeletal fracture, spinal compression and the necessity for palliative bone surgery or radiation therapy. Needless to say, SREs lead to increased pain, decreased quality of life and worsened patient survival.
This is clearly an important and currently unsolved clinical problem, but what is the current state of affairs? How do these bone metastases thrive? What therapies are currently available to treat them? What research is ongoing to identify novel therapeutic options?
Bone metastases survive by usurping the normal bone microenvironment to facilitate the growth of the cancer cells. Normal bones contain cells known as osteoblasts that build bone and cells known as osteoclasts that ‘eat’ or destroy bone. In addition to these bone cells, many growth factors and other molecules contribute to maintaining a stable bone microenvironment by controlling the delicate balance of activity between osteoblasts and osteoclasts.
This balance is especially important during the normal bone remodelling process, which maintains a healthy skeleton whereby old bone tissue is removed from the skeleton by the osteoclasts in a process known as bone resorption and is replaced with fresh, healthy bone tissue by osteoblasts.
Cancer cells can disrupt this balance in a process known as ‘the vicious cycle of bone metastasis’ to cause areas of too much bone growth (osteogenic lesions) or bone loss (osteolytic lesions). Once in the bone, cancer cells initiate this vicious cycle by releasing growth factors into the bone microenvironment that stimulate the osteoblasts to generate more bone.
This new bone then releases factors into the bone microenvironment, in particular a protein named RANKL, which stimulates the osteoclasts to begin ‘eating’ or resorbing bone. This bone loss releases yet more factors into the bone microenvironment that incite the cancer cells to flourish and produce more osteoblast-stimulating factors and thus the cycle continues. For reasons that are only beginning to be understood, prostate cancer bone metastases are composed of areas of both abnormal bone growth and bone loss, whereas multiple myeloma and breast cancer bone lesions are overwhelmingly osteolytic in nature.
Figure 1. The vicious cycle of bone metastasis
Several therapies have been developed in an effort to thwart this vicious cycle. These are outlined in Figure 1. Hormone therapies and chemotherapies target the prostate cancer cells themselves. Although the hormonal agents have been shown to extend survival and delay time to SRE in mCRPC, the use of ADT has also been shown to cause a loss in bone mineral density (BMD) or weakening of the bone. This can lead to the development of osteoporosis and increase the risk of patients experiencing SREs. In an effort to combat this, compounds that target the osteoclast ‘bone-eating’ cells are prescribed to prevent bone loss.
One such class of drugs, known as bisphosphonates (for example zoledronic acid), are injected into the bloodstream and are chemically attracted to the structure of bone. Once they reach the bone, they impair osteoclast-mediated bone resorption. These drugs are commonly prescribed to treat osteoporosis and have been shown to reduce the occurrence on SREs in metastatic bone lesions. Denosumab, an antibody that targets and neutralises the RANKL protein that promotes the osteoclast cells to resorb bone, has also been shown to delay the time to SRE in mCRPC.
One of the most successful recent developments in the field has been a radiopharmaceutical known as radium-223. Radium-223 is chemically similar to calcium, allowing it to stick to areas of bone turnover when injected. Once stuck to the bone, it delivers radiation to its surrounding area to kill the nearby cancer cells. The particular type of radiation delivered by radium-223 is known as alpha radioisotopes. These deliver higher-energy radiation over a shorter distance than previous radiopharmaceuticals, meaning the dose is better at killing cancer cells while reducing the exposure of normal tissue to unnecessary radiation. This is the only new bone-targeted agent that has been shown to both reduce time to SRE and extend patient survival, albeit by 3.6 months.
Although modest improvements in treatment are being made, there is clearly a need to further understand the molecular mechanisms that drive cancer metastasis to bone in order to facilitate the discovery of novel therapeutic targets that treat this devastating clinical problem.
In order to further the research in this area, I was awarded an ELEVATE: Irish Research Council International Career Development Fellowship, co-funded by the European Union Marie Curie Actions. This fostered a new collaboration between the National Institute for Cellular Biotechnology (NICB) in Dublin City University and the Moffitt Cancer Centre in Tampa, Florida, US. The Moffitt Cancer Centre is the third-largest cancer centre (by patient volume) in the US and its guiding mission is to “contribute to the prevention and cure of cancer”. The centre is designated as a centre of excellence for cancer detection and treatment and is a National Cancer Institute (NCI)-designated Comprehensive Cancer Centre, of which there are only 68 across the US.
This fellowship allowed me to bring my molecular biology expertise to Dr Conor Lynch’s specialist bone metastasis lab in the Moffitt Cancer Centre. Dr Lynch is an expert in the field of bone metastasis and together with mentorship from Prof Martin Clynes, a world-renowned cell biology expert in the NICB, we sought to uncover new biological mechanisms that promote prostate cancer progression.
The project has focused on studying tiny molecules within cells known as micro RNAs that control cell behaviour. These micro RNAs have been shown to be altered in every cancer that they have been investigated in, and to contribute to multiple facets of cancer progression, however their role in bone metastasis remains largely unknown. The project began with assessing the presence of these molecules in human metastatic prostate cancer samples to identify clinically-relevant microRNAs to investigate functionally in the lab. Over the course of the past two-and-a-half years, we have identified and characterised one particular micro RNA that may have tumour-suppressive properties.
We are currently focused on identifying the mechanisms within the cells through which this micro RNA is acting and aim to publish the research before the end of the year. In addition to investigating the molecular cell biology of bone metastasis, the Lynch lab is also developing innovative therapies to treat bone metastasis lesions. The group recently published an article in Molecular Cancer Therapeutics describing novel inhibitors developed by Dr Marilena Tauro that harness the bone-seeking properties of bisphosphonates to target another important protein in the bone metastasis microenvironment known as MMP-2. These new inhibitors showed promise in reducing metastatic breast cancer burden in pre-clinical studies.
To support Irish Cancer research funding and for cancer support information visit, the Irish Cancer Society: www.cancer.ie/information-support.
A full list of ongoing clinical trials can be found at Cancer Trials Ireland: www.cancertrials.ie/.
The National Comprehensive Cancer Network of America produced an excellent, in-depth patient guidelines document that explains everything from diagnosis to treatment options in a very clear way: www.nccn.org/patients/guidelines/prostate/.