Highly accurate early stage lung cancer test; from cutting edge science to clinical utility.

microrna research to advance cancer diagnostics

One day, in the not too distant future, some of you will be able to have a straightforward minimally invasive blood test for early diagnosis of cancer during a visit to your family doctor. Although this is not yet a reality in the clinical setting, many recent advances and technological breakthroughs have already made it possible in the laboratory to accurately detect early stage lung cancer in patients on the basis of a blood sample. What's more, very recent developments in cancer therapeutics will mean that some current cancer patients may be able to benefit from an entirely new class of cancer treatments, that are based on miRNA chemistry (see further down for details on clinical trials).

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Discovery of blood-based miRNA biomarker signature

Dr Wozniak, a cancer researcher who is a specialist in molecular epidemiology, presented her latest laboratory findings on early cancer detection in plasma samples (blood plasma is the pale yellow liquid fraction that is obtained after centrifugation of a blood sample) whilst attending the American Association for Cancer Research (AACR) Annual meeting 2014.

Dr Magdalena Wozniak presented her most recent
laboratory findings at the American Association for
Cancer Research (AACR) Annual Meeting 2014.

The study that was conducted by Dr Wozniak at the International Agency for Research on Cancer (IARC – WHO) demonstrates that it is feasible to detect lung cancer accurately at a very early stage using a minimally invasive technique that relies on the detection of microRNAs (this type of RNA is a novel class of small, highly stable, non-coding, single-stranded RNA that negatively regulates gene expression via translational inhibition or mRNA degradation followed by protein synthesis repression). Her research shows that a panel of 24 biomarkers (out of 754 that were tested on 200 different patient samples) was able to detect early stage lung cancer approximately 90% of the time.  That level of accuracy is much higher than any other type of minimallyinvasive biomarker assay which is currently used in the clinic. 

Given that only a minute quantity of miRNAs is present in a “straightforward” minimally invasive liquid biopsy of body fluids (e.g. cerebrospinal fluid or blood), development of this assay was anything but straightforward, particularly, when taking into consideration the governing complexities that determine the sensitivity and robustness of tests used in the diagnosis of lung cancer on the basis of microRNAs. As such, equipment, protocols, and bioinformatics analysis tools had to be optimised in order to accurately detect these lung cancer associated microRNA signatures.

Importance of accurate early lung cancer detection

This new development in early detection assays for lung cancer is incredibly important as it can literally make the difference between life and death. The 2014 WHO World Cancer Report, documents nearly 1.6 million lung cancer deaths per year world-wide (by far the highest number of cancer deaths caused by a specific type of cancer). This level of mortality is thought to be due to the late stage at which this cancer is usually detected.

Hence, even though this technology will not yet be available in the clinic, the development of tests that can make very early stage cancer detection a reality should be welcomed. Early detection of cancer is the ultimate goal (particularly in lung cancer), as early detection could save many lives. The earlier a cancer is detected, the more treatment options are available to the patient and the less debilitating the aftermath is likely to be.

miRNA biomarker diagram visualising process of minimally invasive

blood test for early diagnosis of cancer.

Dr Wozniak and colleagues are not the only ones searching for biomarkers that can accurately diagnose early stage lung cancer. A number of renowned cancer centres are working towards this “holy grail” of early cancer detection, and includes groups investigating cell free DNA (cfDNA) / circulating tumor DNA (ctDNA) diagnostic biomarkers.

The other reason this is such a pressing matter is because when you have a very early stage tumour (e.g. stage 1 tumor), you will feel healthy. A patient with such a tumour is unlikely to present him- or herself to the doctor, because he or she is still actively engaged in daily live (e.g. exercising, running errands, etc…) without any sort of feeling that something's wrong (a patient is likely to be unaware of his or her condition until it is literally too late). The blood test that has been developed by Dr Wozniak and her colleagues will be able to detect lung cancer at a very early stage, and could perhaps be introduced as a routine test to increase early stage detection rates.

Cost of early detection in vitro diagnostics (IVD) tests offset

While some people may argue that these types of new medical technologies will drive up the cost of care, it is likely that these cancer blood tests will in fact do the opposite, when they are made available for a few hundred dollars / Euros within the next few years. Ultimately, it could help patients avoid costly scans, and perhaps most importantly avoid late-stage diagnoses, when cancer is often more difficult and more expensive to treat.

Although, these researchers have come up with a novel and exciting minimally invasive cancer test, they also council caution for too much optimism while they conduct an Independent prospective validation of the clinical potential of the panel within a cohort with pre-diagnostic samples.

When and where can you expect gain access to microRNAs that are used to treat cancer?

While it is outside the scope of the research performed by the above mentioned authors, it is perhaps useful to explain in a brief summary how microRNAs can be exploited for not just diagnosing cancer but also for the treatment of cancer and what the future may hold in this regard.

Timeline illustrating breakthrough discoveries in the field of miRNA

research with a primary focus on discoveries and inventions that

have had an impact on cancer.

The observation that specific cancer types have particular microRNA signatures associated with them (based on research using surgically resected tissue samples) has led certain biotech companies to develop microRNA profiling arrays that enable clinical labs to characterise a malignant metastatic cancer and establish with a high degree of accuracy what the primary site of such a tumour is. It is these types of microRNA profiling experiments that can determine a patient’s outlook on the basis of specific microRNA profiles, and it is likely that more of these types of tests and assays will enter clinics in the near future (e.g. tests which are in development for establishing the characteristics of different tumour types include: specific ovarian and uterine cancers that are particularly difficult to distinguish histologically).  

However, utilising the therapeutic potential of microRNAs in the mainstream cancer care is still some way off, although a limited number of human clinical trials are currently being prepared (e.g. a multi-centre phase-I clinical trial where the safety, Pharmacokinetics and Pharmacodynamics of the micro ribonucleic acid (microRNA) MRX34, in patients with inoperable primary liver cancer or advanced or metastatic cancer with liver metastasis is studied and a clinical study that aims to assess the safety and efficacy of gemfibrozil in modulating microRNA-107 levels for the prevention of Alzheimer's disease).

Different types of microRNA - two sides of the same coin

As discussed earlier, it is known that in many different cancer types, particular microRNAs get up-regulated or overexpressed. A select number of scientists are currently trying to identify ways that will allow for targeting, and knocking-down of these “oncogenic” microRNAs in a clinical setting. Systematically knocking-down microRNAs has already been established in pre-clinical mouse models as being a feasible procedure in cancer therapeutics. Importantly, these drugs are apparently well tolerated in humans. It is likely that more phase I and phase II clinical trials will be set up in the near future to investigate antisense molecules that can target such oncogenic microRNAs.

However, in many cancer types, specific microRNAs have reduced expression levels (these are so-called tumour suppressor microRNAs). When these types of microRNAs are eliminated tumours form more readily inside your body. Re-introducing these types of microRNAs back into your body is an approach that is also actively being investigated (including microRNAs as well as microRNA mimetics (molecules that resemble microRNA and can act as a superior surrogate for the tumour suppressor microRNA).

Outlook for microRNA therapeutics

Ultimately, a combination of both strategies (a therapy in which oncogenic microRNAs are knocked down and levels of tumour suppressor microRNAs are restored) is most likely to result in a more durable response.

One important aspect to note with regards to using microRNAs as a therapeutic intervention is the fact that these RNAs are natural products made from your genes and have a long evolutionary history in all living things (including humans). This is also likely the reason why scientists investigating these molecules have not seen any strong side effects when microRNAs have been administered in pre-clinical studies.

In summary, microRNA based diagnostics or therapeutics within a clinical setting holds great promise for the future in the treatment of various types of cancer as well as other diseases.

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