Progress with targeted drugs for cancer

7-Mar-2016

Cancer remains one of the biggest killers but new treatments are progressing. Dr Johannes Rauschnabel, Chief Pharma Expert, Bosch Packaging Technology, reviews the new modes of therapeutic action and further areas for R&D

‘Diagnosis cancer’ – this is a life-changing moment for many people. Cancer is the second most common cause of death worldwide, after cardiovascular diseases. In 2012, some 8.2m people died as a result of cancer.1 The World Health Organization forecasts that this number will continue to rise until 2030. Fortunately, recent years have seen a quiet revolution in terms of treatment, with an improved understanding of the molecular biology of tumour cells leading to increasing success in addressing the specific factors that distinguish each patient’s illness.

For men, the most common diagnoses involve cancers of the lungs and prostate, while for women it is breast cancer. And for breast cancer there are already 20 different subtypes. Malignant tumours occur when sections of DNA change, and the body is no longer able to counteract these mutations. Furthermore, the gene repair system becomes increasingly unreliable with age. The overall risk of developing cancer depends on a combination of hereditary factors, lifestyle habits and environmental influences – smoking, excess weight, UV radiation exposure, certain viruses and inhaled particulates.2 Therefore, cancer can be ultimately understood as a collection of different mutations. As a result, the best chance of success is generally found in combining different treatments, whether in parallel or sequentially.

The conventional triad of drug therapy, radiation sessions and surgical intervention represents a strenuous but proven course of action, and is generally successful. While radiation therapy uses ionising radiation to completely deactivate or at least diminish the tumour, chemotherapy relies on the administration of cytostatic drugs to inhibit cell growth and deactivate dispersed tumour cells. The exact treatment plan depends on the tumour’s characteristics, the patient’s general condition and the stage of the disease.

Chemotherapy is used in many cases – mainly by infusion, although certain cytostatic drugs are also suitable for oral administration. Since researchers have tested and re-combined proven active ingredients in different dosages, as well as created new combinations and introduced new substances, today’s chemotherapy frequently achieves good results at higher tolerance. While conventional chemotherapy remains the focus of treatment in emerging countries, it is increasingly combined with new, highly targeted therapies in the industrial world.

Dr Johannes Rauschnabel, Chief Pharma Expert, Bosch Packaging Technology

Dr Johannes Rauschnabel, Chief Pharma Expert, Bosch Packaging Technology

The understanding of the molecular biology of tumour cells has deepened considerably in recent decades. Scientific knowledge of how the immune system reacts to cancer is also increasing. As a result, researchers have become more capable of developing therapeutic approaches that can be tailored to each patient, using new points of attack. Above all, this involves targeted or molecular cancer drugs. Unlike cytostatic drugs, which function as cellular toxins that attack not only tumour cells but also healthy cells that divide quickly, the drugs of targeted therapies take aim at tumour-specific traits.

The cell division of healthy people is strictly regulated. A cell is only reproduced when it receives the appropriate signal. Receptors on the cell surface project into the interior, providing exterior docking sites for the signalling molecule. In cancer cells, however, mutations disrupt this regulated balance between growth, division and cellular death. The cell receives a continuous signal to divide. Modern cancer therapies act on the molecular foundations of this defective signal transmission.

Here, enzymes known as kinases play an important role. Researchers have developed small-molecule agents called kinase inhibitors that work by blocking the action of one or more kinases. As tiny signalling molecules, they bind to part of the receptor inside the cell and thus interrupt the signal cascade that leads to cell division. These therapies slow down cell growth significantly. The first approved compound in this class was imatinib,3 which is used particularly for the treatment of chronic myeloid leukaemia. Its great success has spurred further research, with many kinase inhibitors currently on the market or in clinical trials. Most kinase inhibitors are administered orally in the form of capsules or tablets, sometimes employing extremely complex formulations. Other injection-based targeted therapies such as those with cytokines (particularly interferon and interleukin) tackle the mediators between cells, thereby also affecting cell growth.

Angiogenesis inhibitors cut blood supply

Angiogenesis inhibition is the process of starving the tumour by antibody action. To survive, cancer cells need oxygen and nutrients delivered by red blood cells. After reaching a certain size – around that of a pinhead – a solid tumour will need newly formed blood vessels for its continued growth. Since the tumours themselves pull in new blood vessels to secure their own supply, cancer researchers have turned their attention to this blood vessel formation process, known as angiogenesis. With antibodies that bind to vascular endothelial growth factor (VEGF), angiogenesis inhibitors try to retard blood flow, thereby shrinking the tumour or at least curbing its growth. This therapy is used particularly for breast, colon and ovarian cancer. It has been shown that for women with advanced ovarian carcinomas, progression-free survival is significantly prolonged by angiogenesis inhibitors.4

Some tumours depend on the body’s own hormones for growth. For some time now, hormone-responsive tumours have also been treated with targeted therapies using hormone supplementation, hormone receptor antagonists and/or hormone synthesis inhibitors. In the case of breast cancer, the prognosis for hormone-responsive tumours is generally good. Also for men with prostate cancer, antihormone therapy is often an effective way to retard tumour growth.

Using the relatively new technique of immunotherapy, the body’s own immune system is stimulated to fight against tumour cells. Here, tissue cultures in fermentation chambers are used to produce monoclonal antibodies (mAbs) that can attach themselves to the characteristic structures (antigens) on the tumour surface. This allows them to act on various tumour mechanisms e.g. inhibiting cell proliferation, or inducing cell death. Since antibodies are complex protein structures that are digested and destroyed by the gastrointestinal tract, this therapy is administered via infusion.

The infeed on Bosch's oncology line

The infeed on Bosch's oncology line

Recently, particular attention has been given to mAbs in the context of checkpoint inhibition.5 To protect the body against autoimmune reactions that would destroy its own tissues, the immune system is equipped with checkpoint molecules that prevent an overreaction of the immune system. Checkpoint inhibitors are used to turn off the checkpoint mechanism, thereby opening the way for the immune system to fight the tumour. In 2011, ipilimumab6 became the first checkpoint inhibitor approved for the treatment of advanced malignant melanomas. The academic journal Science declared checkpoint inhibition the Breakthrough of the Year 2013.7

According to the latest research, checkpoint inhibitors are most suitable for patients whose immune systems have already reacted to the tumour even before treatment. Checkpoint inhibitors are effective in some 20% of treated patients. In these cases, they significantly increased the reaction of T cells against the tumour. As a result, the long-term survival rate of patients with malignant melanomas was increased by around 20%.8 In addition, there is now clinical study data on the effectiveness of checkpoint inhibitors in treating non-small cell lung carcinomas and urological tumours. Research results suggest the emergence of a large new market here. In addition to ipilimumab, the US Food and Drug Administration also approved pembrolizumab in 2014 as yet another immunotherapy agent for the US market.

Antibodies can also be used to augment the effects of other cancer medications. With a new class of high-grade biopharmaceuticals – antibody-drug conjugates (ADCs) – a particular drug is coupled to an antibody, which then attaches itself to a specific target structure, such as an antigen on the surface of a tumour cell. This allows cytostatic drugs to take effect at a very precisely targeted location. Applying nanotechnology to cancer treatments is yet another way to facilitate the targeted transport of active ingredients, thereby reducing side-effects.

The outfeed on Bosch's oncology line

The outfeed on Bosch's oncology line

An indispensable component of the overall treatment is the use of supportive medications. It is no longer conceivable to use chemo, radiation or even modern immunotherapy without supplemental drugs to address the general symptoms of the disease as well as the side-effects of the treatment. This includes antiemetics, painkillers and antibiotics, as well as hematopoietic growth factors. These supportive therapies will be more important with the increasingly customised therapies of the future.

Growing market for companion diagnostics

The overall trend is clearly towards individually tailored therapies that use new diagnostic techniques to evaluate the precise needs of the patient and specific characteristics of the tumour before assembling a co-ordinated combination of high-grade medications. Thus, another major focus of drug development is now on companion diagnostics as a means to verify effectiveness for each individual patient before treatment begins. This is indispensable because of the need to control expenses in the healthcare sector, since some therapies can entail medication costs in the five-figure range, and the relevant budgets make no allowance for their inefficacy. For example, to test the efficacy of the trastuzumab mAb in a patient with breast cancer, a biomarker test is used to diagnose over-expression of the HER2 receptor.9

Because regulatory bodies such as the FDA are increasingly requiring the use of companion diagnostics for certain therapeutic agents,10 the global market for companion diagnostics could grow by almost 20% annually, reaching an estimated US$3.5bn in 2020.11 As a result, pharma companies are developing corresponding tests for existing therapies as well as new medications and are co-operating ever more closely with diagnostics and medical device manufacturers.

The trend towards more specialised therapies means that clinical studies have ever smaller pools of potential patients, so that the line between drug development and patient treatment is becoming increasingly blurred. Known as ‘translational medicine’, this field presents immense challenges, but also holds great potential for success in fighting tumours previously considered difficult to treat. The efforts of medical researchers and the pharma industry to develop new, effective and increasingly targeted tumour therapies will transform the image of cancer – from a death sentence to a serious but manageable chronic condition.

References

1. http://www.who.int/mediacentre/factsheets/fs297/en/

2. http://www.hopkinsmedicine.org/news/media/releases/bad_luck_of_random_mutations_plays_predominant_role_in_cancer_study_shows

3. Cf. Vasella, Daniel (2003): Magic Cancer Bullet: How a Tiny Orange Pill May Rewrite Medical History

4. http://www.pharmacylearningnetwork.com/articles/new-anti-angiogenic-drug-improves-progression-free-survival-ovarian-cancer

5. http://www.faz.net/aktuell/wissen/medizin/neue-methoden-der-onkologie-die-selbstverteidigung-gegen-den-krebs-13405363.html

6. http://www.cancer.gov/aboutcancer/treatment/drugs/ipilimumab

7. http://news.sciencemag.org/people-events/2013/12/sciences-top-10-breakthroughs-2013

8. http://www.pharmazeutische-zeitung.de/index.php?id=54321

9. http://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/her2-testing-breast-cancer

10. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery

11. http://www.reportsandintelligence.com/companion-diagnostic-technologies-market

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