EH 6/2014

www.totoku.eu The new CCL650i2 When size matters - 6 Megapixel - 30inch - 800cd/m² brightness LEDBACKLIGHT C M Y CM MY CY CMY K EUROPEAN HOSPITAL Vol 23 Issue 6/14 4 ONCOLOGY The combination of molecular profil- ing and proteomics to create indi- vidualised breast cancer treatment is continuing to show promise, with the results of the second Side Out clinical trial published online 11 September 2014 in Breast Cancer Research and Treatment. Proteomics is the use of molecular biology, biochemistry, and genetics to analyse the structure, functions and interactions of proteins produced by the genes of a particular cell or tissue. Proteomic tests provide information that genetic analysis cannot. Genetic analysis can identify all the proteins that a tumour is capable of making. Proteomics measure the activity levels within the signalling pathways of indi- vidual tumours – pathways that drive the growth, activity and reproduc- tion of cancer cells, and thus identify the proteins that are responsible for tumour growth. The two pioneering Side-Out clini- cal trials conducted between 2010 and 2012 created individual therapies for women with advanced breast cancer metastases who had already received multiple treatments. Their objective was to determine if individualised treatment could produce better out- comes than their most recent treat- ment – and they did. ‘Genomic sequencing and proteom- ic pathway mapping of metastatic lesions have recently shown that the molecular factors driving the growth or drug resistance of metastatic colo- nies may be quite different from the primary tumour from which they are derived. What this has meant is that conventional treatments may not be very effective, as evidenced by the fact that metastatic breast cancer patients tend to undergo a series of different consecutive treatments, each with diminishing effectiveness,’ said Professor Lance A Liotta MD PhD, co-director of the Centre for Applied Proteomics and Molecular Medicine at George Mason University in Fairfax, Virginia, USA. Dr Liotta discussed the Side Out trials, of which he is a co-investiga- tor, with European Hospital. These were sponsored by the Side-Out Foundation, a U.S. organisation of vol- leyball players and coaches dedicated to making significant and identifiable differences in the lives of breast can- cer patients. He has spent much of his career investigating the process of tumour invasion and metastasis at the molecular level. ‘These trials are exciting because this is the first time that treatment for metastatic breast cancer has been individualised. Participants’ metastatic lesions were biopsied and profiled. A multidisciplinary treatment selection committee then reviewed the patient’s data, and recommended therapeutic options based on the molecular find- ings. The most effective drug or drugs identified were either donated by pharmaceutical companies or paid for by the foundation,’ he said. ‘Our primary objective was to determine if the individualised ther- apy would produce 30% longer time to progression as compared to the patient’s most recent prior treatment. A secondary objective was to deter- mine the percentage of time that the patient’s oncologist would have selected a different treatment than that selected by the investigators.’ 21 patients participated in Side-Out I, six of whom had partial responses and 12 had stable disease. The disease control rate was 72%. Forty percent experienced 30% or longer time with a progression-free response. Side-Out II treated 25 patients, who had had undergone anywhere from three to 12 prior treatments. Five had partial response and eight had stable dis- ease. An addition 4% – or 44% of the total experienced 30% or longer time with a progression free response. Significantly, none of the physicians of any of the patients had selected the treatment that was actually adminis- tered. ‘This type of individualised thera- py shows huge promise,’ Liotta con- firmed. The Side Out Trials target Future research that stems from the Side Out Trials may greatly benefit metastatic breast cancer patients by identifying and delivering the most likely effective treatment as soon as metastasis is identified. At a mini- mum, this could eliminate treatments that won’t be effective because of the molecular differences of the metastatic lesion compared to the primary one. On the other end of the time course of cancer, Dr Liotta and his colleagues are currently conducting a breast can- cer trial aimed at stopping breast cancer before it starts. The PINC trial (Preventing Invasive Carcinoma with Chloroquine) is a neo-adjuvant trial accepting all patients diagnosed with ductal carcinoma in situ (DCIS). Women with a biopsy diagnosis of DCIS receive a one-month oral dose of an anti-autophagy inhibitor before surgical therapy of their DCIS lesion. The advantage of the DCIS trial design is that the DCIS lesion size and proliferation index can be compared before and after therapy in the same patient, so the therapeutic outcome is known immediately. The team hopes that cancer treat- ment centres in Europe will con- sider enrolling. The future goal is to develop a short-term oral therapy that kills breast cancer precursor lesions to prevent breast cancer. Molecular genetics and proteomics Outwitting cancermecha Women with metastatic breast cancer know they have a slim chance of long-term survival. The question is whether personalised therapy could extend their lives, asks Cynthia E Keen Immunotherapy using synthetic long peptides, Lance Liotta co-directs the Centre for Applied Proteomics and Molecular Medicine at George Mason University,VA.Fairfax,VA The human immune system is usu- ally very efficient in protecting the body against diseases by eliminating pathogens as well as infected, dam- aged or otherwise suspicious cells. However, it often fails because tumours have developed efficient strategies that hamper the system’s ability to detect and destroy the cancer cells. For example, certain structures on the surface of immune cells, such as T cells, act as regulators of the immune system, so that T cells can be prevented from attacking healthy tissue. Cancer cells often produce enzymes and ligands able to manip- ulate these regulators. In this way they can de-activate T cells that are directed against characteristic structures on the surface of cancer cells. The T cells lose their ability to bind to the tumours cells, and thus no action against the tumour is initiated. Most recently, new drugs have been approved that can remove the brakes that tumours apply to the immune system. Antibodies block- ing the negative regulators of the immune system, the so-called ‘check- point inhibitors’, are tremendously successful because they restore the body’s spontaneous anti-tumour immune response. One example is Yervoy ipilimumab, a monoclonal antibody targeting CTLA-4, a protein receptor that down-regulates the immune system. These drugs lead to response rates of up to nearly 50% in various cancers. Even though these figures are impressive, not all treated patients have their spontaneous anti-tumour immunity restored. Additionally, because the drug leads to a general activation of the immune system, some patients experience autoim- mune side effects. Fortunately, however, new strate- gies to overcome those limitations are in development. One approach aims to address and change the tumour’s immune environment. ‘We are delivering modulating signal- ling molecules to the micro-envi- ronment of tumours and infected cells,’ explains Dr Frank Schnieders, CEO of Provecs Medical GmbH in Germany. ‘Once present in sufficient concentration, they restore the vul- nerability of diseased cells and acti- vate the body’s own defence mecha- nisms locally and systemically.’ A local, transient expression of these factors for a few days, is suf- ficient to mount a lasting, systemic immune response against the dis- eased cells, resulting in the elimina- tion of tumour cells, or of cells har- bouring the pathogens, Schnieders adds. A first product, IM01, is in late preclinical development to treat bladder cancer and already licensed to an undisclosed pharmaceuticals partner. At the end of November, researchers from Dutch firm ISA Pharmaceuticals introduced a differ- ent approach in Nature: With a team from the Washington University St. Louis they analysed the T cells unblocked by the checkpoint inhibi- tor drugs and the structures the T cells were directed against. This led to the discovery of two interest- ing new antigens on the surface of tumour cells. Tissue section of a human bladder tumour. Islands of dividing tumour cell (stained red) surrounded by normal bladder wall cells indicate a severe cancer stage

EH 6/2014

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