Thursday, 29 March 2012

The Systematic Identification Researchers Genetic Markers Of Drug Sensitivity In Cancer Cells

In the largest study of its kind, researchers have profiled genetic changes in cancer with drug sensitivity in order to develop a personalised approach to cancer treatments. The study is published in Nature on Thursday 29 March 2012.

The team uncovered hundreds of associations between mutations in cancer genes and sensitivity to anticancer drugs. One of the key responses the team found was that cells from a childhood bone cancer, Ewing's sarcoma, respond to a drug that is currently used in the treatment of breast and ovarian cancers. The lowered toxicity of this treatment may mean it is a safer alternative therapy for children and young adults with this aggressive cancer.
There is an intimate relationship between the way a drug works and the genetic changes present in cancers. This study found that sensitivity to most anti-cancer drugs is influenced by mutations in cancer genes and establishes the utility of using large-scale studies to identify these associations and build them into improved patient treatment.
"Our key focus is to find how to use cancer therapeutics in the most effective way by correctly targeting patients that are most likely to respond to a specific therapy," explains Dr Mathew Garnett, first author from the Wellcome Trust Sanger Institute. "We studied how genetic changes in a panel of >600 cancer cell lines effects responses to 130 anti-cancer drugs, making it the largest study of this type to date."
The team identified biological markers of drug sensitivity to a broad range of cancer drugs. Most of the cancer genes analysed, including those that are not known directs targets of the drugs tested, were associated with either sensitivity or resistance to at least one of the drugs analysed.
"Our research has taken us down unknown paths to find associations that are completely novel," says Dr Cyril Benes, senior author from Massachusetts General Hospital Cancer Centre. "We have identified hundreds of associations, many of which we still don't fully understand. We identified a novel indication for the use of PARP inhibitors, anti-cancer drugs currently used to treat breast and ovarian cancers, for the treatment of Ewing's sarcoma."
Ewing's sarcoma is a cancer of children and young adults with a 15% five-year survival rate in patients where the cancer has spread or they have relapsed after chemotherapy. The use of PARP inhibitors could represent a new treatment option for Ewing's sarcoma patients and these compounds will now be tested in clinical trials to assess their therapeutic benefit.
"Advances in next-generation sequencing technologies are already being translated into the large-scale detection of cancer gene mutations in the clinic," says Dr Ultan McDermott, senior author from the Wellcome Trust Sanger Institute. "There is a compelling need to identify, in a systematic fashion, whether observed mutations affect the likelihood of a patient's response to a given drug treatment. We have therefore developed a unique online open-access resource for the research and medical community that can be used to optimize the clinical application of cancer drugs as well as the design of clinical trials of investigational compounds being developed as treatments."
The team hopes their open-access database will be an important resource for the cancer research community and which will ultimately lead to improved treatments for patients. This research program is a unique Wellcome Trust funded 5-year collaboration between The Cancer Genome Project at the Wellcome Trust Sanger Institute and the Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center.
"Our work is helping to move cancer therapeutics away from the conventional tissue-based treatment to a more molecular-based treatment," says Professor Daniel Haber, senior author from Massachusetts General Hospital Cancer Centre. "The next steps for this collaborative project are to evaluate some of the key findings using tumour samples and test new candidate therapeutic strategies in clinical trials so we can hopefully improve the way we treat cancer patients. We are continuing our screening effort, in particular using drug combinations to discover innovative and better therapeutic options."

Thursday, 22 March 2012

Put Pain to Dance in the Rain

Losing a lifelong partner is hard for anyone, and its taken me five months before I can even begin to put pen to paper.
David and I met in 1973 whilst we were both working for a motoring organisation. He had joined at the age of 16 and both our fathers worked for the company as well - so it was very much a family business. We started dating on the 11th October 1973, and after three days he asked me to marry him. I was 20 and he 21. A month later we got engaged and married the following August in 1974.
I never dreamt I would lose him at the age of 59......
I can honestly say whilst young by today's standards, neither of us regretted a day of our lives. Yes, we would have changed some things, but learnt from them. We spoke every single day even those times when we were in different countries. Our lives were always filled with laughter - he a practical joker at times, but he always lightened the darkest moments even at the end of his life. There are so many stories of the restoration and other funny incidents and he touched many peoples lives.
Our four children were our joy and we did so much together. He taught them honour and courage and handed on his love of life and humour. David had an incredible sense of justice and honesty and a thirst for adventure. He met life head on and taught me so much about business and to always face your fears. Ours was a life of love and laughter and we actually likes each other, spending more time together than anyone I know. We worked together in different jobs four times and whilst there were sometimes heated discussions, we never fell out.
We had our share of tragedies, losing pets (one great dane drowned in our pool), our children's car crashes and even our daughter Georgina almost drowing (saved cooly and calmly by David). And then we had to face a huge battle when David slipped into the world of alcoholism. This was my time to be the strength and together we faced it - and miraculously he beat it with sheer determination and hypnotherapy. The hypnotherapy brought other benefits and David then lost his fear of heights, rats and the dentist - having his teeth done and looking better than he had for years. I cannot say when I was so proud of him. Our children were solid and the love we all share is untold.
Then came our great adventure, in 2002, being unhappy in both our jobs for the first time in our lives we bought an abandoned farmhouse in a relatively unknown part of Italy, restored it and transformed it into an 8 bedroom country house hote. David took on much of the work, and I continued back and forth between Italy and the UK to keep money coming in whilst we were building the business. David did all of the cooking and used his passion for food to win great praise for his food, making us eighth on trip advisor out of four hundred hotels in the region. The business grew and prospered and allowed us to spend valuable time together. We put the house up for sale and David drew on his business experience to put a business plan together for a our return to the UK - and setting up some restaurants. I managed to find some investors and all we needed was our stake from the house sale in Italy.
But then came a scare in january of 2009 - David was diagnosed with a cancerous tumour in his mouth. An operation in Milan gave us hope - the tumour was benign with no need for other interventions. He had always been a smoker, but all but gave up save for 1 a day instead of 30. Our eldest son, Simon lives in Italy as well and he did so much to help- driving for ten hours some days to get David to appointments in Milan and back to Le Marche. We saw a lot of Simon and his wife and our grandson and I am so grateful for that time that David spent with them.
Returning to Le Marche after the operation, we made the most of every day and went off for coffee in the piazza, fish dinners at the coast and actually enjoyed our italian home ourselves, instead of just concentrating on work and guests.
How cruel though is life? in October of 2010 David got an abcess in his mouth, off to the Dentist for an extraction and antibiotics. A week later, another abcess - another extraction and antibiotics. Week later the swelling was back and we were sent to the specialist for a biopsy. I can't tell you how frightened I was. At the same time, I had an operation on my foot and relied on David for everything as I could not walk unaided for months, so he was my chauffeur, tea maker, personal butler and he never complained - teasing me and making me laugh.
The week before Christmas David was called for the result and he went with my brother (to make sure we knew what was being said - in Italian). We knew that he would have to have an operations and the word infection was used. That day returning home, our car blew up. Money was pretty tight as business was slow due to the sterling/euro exchange and the latest financial recession. We borrowed money to hire a car. But it was almost something telling us we should go home to England.
Our daughter Georgina and her boyfriend came out for Christmas and we had to tell everyone that David needed and operation on his jaw. Christmas came and went and David and I spent one of the best times on New Years Eve, in a little restaurant in our hilltop town. Just the two of us, and a week going to the mountain, having coffee in the piazza and enjoying the italian lifestyle.
On the 2nd January 2011, Georgina and I took David to hospital - the operation was scheduled for the next day. As we sat with the specialist he spoke of the cancerous tumour that was to be removed and his jaw would be replaced by a bone taken from his leg. We had no idea at that time that it was cancer, and he had kept it from us, so as not to ruin Christmas. Georgina and I felt that we had been hit by a bus. Oh my God, how we cried when we left the hospital.
We returned at 7am the next day to wish him well and waited. The operation lasted for seven and a half hours. We paced and walked up and down the hallways waiting for his return. I was still on crutches but nothing mattered except the safe return of David. Finally we bumped into the surgeon who told us it was a huge tumour and he thought they had it all, but more biopsys were needed. At 6.30 David was back on the ward. Unable to speak, but he still managed to write a note - 'guess I better give up smoking now!' I could have murdered him, but he still made us laugh.
Later that night, after a check by the surgeon, he was taken back to theatre as they were concerned about the transplant of the bone - one of the blood vessels wasn't functioning. So back un anaesthetic for more work. Georgina and I clung to each other - we were sleeping on blankets on the floor of his room.
At around 2 or 3 am he was brought back to the ward. He looked so thin and grey - barely alive. I can see it as if it was yesterday. Georgie and I took it in turns to sleep whilst the other watched him. Finally he came round, very much worse for wear and being fed by a tube, with monitors and drips. He was such a strong person. Battling every day, he improved and we were so relieved. I slept in hospital for nearly three weeks, with georgie taking some nights.
Then we were told the worst news - they had found 3 of 18 lymph nodes with cancer and a shadow on his lung and adrenal gland. As we were in terrible financial difficulties, I had secured a job in the UK before Christmas and managed to delay the start date, but I had to be in place for the 20th January, so Georgie and the boys took over in Italy. After discussions, we all decided that without work in Italy, no car and David as our priority, we should move permanently back to Italy, which would also empower David and no need for translators.
In February I flew to Italy to pack up a few things and bring David to the UK. He bounced back and was so positive that he would beat the cancer. We lived one day at a time and were under Southamtpon General hospital. They put us under the Maxillo Facial team first, then decided that the lung was more important. Everything seems to take so long when you are battling cancer, but you also become institutionalised, looking forward to appointments. David liked to set targets and he remained positive that he would beat it. We were told that they could not cure him, but could offer palliative care. David did not want to know anymore but I asked. They said he may have a year, but they could try to slow the process and keep him out of pain.
I am so glad we came back. We moved in as temporary lodgers with some incredible friends, without whom I dont know how we would have managed. They found things to tempt his appetite and made us so welcome. David spent his days playing golf - something he hadnt done for years. He was my driver, taking me to work every day and we managed to spend lots of time revisiting old friends and places. In spite of what was going on, we made the most of each day.
In May the chemotherapy started. He was sick and dizzy and it hit him harder than either of us could have forseen - I expected him to sail through it.
We finally moved into our own rental house in May and Mum came back from Italy - staying at Auntie Hildas for a while, befoe joining us. Georgie and I were joint tenants and it was so nice to have our own place, especially with David battling the side effects of chemo.
Then in July just before the last chemo, he was not right. Not just dizzy, he could hardly walk, lost his balance and his speech was impaired. I thought he had a stroke. Phoning the emergency chemo line, he was admitted. A scan revealed that a brain tumour was blocking the spinal fluid. he was prescribed steroids, and miraculously he bounced back - after a few days in hospital, they did another full body scan and oh my god - it revealed that not only had the chemo done nothing, the lung and adrenal tumours had grown, the one was back in his face, and of course the new brain tumour. It was at this point I was told he probably had about three months. I passed out. I was going to lose my love, my life and my best friend with whom I shared everything.
David was still battling and we tried vitamin B17, with high doses of vitamin c - a special anti cancer diet and alternative therapies - reiki, healing etc. Anything that would not do the damage that chemo had done. The steroids really did some good and David got to a point when he got out of the tired phase after chemo and was cooking again and in good spirits. The boys came a lot and simon came from italy with his wife and our grandson. We spent a day in Bournemouth and went to the aquarium with lunch in Harry Ramsdens - its only looking at the photos now, that I can see just how poorly he was, but he put on his brave face and made the most of the family.
David loved surprising me, and bought tickets for Les Miserables for my birthday, which we werent sure we would make, but he perked up and in August we travelled to London to see the show we both loved. Then for our 37th wedding anniversary, he bought tickets for Phantom, again travelling to London with a wonderful supper in an italian restaurant - the date was the 8th September. After the performance finished, he had great difficulty getting up - the steroids and the cancer were taking their toll on his legs and I was frantic, trying to find a cab to ease his pain.
From this date, he got slowly worse - I lost a little of him every day. Not his mind, which was a sharp as ever - but he drifted away sometimes although he never let any of us know just how bad he was. He only took paracetamol and ibruprofen for the muscle pain.
Then on the Thursday, 13th October 2011, he woke and said he didnt feel very well. He couldnt say why or where, but I phoned work and said I would not be in. At 11 am he had a massive seizure and was unconscious. Georgie called the paramedics and we got him back. She also made frantic calls to the boys, who arrived. I could see that there may not be much time left. Over this week his mobility was severely impaired and in the space of 10 days, he went from crutches to a zimmer and then a wheelchair. We had to raise the cushions on the sofa and he needed help to get up and get in and out of bed. The doctors who were amazing along with the paramedics prescribed a higher dose of steroids, which seemed to do the trick.
We had an amazing weekend with him, laughing at X factor, and he chatted with our great friends over afternoon tea on the Saturday - about the grandprix. He was back to his old self. Thank god we had the boys and Georgie's boyfriend, who did so much to help him get up and move.
My big regret was that I told Simon that he had bounced back and he decided not to come on saturday, but the following wednesday.
In the early hours of Monday morning (17th October - Simon's birthday) he was in pain and had trouble breathing. Another call to the paramedics and doctor - they gave him oxygen and he was prescribed some stronger pain killers, which settled him. Our own doctor came out that morning and prescribed oromorph and a patch. He was certainly more comfortable, but very tired. Then early hours of Tuesday morning (18th October) he was in terrible pain in his lower rib cage again - the patch, which was slow release hadnt kicked in yet - so a call again to the paramedics and oxygen calmed everything and a dose of the liquid oromorph. We ordered oxygen for home use and a hospital bed was coming to help him to sit up, unaided.
We both woke at 6am and he asked me if today was the day? Taken by surprise I replied that only if he wanted it to be. Usually he would watch sky news, but I asked if he would prefer some music. He said yes, and I put santana on the ipod. The district nurse turned up to fit a catheter, as he was having difficulty and two social workers to help wash him, change the bed etc. I sat with him while he had the catheter fitted and then the girls suggested I leave them to wash him. I so wish I had stayed. He slipped away and I only caught his last breath.
The boys were on their way from London and David's parents had arrived to visit. Whilst I knew that he may not have long, nothing prepared me for losing him so finally.
I sailed through the next week and even delivered a tribute to him at the funeral. But I know now, that I was on autopilot. I was afraid to lose it and now some 22 weeks on, I cannot believe he is gone. No one knows how hard it is as I have a great public face. But I miss him more than I can describe.
I have amazing children and family and incredible friends. But I have lost my best friend, and myself. I no longer really know who I am anymore. Challenges face me, but nothing will affect me as the very worst has already happened.
I know he wouldn't want me to be this way and I do appreciate everyone, everyday and everything. But for now its too early to rebuild myself. A weekend with David was worth more than a lifetime with someone else.
The moral of this tale is that I was lucky enough to meet someone who was everything through good and bad, we took every opportunity that came our way. Whilst I miss his desperately we did so much together and I would not have wished him to suffer anymore. I am so happy that I told him every day that I loved him.
Live your lives with courage and remember, as someone wrote 'life isn't about learning to survive the storm, but rather - learning to dance in the rain.

Tuesday, 6 March 2012