Hope for leukaemia patients through discovery at Karolinska University Hospital

 

 

In a recently published study, Nikolas Herold and Martin Jädersten from Karolinska University Hospital show how acute myeloid leukaemia can be treated more effectively. They have reused an already proven medicinal product.

Acute myeloid leukaemia (AML) is an aggressive blood cancer with a high mortality that affects about 350 people annually in Sweden. Over 70 percent of patients die within five years of falling ill. One reason for the high mortality rate is that chemotherapy often has an inadequate effect, which causes the disease to reoccur after some time.

The protein (SAMHD1) in the leukaemia cell has been shown to be a resistance factor for the medicinal product cytarabine.
Nikolas Herold, a paediatrician at the Paediatric Oncology Clinic at Astrid Lindgren's Children's Hospital in Solna, discovered with his research group at Karolinska Institutet that another medicinal product, hydroxyurea, can block SAMHD1 and thereby make the chemotherapy cytarabine more effective. Together with Martin Jädersten, haematologist at Karolinska in Huddinge, an academic study was designed for patients with AML where hydroxyurea was added to the standard treatment in order to enhance the effect of cytarabine.

“The results from our study are very promising. All patients have had an excellent response to the treatment and the addition of hydroxyurea has been well tolerated. We have also been able to demonstrate in the laboratory that the combination gave a higher concentration of active cytarabine within the leukaemia cells and that the leukaemia cells were killed more efficiently,” says Martin Jädersten.

It is not uncommon that it takes more than 15 years to develop a new drug and it is also not uncommon for the lifespan of a medicine to be shorter than the aforementioned 15 years. This entails high costs and causes the medicines to be expensive. For Herold and Jädersten, it has only taken five years from discovery to publication of a clinical study.

“Thanks to reusing an existing and proven drug that is already on the market, the additional cost per patient will be a couple of hundred kronor, i.e., the same as a pack of over-the-counter pain killers. It also makes the treatment available in less resourceful countries worldwide. Hydroxyurea has previously been used in leukaemia to slow disease progression, but we are now using it for a new purpose - as a modern precision medicine,” says Nikolas Herold.

The study is the result of a successful collaboration between the Theme Children and Theme Cancer at Karolinska University Hospital, but also of a close collaboration with several units at Karolinska Institutet, including the Science for Life Laboratory. The study is now published. It is a successful example of translational research where a clinical question from the hospital's everyday life, in this case treatment failure, is taken to the research laboratory where the cause is mapped and strategies are developed, and subsequently shown with clinical studies that the standard treatment can be improved.

The study has been published in the Journal of Internal Medicine. The next step is to recruit an additional 60 patients across the country to the phase 2 part of the study. The authors hope that an addition of hydroxyurea may become part of the standard treatment against AML as early as within the next few years.

“Magic mushroom” anti-depressive psychedelic affects perception of music

 

Scientists have found that the psychedelic drug psilocybin, in development as an anti-depressive treatment, changes the emotional state of people listening to music. Psilocybin is the active psychedelic ingredient in ‘magic mushrooms’. Clinical trials of psilocybin generally use selected music playlists to support the drug-induced psychedelic experience, and this work shows that enhanced emotional processing may be a positive outcome of combining psilocybin with music, suggesting that music should be an active component of psilocybin therapy.   This work is presented at the ECNP Congress in Lisbon. There has been considerable interest in the use of psychedelics in the treatment of hard-to-treat depression and other mental health conditions. Psilocybin, found naturally in several species of mushrooms, is the psychedelic most suitable for clinical development, in part because the psilocybin ‘trip’ can be contained within a working day, which is important for a supervised clinical treatment.  In the treatment of depression, psilocybin is normally administered with psychological support, and with accompanying music. Previous studies have shown that the psychedelic LSD interacts with music*, and of course in the 1960’s psychedelics were intimately related to the experience of music for many. Now for the first time a group of Danish scientists have shown that psilocybin affects the way that music elicits emotions. In the study, 20 healthy participants (50% women) were tested on their emotional response to music before and after given psilocybin; 14 of these participants were also tested after being given ketanserin (ketanserin is an anti-hypertension drug, commonly used to as a comparison in psychedelic experiments). Whether ketanserin or psilocybin was given first was randomly selected and each person was thus able to report on the changes effected by both psilocybin and ketanserin. At the peak of drug effects participants listened to a short music programme and rated their emotional response. The emotional response to the music was rated according to the Geneva Emotional Music Scale.  The music used was a short programme comprising Elgar’s Enigma Variations no 8 and 9, and Mozart’s Laudate Dominum, together lasting around 10 minutes. According to lead researcher, Associate Professor Dea Siggaard Stenbæk (University of Copenhagen): “We found that psilocybin markedly enhanced the emotional response to music, when compared to the response before taking the drugs. On the measurement scale we used, psilocybin increased the emotional response to music by around 60%. This response was even greater when compared to  ketanserin.  In fact, we found that ketanserin lessens the emotional response to music. This shows that combination of psilocybin and music has a strong emotional effect, and we believe that this will be important for the therapeutic application of psychedelics if they are approved for clinical use. Psilocybin is under development as a drug to treat depression, and this work implies that music needs to be considered as a therapeutic part of the treatment. Our next step is to look at the effect of music on the brain while under the influence of psilocybin in data material we have already collected, using an MRI”. She continued: “Interestingly, some of the music we used, Elgar famous ‘Nimrod’ variation (the 9th variation) describes his close friend Augustus Jaeger. Jaeger encouraged Elgar to write the variations as a way out of depression, so we’re pleased to see it used again to help understand more about mental health”. Commenting, Professor David J Nutt (Imperial College, London) said: “This is further evidence of the potential of using music to facilitate treatment efficacy with psychedelics. What we need to do now is optimise this approach probably through individualising and personalising music tracks in therapy”. This is an independent comment; Professor Nutt was not involved in this work   There is evidence that Magic mushrooms have been taken by humans for over 6000 years. Psilocybin was first isolated and synthesised in 1958, by the Swiss Chemist Albert Hoffman, the same man who first synthesised LSD. There was extensive early research into medical uses of psychedelics, but this became difficult after the US introduced a ban on their use in 1970. https://www.scientificamerican.com/article/end-the-ban-on-psychoactive-drug-research/ for background. *See: LSD enhances the emotional response to music, Kaelen et al, Psychopharmacology 232, 3607–3614 (2015). https://link.springer.com/article/10.1007/s00213-015-4014-y   The 34th ECNP Annual conference takes place in Lisbon and online from 2-5 October, see https://www.ecnp.eu/Congress2021/ECNPcongress . The European College of Neuropsychopharmacology is Europe’s main organisation working in applied neuroscience.

Scientists report genetic test to help predict men at most risk from aggressive prostate cancer

Scientists are reporting a test which can predict which patients are most at risk from aggressive prostate cancer, and whether they suffer an increased chance of treatment failure.  This test, reported at the European Association of Urology conference in London, and published in the Journal of the National Cancer Institute*, may give men a better view on how to deal with their prostate cancer risk.

Prostate cancer is the most common male cancer, killing almost 100,000 men each year in Europe. But it is not invariably fatal, in fact more men die with prostate cancer than of prostate cancer. Current screening methods, and in particular the well known PSA blood test,  can identify prostate cancers, but are not good at identifying how dangerous they are or even whether they should be treated. This makes if difficult to identify which men with prostate cancer are at real risk and need rapid treatment, and which don’t.

Prostate cancer is has a genetic component but it has until now been impossible to understand how aggressive the cancer might be  Now a new multi-national study has discovered the basis of a simple blood test which can predict whether a man is susceptible to aggressive prostate cancer.

Recent years have seen extensive research on the genetics of prostate cancer, with over a hundred mutations identified, however most of these are only present in a small number of men. Recently there has been a particular focus on the “Kallikrein” region of chromosome 19. This is a group of 15 closely-linked genes which code for proteases – molecules which break down proteins. In fact, the well-known test for prostate cancer, the PSA test (Prostate Specific Antigen), is based on one of the Kallikrein genes, KLK3.

The researchers, led by Dr Alexandre R. Zlotta, of the Lunenfeld-Tanenbaum Research Institute (Toronto, Canada) and Paul Boutros (Ontario Institute for Cancer Research) intensively searched for small single-point inherited mutations in the whole Kallikrein region, in a large group of 1858 men with aggressive prostate cancer (defined as having a Gleason score above 8). The men came from three independent groups, in Switzerland (part of the European Randomized Screening Study for Prostate Cancer, Pr Recker and Dr Kwiatkowski), Canada, and the USA. They were able to show that variants of the Kallikrein 6 gene were associated with more aggressive prostate cancer.

“These genes are found in between 6 and 14% of men” said Alexandre Zlotta, “This makes it one of, if not the, most common genes yet found to be associated with aggressive prostate cancer. Even if we take the lower, 6% figure, then that means around 17m North American men and 22m European men carry these gene variants”.

The KLK6 variants also independently predicted treatment failure after surgery or radiation for prostate cancer in a Canadian cohort of men from the International Cancer Genome Consortium (ICGC).

Dr Zlotta said “We found that in those men with prostate cancer treated by surgery or radiation, who had these inherited gene variant mutations had a three-fold increase in the risk of treatment failure, which means that after treatment, they were three times more likely to have the cancer recurring** than the rest of the population. This is really a quite significant increase in risk. Similarly men with these gene variants were three times more likely to be diagnosed with aggressive prostate cancer (Gleason 8 or more). To put this into context, around 10 to 15% of all prostate cancers are the aggressive prostate cancer we are dealing with here, but of course they lead to a greater mortality.

“What does this mean? Firstly the test has only just been developed – it’s still science, rather than something which is generally available. So it needs to be further validated and costed. It should mean that if you have a high PSA level but are unsure about having a biopsy to confirm whether you have cancer, this test could help you decide. It also means that we can begin to look at better screening for those who are at risk, for example among those men with a family history. As the test is refined we may be able to move towards more intelligent prostate screening”.

Prof Ros Eeles of The Institute of Cancer Research London commented:

“It is very important to try to identify markers of aggressive disease in prostate cancer patients as these will help us to target treatments to those most likely to benefit. Genetics is increasingly being brought into the management pathway and this result if validated will be important in adding to the algorithm of a panel of genetic variants which may be become part of routine testing in the coming years”.