A DNA repair pathway-focused score has the potential to help determine if first-line platinum based chemotherapy can benefit advanced-stage ovarian cancer patients, according to a study.
Most ovarian cancer patients are diagnosed with advanced disease (stages III and IV). They undergo surgery to remove as much tumour as possible, and then undergo platinum-based chemotherapy. But tools to predict response to platinum-based chemotherapy in ovarian cancer patients have been inadequate.
In order to determine if a DNA repair pathway-focused score could help predict outcomes for ovarian cancer patients treated with platinum-based chemotherapy, Josephine Kang, M.D., Ph.D., of the Department of Radiation Oncology at Dana Farber Cancer Institute, and colleagues gathered gene expression data from The Cancer Genome Atlas (TCGA) database for patients with advanced stage ovarian cancer, and established a molecular score by looking at the genes involved in platinum-induced DNA damage repair pathways. The patients were placed either into low or high score categories, and the prognostic value of the score for overall survival, recurrence free survival, and progression-free survival was assessed.
The researchers found that patients with high scores showed a statistically significant improved overall survival compared to the patients with low scores. These patients’ score was positively correlated with complete response rate, recurrence-free survival, and progression-free survival. The researchers also found that the patients’ scores outperformed other known clinical factors in predicting overall survival in the TCGA dataset as well as in two additional validation sets. ‘Developing the ability to predict OS and outcomes to chemotherapy using prognostic markers such as the score is critical, particular in ovarian cancer, because there are presently no other good clinical measures to predict response to standard platinum-based chemotherapy,’ the authors write.
They also note the study’s limitations, namely that the score has not yet been tested prospectively in a clinical trial, although they do believe it is ready for testing. ‘With additional prospective validation in clinical trials, we hope that the score can become a powerful tool that is useful in stratifying advanced-stage ovarian cancer patients toward optimal treatments incorporating new treatment regimens vs. current standard of care,’ the authors write. EurekAlert

Fibroid uterine tumours affect an estimated 15 million women in the United States, causing irregular bleeding, anaemia, pain, and infertility. Despite the high prevalence of the tumours, which occur in 60 percent of women by age 45, the molecular cause has been unknown.
New Northwestern Medicine pre-clinical research has for the first time identified the molecular trigger of the tumour — a single stem cell that develops a mutation, starts to grow uncontrollably and activates other cells to join its frenzied expansion.
‘It loses its way and goes wild,’ said Serdar Bulun, MD, the chair of obstetrics and gynaecology at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital. ‘No one knew how these came about before. The stem cells make up only 1.5 percent of the cells in the tumour, yet they are the essential drivers of its growth.’
The stem cell initiating the tumour carries a mutation called MED12. Recently, mutations in the MED12 gene have been reported in the majority of uterine fibroid tissues. Once the mutation kicks off the abnormal expansion, the tumours grow in response to steroid hormones, particularly progesterone.
For the study, researchers examined the behaviour of human fibroid stem cells when grafted into a mouse, a novel model initiated by Northwestern scientist Takeshi Kurita, PhD, a research associate professor of obstetrics and gynaecology. The most important characteristic of fibroid stem cells is their ability to generate tumours. Tumours originating from the fibroid stem cell population grew 10 times larger compared to tumours initiated with the main cell population, suggesting a key role of these tumour stem cells is to initiate and sustain tumour growth.
‘Understanding how this mutation directs the tumor growth gives us a new direction to develop therapies,’ said Bulun, also the George H. Gardner Professor of Clinical Gynecology. University Feinberg School of Medicine

Researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital have identified several gene mutations responsible for the most common childhood brain tumour, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.
‘We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumours are at the molecular level,’ said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children’s and the senior author of the new research. ‘This paper represents a finer-grained view of the genetic landscape of these tumours and provides us with some leads on how to develop new therapies.’
The research is part of a large, ongoing effort to characterise genetic errors in medulloblastoma. Two companion studies on which Cho is a co-author will be published simultaneously with his paper. The three papers came from a consortium that involves scientists at Stanford, Packard Children’s, the Broad Institute, Children’s Hospital Boston, the Dana-Farber Cancer Institute, the German Cancer Research Center, Brandeis University and the Hospital for Sick Children in Toronto.
Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumour as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumour’s genetic characteristics.
Cho’s team extracted DNA from 92 medulloblastoma tumours and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant ‘point mutations’ — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.
Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumours. ‘Mutations in this gene have now also been identified in other tumour types, such as chronic lymphocytic leukaemia, and head and neck tumours,’ he said.
However, the researchers found that it was rare for the same gene mutated in several different patients’ tumours. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumours — a pattern that is emerging across cancer genome sequencing efforts.
Though no single tumour in the study carried all 12 mutations, the researchers were able to categorise the tumours according to which mutations they possessed. ‘We now understand that there are certain tumours with particular genetic signatures that are really resistant to standard treatments,’ Cho said. Children with medulloblastoma do not routinely have their tumours’ genetic signatures characterised, but Cho believes that such characterisation coupled with targeted therapies could greatly enhance tumour treatment.
About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumour’s genetic profile have the potential to save more patients while reducing side effects, Cho said.
Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. ‘The dysregulation of these ‘epigenetic programs’ is becoming a common theme not only in medulloblastoma but across cancer,’ Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma. EurekAlert

One hundred million treatments of Coartem Dispersible (artemether-lumefantrine), an antimalarial developed especially for children with Plasmodium falciparum malaria, have been delivered by Novartis to 39 malaria-endemic countries, Medicines for Malaria Venture (MMV) has announced.
This antimalarial is the product of the partnership between MMV and Novartis. It is the first WHO prequalified child-friendly artemisinin-combination therapy (ACT) and addresses an unmet need for paediatric medicines. Young children in Africa are disproportionately affected by malaria, with 86% of malaria deaths occurring in children under the age of five years.
Ahead of the international community’s call for better child-friendly medicines, MMV and Novartis signed an agreement in 2003 to develop the first paediatric ACT. The child-friendly formulation was launched in 2009.
Focused measures have been taken to facilitate the uptake of this medicine, including registration in 39 malaria-endemic countries, a without-profit pricing model and special packaging designed to improve compliance. These measures have not only led to increased demand but also to an accelerated uptake, underlining the advantage of the paediatric formulation. By reaching this one hundred million treatments milestone, the Novartis Malaria Initiative and MMV have proven that drug development partnerships can truly advance the fight against malaria.

Tufts Medical Center researchers have shown that presence of a gene strongly linked to appetite regulation is highly predictive of a premature infant’s readiness to feed orally. An analysis of just a drop of an infant’s saliva could be the key to preventing many feeding problems and the expensive medical complications that can occur when infants are fed by mouth too early.
In a study Maron and colleagues have identified a biomarker in saliva that predicts a baby is not yet ready to feed 95 percent of the time. The biomarker, a gene for the neuropeptide Y2 receptor, NPY2R, is a known regulator of feeding behaviour. In their study, the researchers demonstrated that levels of NPY2R in saliva decline as a newborn matures enough to feed orally.
‘There’s a really important need for a better understanding and a more accurate assessment of infants’ feeding skills, ” said Jill L. Maron, MD, MPH, a researcher at the Mother Infant Research Institute at Tufts Medical Center. ‘Nearly every baby born early is at risk for feeding associated morbidities, which often lead to prolonged hospitalisations, short and long term health complications, and significant parental anxiety. This is a way of monitoring the most vulnerable babies very non-invasively. We can help guide clinical care without ever hurting them.”
Currently, caregivers use a variety of subjective measurements, such as evaluating a baby’s sucking and swallowing skills, to determine when it’s safe to feed a baby by mouth. But these methods are imprecise and often lead to feeding a baby too early, which can cause the child to choke, accidentally inhale breast milk or formula into their lungs leading to pneumonia, or other problems. Babies who suffer these early feeding difficulties can also go on to develop long-term feeding problems and are at risk of developmental delays. Research indicates that more than 40 percent of children in feeding disorder clinics were premature babies.
The NPY2R gene has been studied extensively because it helps regulate appetite and plays a role in both obesity and eating disorders. But no one had examined its role in prompting premature babies to eat, because most researchers were not focusing on appetite’s role in newborn feeding problems. Tufts Medical Center