Prostate cancer is a leading cause of cancer-related death in men in the United States. The development and progression of the disease depend on the actions of male sex hormones called androgens, which bind to the androgen receptor to activate signalling pathways involved in cell growth and survival. Therefore, there is a strong need to identify novel drug targets to alter androgen-receptor signalling and treat this often deadly disease.

Sanford-Burnham researchers have discovered that a protein called NWD1 affects androgen-receptor signalling to control the growth of prostate cancer cells. ‘A very limited number of proteins have been shown to specifically and exclusively affect androgen-receptor signalling, so our findings represent a major advance in the field,’ said lead study author Ricardo Correa, Ph.D., staff scientist at Sanford-Burnham. ‘NWD1 could represent a new biomarker for predicting patient prognosis as well as a therapeutic target for a novel class of prostate cancer drugs.’
High levels of androgens are critical for the growth of prostate cancer cells in early disease stages, and one major type of therapy focuses on inhibiting androgens. But over time, prostate cancer cells often respond to hormone therapy by expressing high levels of the androgen receptor, allowing these castration-resistant cells to grow even when androgen levels are low. Castration-resistant prostate cancer is an advanced form of the disease associated with poor survival rates. However, both early and advanced stages of prostate cancer depend on androgen-receptor signalling, highlighting the value of targeting this pathway for treating a broad range of patients.

While searching for novel modulators of androgen-receptor signalling, Correa and his team became interested in the nucleotide-binding domain and leucine-rich repeat (NLR) family of proteins. These proteins are involved in recognising pathogens and cell-injury signals and activating immune-defence pathways, but they have also been implicated in a variety of cancers. In particular, the researchers were intrigued by an NLR-related protein called NWD1, which was previously identified in zebrafish but had not yet been analyzed in humans.

In the new study, Correa and his colleagues found that the expression of the human NWD1 gene was very high in prostate tissue and other parts of the male reproductive system. Moreover, NWD1 expression was higher than normal in human prostate cancer cell lines, especially in castration-resistant and highly metastatic cell lines. Similarly, NWD1 protein levels were higher than normal in advanced-stage and castration-resistant prostate tumour tissue from patients.

Taken together, the findings suggest that NWD1 could be a potential prostate cancer biomarker because high levels of the protein are associated with malignant progression. ‘We believe that NWD1 could represent a promising biomarker because changes in NWD1 expression happen at stages where the levels of prostate-specific antigen (PSA), a protein that is widely used to screen men for prostate cancer, are not very accurate in the clinic,’ Correa said.
In addition to its potential use for predicting patient prognosis, NWD1 could represent a promising therapeutic target. When the researchers inhibited the activity of the NWD1 gene in prostate cancer cells, they noticed a drop in androgen-receptor levels as well as a decrease in cell growth and survival. On the other hand, an increase in NWD1 activity led to a rise in androgen-receptor levels in these cells.

Their experiments also shed light on the molecular mechanisms by which NWD1 affects androgen-receptor signalling. NWD1 silencing fed the activity of cancer-related genes such as PDEF (prostate-derived epithelial factor), which is known to bind to androgen receptors and belongs to a family of proteins that regulate cell growth and survival. Moreover, a protein called sex-determining region Y (SRY), which controls sex determination during fetal development, affected the activity of the NWD1 gene. Thus, the findings not only reveal a novel molecular pathway involved in prostate cancer, but also suggest that drugs targeting NWD1 could eventually become a new class of treatments for the disease. Sanford-Burnham

UCLA researchers led by Dr. Brigitte Gomperts have discovered the inner workings of the process thought to be the first stage in the development of lung cancer. Their study explains how factors that regulate the growth of adult stem cells that repair tissue in the lungs can lead to the formation of precancerous lesions.

Findings from the three-year study could eventually lead to new personalized treatments for lung cancer, which is responsible for an estimated 29 percent of U.S. cancer deaths, making it the deadliest form of the disease.

The study collaborated with Manash Paul and Bharti Bisht, postdoctoral scholars and co-lead authors of the study.

Adult stem cells in lung airways are present specifically to repair the airways after injury or disease caused by smoking, pollution, viruses or other factors. Gomperts and her team found that this reparative process is tightly regulated by molecules called reactive oxygen species, or ROS.

Recent research has shown that low levels of ROS are important for signalling the stem cells to perform important functions — such as repairing tissue damage — while high levels of ROS can cause stem cells to die. But the level of ROS needed for repair to be initiated has remained a subject of debate among researchers.

The UCLA study found that the dynamic flux of ROS from low to moderate levels in the airway stem cells is what drives the repair process, and that the increase in ROS levels in the repairing cell is quickly reduced to low levels to prevent excessive cell proliferation.

Gomperts’ lab found that disrupting this normal regulation of ROS back to low levels is equivalent to pulling the brakes off of the stem cells: They will continue to make too many of themselves, which causes the cells not to mature and instead become precancerous lesions. Subsequent progressive genetic changes to the cells in these lesions over time can eventually allow cancerous tumours to form.

‘Low ROS is what keeps stem cells primed so that your body is poised and ready to respond to injury and repair,’ said Gomperts, who also is an associate professor in the department of paediatrics at UCLA. ‘Loss of this ROS regulation leads to precancerous lesions. Now, with this precancerous model in place, we can begin looking for what we call ‘driver mutations,’ or those specific changes that take the precancerous lesions to full-blown cancer.’

Gomperts said that because many different factors — including cigarette smoke, smog and inflammation — could potentially trigger an increase in ROS in the airway stem cells, researchers might eventually be able to customize treatments based on the cause. ‘There are likely multiple ways for a person to get to a precancerous lesion, so the process could be different among different groups of people. Imagine a personalized way to identify what pathways have gone wrong in a patient, so that we could target a therapy to that individual.’

The research’s ultimate goal is to develop a targeted strategy to prevent pre-malignant lesions from forming by targeting the biology of these lesions and University of California – Los Angeles

Researchers at UT Southwestern Medical Center and the Gill Center for Cancer and Blood Disorders at Children’s Medical Center, Dallas, have made significant progress in defining new genetic causes of Wilms tumor, a type of kidney cancer found only in children.

Wilms tumour is the most common childhood genitourinary tract cancer and the third most common solid tumour of childhood.

“While most children with Wilms tumour are thankfully cured, those with more aggressive tumours do poorly, and we are increasingly concerned about the long-term adverse side effects of chemotherapy in Wilms tumour patients. We wanted to know – what are the genetic causes of Wilms tumour in children and what are the opportunities for targeted therapies? To answer these questions, you have to identify genes that are mutated in the cancer,” said Dr. James Amatruda, Associate Professor of Pediatrics, Molecular Biology, and Internal Medicine at UT Southwestern and senior author for the study.

Collaborating with Dr. Amatruda on the study were UT Southwestern faculty members Dr. Dinesh Rakheja, Associate Professor of Pathology and Pediatrics; Dr. Kenneth S. Chen, Assistant Instructor in Pediatrics; and Dr. Joshua T. Mendell, Professor of Molecular Biology. Dr. Jonathan Wickiser, Associate Professor in Pediatrics, and Dr. James Malter, Chair of Pathology, are also co-authors.

Previous research has identified one or two mutant genes in Wilms tumours, but only about one-third of Wilms tumors had these mutations.

“We wanted to know what genes were mutated in the other two-thirds. To accomplish this goal, we sequenced the DNA of 44 tumours and identified several new mutated genes,” said Dr. Amatruda, who holds the Nearburg Family Professorship in Pediatric Oncology Research and is an Attending Physician in the Pauline Allen Gill Center for Cancer and Blood Disorders at Children’s Medical Center. “The new genes had not been identified before. The most common, and in some ways the most biologically interesting, mutations were found in genes called DROSHA and DICER1. We found that these mutations affected the cell’s production of microRNAs, which are tiny RNA molecules that play big roles in controlling the growth of cells, and the primary effect was on a family of microRNAs called let-7.”

“Let-7 is an important microRNA that slows cell growth and in Wilms tumours in which DROSHA or DICER1 were mutated, let-7 RNA is missing, which causes the cells to grow abnormally fast,” Dr. Amatruda said.

These findings have implications for future treatment of Wilms tumour and several other childhood cancers, including neuroblastoma, germ cell tumour, and rhabdomyosarcoma.

“What’s exciting about these results is that we can begin to understand what drives the growth of different types of Wilms tumours. This is a critical first step in trying to treat the cancer based on its true molecular defect, rather than just what a tumour looks like under a microscope,” Dr. Amatruda said. “Most importantly, we begin to think in concrete terms about a therapy, which is an exciting translational goal of our work in the next few years. UT Southwestern Medical Center

Scientists have identified four biomarkers that may help resolve the difficult differential diagnosis between malignant pleural mesothelioma (MPM) and non-cancerous pleural tissue with reactive mesothelial proliferations (RMPs). This is a frequent differential diagnostic problem in pleural biopsy samples taken from patients with clinical suspicion of MPM. The ability to make more accurate diagnoses earlier may facilitate improved patient outcomes.
‘Our goal was to identify microRNAs (miRNAs) that can aid in the differential diagnosis of MPM from RMPs,’ says lead investigator Eric Santoni-Rugiu, MD, PhD, of the Laboratory of Molecular Pathology at the Department of Pathology of Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. miRNAs, which are small, non-coding RNA strands composed of approximately 22 nucleotides, have been shown to be potential diagnostic, prognostic, and predictive markers in other cancers.
After screening 742 miRNAs, the investigators identified miR-126, miR-143, miR-145, and miR-652 as the best candidates to diagnose MPM. Using results from these four miRNAs, tissue samples from patients with known outcomes could be classified as MPM or non-cancerous with an accuracy of 0.94, sensitivity of 0.95, and specificity of 0.93. Further, an association between miRNA levels and patient survival could be made.
‘The International Mesothelioma Interest Group (IMIG) recommends that a diagnostic marker of MPM have sensitivity/specificity of >0.80, and these criteria are fulfilled by our miRNA classifier,’ comments Dr. Santoni-Rugiu. The authors suggest that diagnostic accuracy can be further improved by adding immunohistochemical testing of miRNA targets in biopsy tissue to their miRNA assay. This combined assay could enable analysis of samples with low tumour cell count.
MPM, which is linked to long-term asbestos exposure, is an aggressive cancer originating from the mesothelial cells that line the membrane surrounding each lung, known as the pleura. Distinguishing MPM from non-cancerous abnormalities, such as reactive mesothelial hyperplasia or fibrous pleurisy (organising pleuritis), can be challenging as there are no generally accepted diagnostic biomarkers for differentiating these two conditions. As a result, patients often present with the disease when they are already at an advanced stage, and less than 20% of patients can be successfully treated surgically.
The current study, however, suggests that miRNAs may provide new opportunities for improving the accuracy of the differential diagnosis between MPM and noncancerous pleural conditions. If further validated, the combination of ISH for miRNAs with immunohistocemical testing of miRNA targets may therefore have the potential to aid in the diagnosis, and thus outcome, of MPM. EurekAlert