Enzyme Inhibition May Lead to New Melanoma Therapy, Say Researchers at Fox Chase with Support from Sbarro Institute

Newswise — Inhibition of the cellular enzyme thymine DNA glycosylase (TDG) may be an effective treatment for melanoma, according to research published in the journal Oncogene in January. The paper, “Thymine DNA glycosylase as a novel target for melanoma,” describes how inhibition of TDG, known for its role in cell repair and proliferation, may be used to trigger cell death of cancerous melanoma cells and halt tumor growth.  

“These findings suggest that TDG may provide critical functions specific to cancer cells that make it highly suitable as an anti-melanoma drug target,” said senior author Alfonso Bellacosa, MD, PhD, professor of cancer epigenetics at Fox Chase Cancer Center at Temple University. “By potentially disrupting both DNA repair and the epigenetic state, targeting TDG may represent a completely new approach to melanoma therapy.”

Researchers at the Sbarro Health Research Organization (SHRO) and the Sbarro Institute for Cancer Research, directed by Antonio Giordano, MD, PhD, also contributed to the study at Temple University. Scientists at SHRO assisted with statistical analysis of animal model data used in the study, among other things.  

“This is an important study that may lead to the identification of powerful TDG inhibitors for pre-clinical and clinical studies,” said Giordano. “A few pharmaceutical companies have already shown a lot of interest and enthusiasm towards this approach.”  

The research was conducted by lead authors Pietro Mancuso, PhD, and Rossella Tricarico, PhD, in Bellacosa’s lab at Fox Chase Cancer Center, with a team of international collaborators including scientists at the Curie Institute, France, and at the University of Siena, Italy, where Mancuso was recently awarded the prestigious title of Doctor Europæus.

“This study highlights the mission of SHRO to support junior investigators from Italy,” added Giordano. “This research was the PhD thesis of Pietro Mancuso, who I have had the privilege to co-mentor at the University of Siena, along with Prof. Bellacosa at Fox Chase, and Prof. Larue at the Curie Institute,” concluded Giordano.  

To read more about the study, visit https://www.foxchase.org/news/2019-01-23-Bellacosa-Inhibiting-Enzyme-May-Lead-to-Innovative-Melanoma-Therapy

About the Sbarro Health Research Organization

The Sbarro Health Research Organization (SHRO) is non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visit www.shro.org

Original NewsWise Post

Decoy Damaged DNA Discovers New Gene Repair Protein

Research identifies HNRNPD as a new safeguard of genome integrity

Alfano-Giordano-Pentimalli

Luigi Alfano (left), Antonio Giordano (center), Francesca Pentimalli (right)

Newswise — Researchers used a synthetic DNA structure to mimic an intermediate of homologous recombination, the most reliable cell cycle process to repair DNA correctly. This DNA structure was then used as bait to capture nuclear proteins in the hopes of identifying a new player in the cellular response to DNA damage. These proteins were isolated and subsequently identified through mass spectrometry, revealing that the Heterogeneous Nuclear Ribonucleoprotein D (HNRNPD) was indeed able to bind chromatin DNA, a prerequisite for a protein involved in DNA repair, and to re-localize specifically onto DNA damaged sites.

The study reporting on this newly discovered role for HNRNPD, previously known for its role in messenger RNA regulation, was recently published in Nucleic Acids Research, one of the most authoritative journals in the field, from the Oxford Academic Press, by the research team lead by Antonio Giordano, M.D., Ph.D., Director of the Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, and Professor of Pathology, University of Siena, Italy.

Because protecting the genome against DNA damage is crucial to prevent harmful mutations and cancer development, the authors utilized a ‘gene fishing’ approach using the synthetic DNA structure that was designed by Luigi Alfano, a postdoctoral fellow at the National Cancer Institute of Naples, Pascale Foundation-CROM in Mercogliano, working in the Cell Cycle & Cancer Lab coordinated by Francesca Pentimalli, a longtime collaborator of Prof. Giordano and Adjunct Professor at the Sbarro Institute. The captured proteins were analyzed under mass spectrometry by Luca Bini and Claudia Landi at the University of Siena. Alfano and colleagues focused on the RNA-binding protein HNRNPD, the loss of which induces cell senescence and premature aging in mice, two features associated with a defective DNA damage response.

Upon DNA damage, cells activate homologous recombination repair to cut the DNA near the break (a process known as DNA end resection), generating a single stranded DNA tail that is able to find the complementary homologous sequence within the sister chromatid, using it as a template for faithful repair. The authors found that silencing HNRNPD expression impaired the DNA end resection process, affecting the overall DNA damage response. Similarly, depleting HNRNPD through CRISPR/Cas9-mediated gene editing, impaired the cell response to DNA damage induced by the chemotherapy drug camptothecin, making cancer cells more susceptible to this drug and also to olaparib, a drug that targets specifically the DNA repair process used against some types of breast and ovarian cancer.

“The inhibition of HNRNPD, through chemical compounds, can be used as a new strategy for cancer treatment in a combination therapy with the PARP1 inhibitor (Olaparib),” Giordano says. “Based on the concept of synthetic lethality, this potential clinical application is analogous to the situation described for the BRCA cancers.”

Delving deeper into the underlying molecular mechanisms, the authors found that HNRNPD interacts with SAF-A, another RNA-binding protein previously found correlated to the DNA damage response. The authors showed that HNRNPD silencing impaired the loading of SAF-A onto chromatin upon DNA damage. Moreover, HNRNPD silencing caused an accumulation, onto damaged DNA, of DNA:RNA hybrids (also called R-loops) whose proper removal is required to preserve genome integrity. Indeed, expressing RNase H, an enzyme that digests the RNA within the hybrids, or inhibiting RNA formation through alpha-amanitin, could rescue the phenotype of HNRNPD knockout cells, reinstating an effective DNA damage response.

“Overall, our data strengthens the role of RNA-binding proteins in the DNA repair mechanism and identify HNRNPD as a new key player in DNA repair,”  says lead author Alfano. “They also provide new clues on the still poorly defined function of R-loop role in DNA damage repair.”

“Targeting DNA repair pathways proved to be a powerful approach for cancer therapy, as epitomized by the clinical use of olaparib for various tumors,” say co-authors Pentimalli and Giordano. “The identification of HNRNPD as an homologous recombination protein could be useful to design new synthetic lethal approaches and also inform genome editing strategies that use endogenous cell repair pathways to modify DNA sequences.”

The discovery caught the attention of Italian Deputy Prime Minister and Minister of the Interior, Matteo Salvini, commenting on Facebook, “Exceptional discovery by the team of Italian researchers led by Professor Antonio Giordano. You are the symbol of the best minds of our country in the world.”

Also sending congratulations via social media, Minister of Education, University and Research Marco Bussetti wrote on Twitter, “Congratulations to the team led by Professor Antonio Giordano, who I recently appointed to the Governing Committee of the newly established Southern University in Naples.”

About the Sbarro Health Research Organization

The Sbarro Health Research Organization (SHRO) is non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visit www.shro.org

SEE ORIGINAL STUDY

Original NewsWise Release           PubMed Abstract

Potential to Better Treat Mesothelioma Revealed by Precision Medicine Research

Newswise — Researchers have successfully identified two genetic markers for potentially effective treatment of Mesothelioma, an orphan disease most commonly associated with asbestos exposure, and for which few treatments exist. Two recent studies co-authored by researchers from the Sbarro Health Research Organization (SHRO) at Temple University describe the findings of the relationship between p53, BAP1, and Mesothelioma, and the treatment pathways they may reveal.

Published in October, 2018, the paper “p53 Modeling as a Route to Mesothelioma Patients Stratification and Novel Therapeutic Identification,” appeared in the Journal of Translational Medicine, and January, “BAP1 Status Determines the Sensitivity of Malignant Mesothelioma Cells to Gemcitabine Treatment,” was published in the International Journal of Molecular Sciences.

The studies represent the potential of Personalised Medicine, an innovative approach to clinical medicine meant to customize treatment for an individual patient. In oncology, this most often refers to gene expression-based therapeutic decisions aimed at the identification of “driving genes” responsible for carcinogenesis and tumour progression.

Unfortunately, in the clinical setting, the simple idea of finding one mutated gene causing cancer is rare, and despite some encouraging results, only 4-7% of patients really benefit from treatment based on the tumour genetic profile. Complications such as tumor heterogeneity may determine the poor performance of genetic profiling to reveal effective treatments: different genetic profiles co-exist within the same tumour, epigenetic abnormalities not directly affecting DNA are indirectly responsible for genome expression, and the tumor microenvironment can also exert a pivotal role in gene expression.

In spite of these challenges, researchers have identified ways in which p53, a well-known tumor suppressor gene, may be used to stratify patients for the most favorable treatment protocol. Often referred to as the “guardian of the genome,” p53 functions to limit the proliferation of deformed cells and cells with imperfectly replicated DNA.

The prevalence of p53 inactivation in Mesothelioma prompted researchers to carry out a combined biological and bioinformatic study to explore how data about p53 can be used in translational research. The comparison of model simulations with experimental data resulted in a successful prediction from 52-85%, depending on the drug, algorithm, or sample used for validation.

“This study offers a good approach to test the real impact of genetic studies in precision medicine,” says Luciano Mutti, M.D., Adjunct Professor of Translational Oncology, SHRO, and co-author of the study. “We included in silico and in vitro analysis with cellular validation of the p53 model,” Mutti says, “and we believe it will have a potential for use in Mesothelioma treatment by identifying patient sub-populations that are likely to respond to particular drugs.”

The model may also aid in the identification chemotherapy resistance, the authors conclude, which is common in Mesothelioma.

Mutti collaborated on the study with Marija Krstic-Demonacos, Ph.D., Chair of Molecular Medicine at the University of Salford in Manchester, UK. The authors would like to thank the non-profit association Gruppo Italiano Mesotelioma (GIMe) for their support.

BRCA Associated 1 gene (BAP1) is another tumour suppressor gene recently shown to be inactivated in up to 60% patients with Mesothelioma. Therefore, researchers designed a study to exploit the strictly defined role of BAP1 to repair imperfections in cellular DNA, and tested for indications that BAP1 status could drive chemosensitivity and help identify the right drugs for Mesothelioma treatment. For example, testing the effect of the common Mesothelioma chemotherapy agent, Gemcitibine, on tumor cells with either normal or inactivated BAP1, researchers found that the cells with inactivated BAP1 were resistant to the effects of Gemcitabine, rendering the chemotherapy less effective.

“The results have been unusually clear-cut,” says Antonio Giordano, M.D., Ph.D., Director of SHRO, and co-author of the paper with Mutti, “and further study of BAP1 and p53 can help us identify the best treatment for Mesothelioma in clinical oncology.

“These studies serve as a sign that Personalised Medicine can become an important weapon against Mesothelioma,” Giordano concludes.

NewsWise Release

Metastatic Breast Cancer Survival Improves with New CDK-Inhibitor Plus Endocrine Therapy

Patients with HER2 negative, hormonal receptor positive metastatic breast cancer experienced improved survival when treated with a combination of endocrine therapy and the new CDK-inhibitor, palbociclib. Results from a recent study, published in the Journal of Cell Physiology, suggest that palbociclib, in combination with either letrozole, an aromatase inhibitor, or fulvestrant, a selective estrogen receptor down-regulator, improves the so-called progression free survival in women with HR+HER2-metatastatic breast cancer by as much as 10 months when compared to endocrine therapy alone.

The study, “Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor positive, advanced breast cancer. A real-world experience,” was conducted by a multidisciplinary Italian-American team with a long and productive history of collaboration with Prof. Antonio Giordano, M.D., Ph. D., Director of the Sbarro Institute for Cancer Research, and the Sbarro Health Research Organization, Temple University.

“Palbociclib is the first of a new class of drugs that work by inhibiting two crucial cell division proteins called CDK4 and CDK6,” explains Dr. Patrizia Vici, medical oncologist at the Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

In the study, researchers focused on the use of Palbociclib in clinical practice, in order to collect data on the new drug’s efficacy and toxicity in support of evidence established from clinical trials.

“In this study, we sought confirmative evidence from the real world setting concerning the use of palbociclib in HR+HER2-metatastatic breast cancer,” says Dr. Maddalena Barba, researcher at the Regina Elena National Cancer Institute of Rome. “Clinical trial results do not always tell us everything we need to know for the clinical setting, because metastatic breast cancer patients are often heavily pre-treated, and may present related comorbidities.”

“When globally considered, these characteristics may be more often associated with less favorable outcomes,” says Barba.

“Overall, the evidence emerged from this cohort of Italian HR+HER2-metatastatic breast cancer patients, the largest ever treated with palbociclib in clinical practice so far, confirming the efficacy and toxicity data from the clinical trials,” explains Giordano, senior scientist and scientific advisor for the entire project.

“In addition, some intriguing findings have emerged from subgroup analyses showing less favorable outcomes in women pre-treated with the chemotherapy agent everolimus,” says Giordano. “This is a first time finding, which suggests the need for confirmation and further investigation of the underlying mechanisms in a future study.”

Original Newswise Post              Pubmed Abstract           Journal of Cellular Physiology

New MicroRNA Target May Inhibit Mesothelioma and Unveils Method to Identify Potential Treatments

Newswise — Inhibition of miR-24-3p reduced growth of cancer cells and was found to regulate proteins as a potential treatment target for Mesothelioma (MPM). The new potential target, and the method researchers have used to identify it, is an important step in addressing this challenging disease.

MPM is a lethal cancer with increasing worldwide incidence and resistance to treatment. Despite this dreadful scenario, preclinical research has struggled to identify potential treatments.

“The ‘one more indication’ strategy is not the right approach for Mesothelioma,” say Professors Antonio Giordano and Luciano Mutti from the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University and the Italian Group for Mesothelioma (GIMe), referencing attempts to discover existing drug combinations that may yield an effective treatment. “Drugs with some activities in other tumours have utterly failed in MPM,” they say, “providing evidence we have to rethink what we have been doing so far and start over from a solid biological background.”

Researchers published their findings this month in Cancer Research, in the study titled A polysome-based microRNA screen identifies miR-24-3p as a novel pro-migratory miRNA in mesothelioma.

MicroRNAs (miRNAs) are small, non-coding RNA molecules, which target genes and regulate gene expression and function. Abnormal expression of miRNA plays a relevant role in cancer biology and they are therefore a potential target for the development of innovative cures.

“We have identified a novel approach for identifying relevant miRNA in cancer biology,” Professor Biffo of the National Institute of Molecular Genetics in Milan explains. “By examining the polyribosomes where translation occurs, this ‘focused’ search has allowed us to identify that miR-24-3p (a particular miRna) expression is relevant to cancer progression and metastasis.”

Biffo, in collaboration with the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University, University of Siena, Columbus University, Leicester University, and supported by GIMe, has conducted a research program that has made significant steps forward in the fight against MPM.

“The first take home message for us is, ‘hunt where the ducks are,’” the authors say. “High levels of miR24-3p are detected only where they exert their biological effects (the polyribosomes), and increase tumour cell migration and Mesotheliomia progression via an enzyme family called Rho Kinase. These enzymes can be inhibited by specific drugs. Now it is time to translate our research into a pharmaceutical solution to develop this potential therapy,” the authors conclude.

Original Newswise Release

Olive Oil Production Threatened by New Deadly Plant Pathogen Recently Introduced to Europe

One of the iconic ingredients of the Mediterranean diet, which often has been associated with beneficial effects in the prevention of cancer as well as several other disorders, is extra-virgin olive oil. For thousands of years, olive trees were planted on Mediterranean coasts, initially by ancient Greek colonists, followed by several other civilizations and cultures, one generation after the other. This enduring agricultural practice led to the formation of the so-called “olive tree forest,” a monument to the Mediterranean environmental and cultural heritage containing millennial trees, found particularly in Southern Italy, in the Apulia region. Olive oil production from this region propelled and sustained olive oil consumption; however, this production is now endangered by a new, deadly plant pathogen, which arrived in Europe a few years ago.

“The olive orchards in Southern Italy are facing an ominous threat,” says Temple’s adjunct professor Enrico Bucci, PhD, Director of the Cancer Systems Biology & eHealth Programs of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University. Earlier in 2017, under appointment by the revered Accademia dei Lincei (one of the oldest and most prestigious scientific academies in the world), Bucci applied his skills in the fields of data mining and analytics, which he usually deploys in the field of Systems Biology, to extract and process data on thousands of Apulian olive trees, which led him to confirm the correlation between the bacterium and the disease. After that, he revised hundreds of scientific papers, detailing the ecology, the pathogenic potential, the molecular biology and all other relevant aspects of the interactions between the bacterium, its vectors and the host plants, publishing a new, state-of-art review, which got the cover of the Elsevier journal “Biochemical and Biophysical Research Communications.”

Fig. 3 from original research article: Some molecular details of the X. fastidiosa life cycle. rpfF, fimA, hxfA, hxfB, chiA, phoP/phoQ, PD1671 are all bacterial genes differentially expressed at various stages. DSF stands for “diffusible signalling factor”. See full text article for further details.

“The culprit of the epidemic, which is killing millennial olive trees and devastating the Apulian agricultural landscape, is the bacterium Xylella fastidiosa. Its pauca subspecies, which is colonizing Italy, is able to rapidly kill the olive trees, at odds with all the subspecies established in California, which mainly threaten vineyards and almonds,” says Bucci

There is no established cure for the infection; however, containment policies applied in California to prevent further spreading of the epidemic of Xylella in vineyards seem to work, suggesting that similar policies should also be enforced in Italy – after taking into accounts the obvious differences between olives and grapevines.

“As I learned by studying the available scientific literature, researchers from all over the world are working hard to find solutions, and there are indeed some promising approaches under study, aiming e.g. at blocking the infection or finding resistant olive cultivars – however, scientists need more time to accumulate stronger evidence. That’s why containing the infection in Southern Italy by all available means is crucial,” says Bucci, in line with the prevalent opinion in the scientific community.

“I hope that my article, by providing a revision of all the best available scientific evidence, will inspire politicians and local authorities to follow the scientific consensus, instead of the opinions of non-expert influencers or isolated, controversial hypotheses which lack solid scientific ground,” concludes Bucci.

Original Elsevier News Posting                      ScienceDirect Article        PubMed Abstract

Understanding Cancer Heterogeneity Could Further Reduce Chemo Use, Says Expert

giordano

Credit: Antonio Giordano

“Understanding cancer heterogeneity could further reduce chemo use,” says cancer research expert Antonio Giordano, MD, PhD, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University. “Further study of cases that can successfully be treated with hormone- and immunotherapy, and how to identify them, will unlock this potential.”

Giordano refers to the TAILORx study, published by The New England Journal of Medicine this week, which describes treatment outcomes in breast cancer comparing cases receiving both endocrine therapy and chemotherapy, versus those receiving only endocrine therapy. Under certain conditions, including the early-stage development of tumor size, and the tumor not having spread to any peripheral lymph nodes, endocrine therapy alone resulted in nearly identical rates of survival and recurrence as endocrine- and chemotherapy combined.

“It is important to underscore that this specific study refers to patients with small tumors and no lymph node infiltrations,” says Giordano. “Women with early-stage breast cancer may be able to avoid chemotherapy, which is exciting, because there are pros and cons associated with it. The treatments have unavoidable effects on healthy cells as well as cancer cells”

“The goal of precision medicine moving forward,” Giordano says, “is to identify more sophisticated approaches to this problem of cancer heterogeneity. Every type of cancer, at the molecular level, can have a cell environment that changes and evolves through the course of the disease. Or from patient to patient.”

“Only by understanding specific targets or molecules responsible for key cellular processes will we be able to understand, with precision, new options of therapeutic target that could replace chemotherapy altogether,” Giordano says.

“The precision target is not yet precise enough,” Giordano says. “But the option to spare many patients the potential harmful effects of chemo is a sign we are moving in the right direction.”

Antonio Giordano, MD, PhD, Director of the Sbarro Institute for Cancer Research and Molecular Medicine and Center of Biotechnology, College of Science and Technology, Temple University and Professor of Pathology at the University of Siena, Italy.

In 1993, Antonio Giordano, M.D., Ph.D., founded the Sbarro Institute with a generous donation from Mario Sbarro, the Founder of the Sbarro restaurant chain, following Dr. Giordano’s discovery of the tumor suppressor gene pRb2.

About Sbarro Health Research Organization

Sbarro Health Research Organization conducts research in cancer, diabetes, and cardiovascular disease. Based in Philadelphia, Pennsylvania on the campus of Temple University, our programs train young scientists from around the globe.

Original Newswise Posting                         PubMed Abstract

In Debate of Scheduled Versus Spontaneous Exercise, Which Motivates You More?

Older adults seem to be more motivated by scheduled workouts, including the role of a fitness coach or a significant person involved in their exercise goals, when compared to those getting exercise only through spontaneous physical activity.

Researchers tested a mathematical and psychological model on two different samples of older adults: the first doing spontaneous physical activity, the second engaged in an exercise class. This theoretical model tried to understand what is really important to  encourage and maintain the intention to do physical activity.

The results suggest a psychological construct called autonomous motivation, in which subjects experience a sensation of value and self-worth tied to the activities. Participants that felt a sense of autonomous motivation during an exercise program were more successful at beginning and maintaining a more healthy, active lifestyle, despite possible interruptions caused by physical discomfort or scheduling challenges.

The researchers published their findings in the journal Gerotarget, a section of Oncotarget. Psychologists from the faculty of Medicine and Psychology of Sapienza, University of Rome, led by Prof. Fabio Lucidi, partnered with the American research team of Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Temple University, and University of Siena, Italy to produce the study.

The aging of the world’s population is a steadily growing phenomenon, with the older adult population expected to triple by the year 2050. Therefore, taking care of older adults is considered an important social goal. Physical activity and exercise are two behaviors that may prevent diseases, cognitive decline, and loneliness among older adults. Despite the well-established positive effects of physical activity and exercise, data shows that few older adults are engaged in these behaviors.

“This study,” explains first author Federica Galli, “shows clearly that the sensation autonomous motivation leads older adults to be successful implementing these healthy behaviors.”

“Thanks to the new therapies produced by oncological research, a lot of patients with oncological diseases will be able to live normal life expectancies,” Giordano adds. “For this reason, it’s very important to study the mechanisms to motivate people to exercise, given the therapeutic role of fitness and physical activity in oncological diseases.”

The study provides guidelines for professionals that work in preventive medicine in the older population, so that they can support the perception of autonomy that could increase their motivation to start and maintain physical activity and exercise.

“The NCI of Naples has always been sensitive to this issue,” says Scientific Director of the National Cancer Institute of Naples, Gerardo Botti. “In the future, I am already  considering the implementation of new studies that would consider the application of this model to target populations more at risk such as our oncology patients,” Botti says.

 

Original Newswise Posting

Molecular Inhibitors Can Boost Natural Tumor Suppression to Fight Lung Cancer and Mesothelioma

Inhibition of the oncogenic kinase AKT, a key protein governing the cell cycle, was found to arrest cancer cell proliferation and triggered their programmed death by apoptosis. The study, published today in Oncogene, represents significant progress in the clinical translation of previous basic scientific discoveries.

“Understanding the molecular features that govern cancer cell behavior is the basis for the design of the so-called ‘targeted therapies’ which constitute modern precision medicine,” says senior author on the paper Antonio Giordano, M.D., Ph.D., director of the Sbarro Health Research Organization at Temple University.

The study revealed an important role of the cell cycle protein RBL2/p130 in triggering cancer cell death upon inhibition of AKT, which is hyperactive in many cancer types. The researchers found that RBL2/p130, a known tumor suppressor factor isolated by Giordano himself in the 1990s, is a direct target of the AKT kinase. The pharmacological inhibition of AKT led to RBL2/p130 protein stabilization, in both lung cancer and mesothelioma cell lines, and favored its localization to the cell nucleus, where it can function restricting cell proliferation, a well defined function of RBL2/p130 and of the other retinoblastoma proteins belonging to its family.

Further confirming the crucial role of RBL2/p130 in determining the cell response to AKT inhibition, the authors showed that AKT pharmacological inactivation no longer caused cancer cell death when RBL2/p130 expression was shut down through a specific silencing. Conversely, RBL2/p130 re-expression in previously silenced cells restored cell ability to undergo programmed death following AKT kinase inhibition.

AKT is a recognized target for antitumor strategies owing to its high levels in multiple tumors, and the manner in which it stimulates oncogenic pathways. Therefore, many companies have developed AKT inhibitors which are currently being tested in clinical trials. As RBL2/p130 is crucial in determining cancer cell fate upon AKT kinase inhibition, RBL2/p130 could serve as a predictive factor of the response to such a therapeutic strategy. The authors also assessed whether AKT pharmacological targeting could function in synergy with other approaches aimed at re-activating RBL2/p130 tumor suppressor function. The results confirmed that AKT inhibition functioned in synergy with cyclin dependent kinase (CDK) inhibitors in both preclinical models of lung cancer and mesothelioma. CDKs are the main kinases known to phosphorylate RBL2/p130, restraining its cell cycle-related tumor suppressor function.

“The combined use of these agents, AKT and CDK inhibitors, which converge on RBL2/p130 reactivation and are currently being investigated in the clinical setting, could help to reduce their dosage and consequently their associated toxicities,” says lead author Francesca Pentimalli of the National Cancer Institute of Naples Pascale Foundation, CROM.

“Our findings were conducted in lung cancer and mesothelioma, the latter being a tumor caused by exposure to asbestos, against which no curative approach exists,” says Giordano.  “However, given that RBL2/p130 is rarely mutated in cancer, but rather is mostly inactive by the action of AKT and CDK kinases, it is likely that this therapeutic strategy could work in a wider variety of tumors.”

The study, which was funded by the Italian Association for Cancer Research, the Sbarro Health Research Organization and the Mesothelioma Applied Research Foundation, stemmed from a productive collaboration between the University of Siena and the National Cancer Institute of Naples Pascale Foundation, CROM.

Original Newswise Release         PubMed Abstract

Virtual Reality: An Escape From Painful and Stressful Medical Treatments

image-3-9-18-1Virtual reality (VR) technology allows users to immerse themselves in a three-dimensional computer-generated world, and despite being originally developed as an entertainment tool, over the last two decades VR has found a variety of applications in health care. Among these applications, which include treatment of phobias and anxiety disorders; cognitive and physical rehabilitation; pain management; treatment of eating disorders and obesity; surgical training and aid in surgical planning and performance, VR has shown promise in several clinical trials assessing its possible utility as a distraction tool to alleviate pain and distress during medical procedures.

A review article, recently published in The Clinical Journal of Pain, provides a comprehensive overview of the clinical studies using VR during several painful and stressful medical procedures, including burn injury treatments, chemotherapy, surgery, dental treatment, and other diagnostic and therapeutic procedures.

image-3-9-18-2“VR has proven to be very effective in relieving pain, even in patients subjected to extremely painful procedures, who do not receive proper relief with pharmacological treatments alone,” says Antonio Giordano, M.D., Ph.D., of the Sbarro Health Research Organization at Temple University, and University of Siena, Italy, and corresponding author of the article. “Moreover, VR decreases cancer-related symptoms in different settings, including during chemotherapy. This is remarkable, considering that identifying interventions able to enhance treatment tolerance is crucial to improve both patients’ quality of life and compliance to therapies, which, in turn, can increase their chances of recovery.”

“Despite these promising results, we wanted to point out that further studies involving a greater number of patients are needed both to generalize the observations and to establish predictive factors to select patients who are more likely to benefit from VR,”  says study author Paola Indovina of the Institute for High Performance Computing and Networking, ICAR-CNR, Naples. “Moreover, more efforts should be put into the evaluation of changes in physiological factors, which might provide objective confirmations of the patients’ self-report measures. Also, more studies should explore VR efficacy after several repeated sessions to assess possible long-term benefits of the VR intervention.”

“It is also important to note that most studies so far used relatively low-tech VR systems compared to the state-of-the-art systems available on the market today, which are more immersive, more user-friendly, more portable, and much less expensive,” adds coauthor Giuseppe De Pietro, Director of the Institute for High Performance Computing and Networking, ICAR-CNR, Naples, Italy. “Therefore, VR has the potential both to become more effective and to find a more widespread use.”

Journal Reference:

Indovina P, Barone D, Gallo L, Chirico A, De Pietro G, Giordano A. Virtual reality as a distraction intervention to relieve pain and distress during medical procedures: a comprehensive literature review. Clin J Pain, 2018.

Original Newswise Release