Oncolytic Viruses Against Mesothelioma: A Possible Weapon to Shrink Cancer and Boost the Antitumoral Immune Response

Mesothelioma is a deadly cancer mainly caused by exposure to asbestos or other toxic mineral fibers. Currently, there is no effective cure against this disease and life expectancy of patients with mesothelioma remains very low. Virotherapy, which is based on the use of viruses to fight cancer cells, has long been investigated as a possible antitumoral strategy. Oncolytic viruses, in particular, have the ability to lyse tumor cells and spread the infection locally. The recent approval by the Food & Drug Administration of an oncolytic virus for the treatment of melanoma, in 2015, has sparked a renewed interest in the field. Indeed, many pre-clinical and clinical studies are evaluating viral-based strategies against mesothelioma. Mesothelioma is particularly amenable to virotherapy because the pleural cavity provides an easy route to direct intratumoral injection eluding viral inactivation in the bloodstream and limiting off-target infection.

A new collaborative study from researchers of the National Cancer Institute of Naples, ‘Pascale Foundation’, Italy; the University of Naples ‘Federico II’; the University of Siena; and the Sbarro Institute for Cancer Research and Molecular Medicine in Philadelphia, PA, USA, explored the possible use of dl922-945, an adenovirus engineered to infect and replicate selectively in cancer cells, against mesothelioma. Adenovirus, a non-enveloped virus with a linear DNA genome, is among the oncolytic viruses most studied for therapeutic approaches. Adenovirus causes the common cold in humans or other diseases that are self-limited in immunocompetent hosts. It has a stable genome that does not mess up with the host genome and is able to self-replicate in the infected cells achieving a local high titer.

In this new study, published in Frontiers in Oncology, an open access peer-reviewed scientific journal, the authors showed that dl922-945 is able to infect and self-amplify within human mesothelioma cells, subverting their cell cycle features and inducing cancer cell death, an effect that is similarly triggered also in other cancer cell lines, such as those of the aggressive thyroid anaplastic carcinomas. The molecular mechanisms underlying dl922-945-induced cell demise, however, are still only partially characterized. In this study the authors showed that dl922-945 infection induces the exposure of calreticulin (an endoplasmic reticulum chaperone) on the surface of dying cells and the release of ATP and HMGB1, three hallmarks of the so called ‘immunogenic cell death’. In fact, the release of these molecules, along with tumor antigens from lysed cells, is crucial to activate a robust anti-tumoral immune response, so that dl922-945 has the potential to act as an in situ cancer vaccine against mesothelioma.

The authors also showed that dl922-947 infection reduces the production of two pro-angiogenic factors that contribute to tumor development, interleukin 8 and the vascular endothelial growth factor A, thereby further shaping the tumor microenvironment towards an antitumoral background.

“Virotherapy through dl922-947 synergized with the chemotherapy drug cisplatin in mesothelioma cell lines, suggesting that this approach could function along with the mainstay of treatment in the clinical setting,” says Carmelina A. Iannuzzi of the Pascale Foundation, who carried out this work as a PhD student at the University of Siena.

“dl922-947 treatment proved effective also in vivo, inhibiting the growth of mesothelioma xenografts, leading to complete tumor shrinkage in some mice and reducing the formation of intratumoral microvessels,” states Sarah Di Somma, co-first author of the study from the University of Naples.

“The ability of oncolytic viruses to reverse the tumor-induced immune tolerance through such modifications of the tumoral microenvironment is a major goal of current cancer therapies and yet another advantage of this class of antitumoral agents,” says Giuseppe Portella, virologist at the University of Naples who has characterized dl922-947 effects also in other tumor types.

“The next step will consist in assessing the potential of virotherapy in combination with the recently developed immune targeted therapies and translate these approaches to the clinical practice upon rigorous clinical trial testing,” says Francesca Pentimalli co-lead author of the study from the National Cancer Institute of Naples, which is under the Scientific Direction of Gerardo Botti, a renowned pathologist who is also a co-author of the study.

“Some studies predict an increase in the incidence of mesothelioma in some areas and therefore new therapeutic strategies able to cure or at least chronicize the disease are urgently needed,” concludes Antonio Giordano, Director and Founder of the Sbarro Institute who has devoted a great part of his latest efforts in findings novel approaches against mesothelioma, establishing dedicated research groups working in network across Naples, Siena, and Philadelphia.

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 Release

Regulation of Cancer Promoting Molecule EphB4 Offers Potential Treatment Target for Mesothelioma, Other Cancers

A novel cancer-promoting molecular mechanism has been discovered by Pierluigi Scalia, M.D., Ph.D., with his co-workers at the Sbarro Institute for Cancer Research and Molecular Medicine, Division of Biology, Temple University, the Department of Medical Biotechnologies at University of Siena, Italy  and the Italian non-profit research organization ISOPROG, in collaboration with the Center of Biocomputational Sciences, part of the College of Science and Technology in Philadelphia.

The new discovery is described in a study published July 3, 2019 in the journal Oncogene, titled “Identification of a Novel EphB4 Phosphodegron Regulated by the Autocrine IGFII/IRA Axis in Malignant Mesothelioma.

“This study identifies a new potential targetable oncogenic mechanism, since it shows how a previously studied tumor self-stimulating signal regulates the function of a molecule known as EphB4, directly involved in malignant cellular behavior such as cancer blood vessels formation, normal tissue invasion and distant site metastasis,” Scalia says.

Scalia continues, “Interestingly, the key components of this newly identified molecular switch appear expressed in all malignant cancer cell lines studied, suggesting that the relevance of this mechanism might extend to many types of solid cancer, beyond mesothelioma.”

According to professor Antonio Giordano, M.D., Ph.D., co-author of the study and director of the Sbarro Institute, “this type of discovery is critical for deadly cancers like Malignant Mesothelioma for which the search for new molecular targets is highly invoked in the medical field due to the growing demand for new treatments towards more effective and personalized interventions.”

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  

Oncogene Article            Original Newswise Post

New Natural Therapeutic Agent to Fight Diabetic Nephropathy

A team of researchers have published in the Journal of  Cellular Physiology that a new natural extract is able to inhibit the development of diabetic nephropathy, a kidney disease that is increasing in incidence throughout the world.

“The new extract of natural origin, obtained from red oranges and lemons, is rich in cyanidin 3-glucoside and other polyphenols,” says Prof. Roberto Ciarcia, MV, associate professor of Veterinary Pharmacology and Toxicology of the Department of Veterinary Medicine and Animal Production at the University of Naples Federico II. “This discovery opens new perspectives to limit kidney damage induced by type II diabetes mellitus and to block the development of diabetic nephropathy.”

The study, “A red orange and lemon by‐products extract rich in anthocyanins inhibits the progression of diabetic nephropathy,” first published online on May 29, 2019, describes how the extract successfully restored the blood glucose levels, body weight, and normalized oxidative stress on renal function in a test group of Zucker diabetic fatty rats.

The study authors include collaborators from the Department of Veterinary Medicine and Animal Production at the University Federico II of Naples and from the Sbarro Health Research Organization (SHRO), at the Center for Biotechnology, Temple University in Philadelphia.

“My research group, through the sophisticated technique of renal micropuncture conducted by Sara Damiano, first author  of the study, has evaluated at the tubular level the mechanism involved during diabetic nephropathy and has discovered an important protective effect of this new extract,” says Prof. Salvatore Florio, full professor of Veterinary Pharmacology and Toxicology of the Department of Veterinary Medicine and Animal Production at the University of Naples Federico II. “It is important to underline that this compound was obtained in collaboration with the Council for Agricultural Research and Economics, Research Center for Olive, Citrus and Tree Fruit, Acireale.”

“The ability of the new extract to reduce the renal damage is remarkable, considering that diabetic nephropathy could induce kidney failure. We hope that this new extract can be a useful compound to fight the progression of diabetic nephropathy and allow an improvement in the quality of life of patients with type II diabetes mellitus,” concludes Damiano.

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           Journal of Cellular Physiology Article       PubMed Abstract

Exploiting RB1 Predictive Value for Cancer Therapy in the Clinical Setting: Lost in Translation

Newswise — The RB1 protein, named after the pediatric tumor retinoblastoma, was discovered in the 80s as the first tumor suppressor and, since then, its pathway has been found inactivated in most human cancers. RB1 ability to halt tumor development and growth has been mainly ascribed to its function in cell cycle regulation, which directly restrains cell division and proliferation. However, besides this canonical role, RB1 has a multitude of other functions, which profoundly affect the destiny of a cell by regulating stemness, differentiation, senescence, and even cell death. Indeed, RB1 status emerged not only as a key factor in cancer development and progression, but also as a crucial determinant of cell fate in response to various anticancer treatments. The idea of tailoring antitumoral strategies based on the patient’s RB1 status has shown potential, but its translation to the clinical setting has proved challenging.

A new commentary article, published last week in Biochemical Pharmacology, discusses many of these challenges and the importance of evaluating the status of RB1 in clinical specimens to support therapeutic decisions. The article provides a thorough overview of studies analyzing the key role of RB1 in the response to different anticancer approaches, spanning both cytotoxic (i.e. chemotherapy and radiotherapy) and cytostatic strategies (i.e. hormonal therapy) routinely used in the clinic. The authors also address the relationship of RB1 status to the effectiveness of targeted agents, such as protein kinase inhibitors including the new generation of highly selective inhibitors of the CDK4/6 cell cycle kinases, and also immunotherapeutics, which are among the most promising alternatives to conventional therapies.

“Through both canonical and non-canonical mechanisms, RB1 exerts opposite effects on the response to cytotoxic and cytostatic agents, limiting the effectiveness of cytotoxic chemotherapy and radiotherapy agents and sensitizing the cells to cytostatic hormone treatments and kinase inhibitor-based therapies,” says Paola Indovina of the Sbarro Health Research Organization at Temple University in Philadelphia (www.shro.org), first author of the article. “Moreover, the recently identified role of RB1 in immune function likely impacts the patient response to immunotherapy and other anticancer strategies.”

“Although a great amount of evidence pointed to the crucial importance of assessing RB1 status in the clinical setting, which could help to select patients who can benefit from a particular treatment, while sparing non-responders the unnecessary side effects, its predictive value is still underused mainly owing to the complexity of RB1 function and to difficulties in evaluating its functional status and context-dependent roles,” says Francesca Pentimalli, a coauthor working at the National Cancer Institute of Naples, Pascale Foundation.

“For the successful translation of RB1 predictive power in the clinical practice, it is crucial to dissect the molecular mechanisms whereby RB1, and its family members, regulate context-specific responses to the wide range of possible antitumoral strategies and to develop rigorous and standardized methods for their evaluation in clinical specimens,” says Antonio Giordano, Director and Founder of the Sbarro Health Research Organization, Professor of Pathological Anatomy at the University of Siena, Italy, who first identified one of the members of the retinoblastoma family, the RBL2 /p130 protein, and contributed to define the role of these proteins in cancer and cell cycle regulation.

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      Original Study

Cervical Cancer During Pregnancy, Though Serious, is Highly Treatable According to New Research Review

Newswise — A team of researchers in the Gynecologic Oncology Unit of the University Hospital of Bologna, in collaboration with Professor Antonio Giordano from the Sbarro Health Research Organization, has published a revision of the literature about cases of cervical cancer in pregnancy, with the addition of new cases treated at the University Hospital of Bologna. Their work appears in the Journal of Cellular Physiology.

“Cancer during pregnancy is defined as a tumor diagnosed in pregnant women, or in the immediate postpartum,” says Myriam Perrone MD, PhD of the Gynecologic Oncologic Unit and first author of the manuscript. “In the last decade, we observed an increase in incidence of this condition, largely due to later childbearing, and although it has been hypothesized that hormones and growth factors necessary for fetal development may accelerate tumor growth, evidence suggests that pregnancy is not necessarily a poor prognostic factor for patients’ survival.

“Cervical cancer is the second most common form of cancer or pre-cancer diagnosed during pregnancy or postpartum, and occurs in approximately 0.004-0.1% of pregnant women. The rarity of the condition makes large trial studies impossible, and guidelines up to now are based on small case and expert opinions,” Perrone concludes.

“For these reasons, today, diagnostic tools and treatment are similar in pregnant and non pregnant women, with some differences,” explains Alessandro Bovicelli, MD, PhD of the Gynecologic Oncology Unit of the University of Bologna and co-author of the manuscript. “In pregnant women, conservative surgery can be proposed as primary treatment of early stage cervical cancer, such as cone and lymphadenectomy. However, in women with advanced stage, neoadjuvant chemotherapy is a possible option of treatment.”

“Individualized therapies are strongly recommended and the treatment decision should be made collaboratively with a multidisciplinary team consisting of obstetricians, gynecologists, oncologists, pediatricians, and psychologists,” adds Professor Pierandrea De Iaco, Director of Gynecologic Oncology Unit of University Hospital of Bologna. “Over the years and with the publication of new studies, the treatment strategy has gradually changed to a more conservative treatment, particularly for patients in second or third trimester with early stage cancer. Furthermore, it has been reported that neoadjuvant chemotherapy has been successful at controlling the disease and delaying delivery until fetal maturity, without serious adverse effects on the mother and foetus.

“Time of delivery must be evaluated with obstetricians, as the point of fetal maturity is the main issue,” concludes De Iaco.

“Cancer in pregnancy is not an acute emergency and clinicians should take all the time necessary to study the case and offer the best diagnosis and therapy,” says Perrone. “Treatment of patients with cancer in pregnancy should be offered in gynecologic oncology centers associated with experienced perinatal centers to provide patients with expertise in all needed aspects.

“In the future, the development of molecular markers and their routine use could help in the clinical decision making,” concludes Perrone.

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 Release          Journal Article

Brain Cancer Drug Reactivates Body’s Natural Defenses

Drug reactivates p53 tumor suppressor protein and increases chemotherapy effectiveness in potential glioblastoma breakthrough.

Newswise — A team of researchers have published in the International Journal of Oncology that RITA, a drug able to reactivate the oncosuppressor function of p53, could be an effective strategy to treat glioblastoma. The study’s authors include collaborators from the Sbarro Health Research Organization (SHRO), at the Center for Biotechnology, Temple University in Philadelphia, the National Cancer Institute “G. Pascale” Foundation of Naples, Italy, and the Oncology Research Center of Mercogliano (CROM).

Glioblastoma, the most common form of brain cancer, is a deadly disease for which there is no cure. Known for resistance to conventional treatments, such as the chemotherapy drug temozolomide, glioblastoma is the form of cancer that ultimately lead to the recent death of U.S. Senator John McCain.

Our study shows the effects of a small molecule designed to reactivate the p53 protein, one of the most important ‘tumor suppressors’, which is turned off in most human cancers, including glioblastoma,” says Antonio Giordano, M.D., Ph.D., Director and Founder of the SHRO and Professor of Pathology and Oncology at the University of Siena. “RITA is able to specifically reduce tumor cell proliferation without affecting healthy cells, and RITA is also able to induce massive apoptosis — a type of programmed cell death.”

“The p53 protein has a crucial role in inhibiting cancer development, inducing cell cycle arrest or triggering apoptosis,” says Paola Indovina, researcher at SHRO and lead author of the study. “Understanding how p53 determines a cell’s fate is crucial in order to identify new therapeutic strategies.

“RITA is also able to reduce expression of MGMT protein,” Indovina adds. “This reduction mechanism is associated with a better response to chemotherapy treatment correlated with increased survival.”

“The ability of RITA to induce apoptosis is remarkable, considering that glioblastoma is a very aggressive tumor,” says Iris Maria Forte, biologist at CROM and co-first author of the paper. “Additionally, this compound worked in synergy with temozolomide in the most aggressive histotype of glioblastoma. These findings suggest that its use in a clinical setting could possibly help to reduce the required doses and to reduce the side effects of chemotherapy.

“We hope that RITA, in combination with other antitumor treatments, could be a useful compound to fight this cancer and to allow at least an improvement in the quality of life of glioblastoma patients,” Forte concludes.


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


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


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