Molecular Subgroups of Non-Small Cell Lung Cancer Predict Tumor Behavior, Reveal Treatment Targets

The discovery of several different subtypes of Non Small Cell Lung Cancer (NSCLC), the most frequent form of lung cancer, has been a major breakthrough in the fight against the leading cause of cancer-related death worldwide. With each subtype displaying peculiar clinic-pathological characteristics, they can be associated with outstanding responses to specific targeted agents, such as anti-tumor drugs and immunotherapy. However, to date there are limited data regarding the possible differences in the metastatic distribution of NSCLCs.

A recent study, published in the journal Oncotarget, describes further scientific insight into the metastatic patters of Epidermal Growth Factor Receptor (EGFR) mutated NSCLCs. The authors determined that bio-molecular characteristics and genotype may influence the metastatic process in NSCLC tumors, and might help the development of enrichment strategies for tumor genotyping in these tumors, especially in the presence of limited tissue availability. Furthermore, the understanding that EGFR-mutated NSCLCs metastasize more frequently in certain sites might help clinicians for a more appropriate selection of patients for EGFR mutational testing beyond current clinical parameters, such as tumor histotype, ethnicity or smoking status.

The study includes work done by Prof. Vincenzo Adamo, of the University of Messina, Italy, in collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia, as well as other colleagues at the University of Siena, Italy

Exploring the link between oncogene status and metastatic behavior in non-squamous NSCLCs, the authors analyzed the different metastatic patterns, at baseline and during the course of the disease in a cohort of 137 Caucasian patients.

They reported unique metastatic distributions between EGFR-mutated and EGFR wild type non-squamous NSCLCs, since EGFR mutated NSCLCs tended to develop at baseline with a higher frequency compared with wild type tumors, brain metastases, lung metastases, pleural involvement, and bone metastases. However, the presence of EGFR mutations is associated with a longer median overall survival (almost double) compared with those without EGFR mutations when treated with specific targeted agents. Moreover, the EGFR mutational status was a predictor of longer overall survival also in the presence of brain metastases, a clinical condition commonly associated with a dismal prognosis.

“In order to move this research into clinical applications for EGFR-mutated NSCLCs, we hope to address the growing list of molecular tests required for an adequate treatment of such patients,” says Dr. Adamo.

“The most pressing challenge is limited tumor tissue availability, due to the disease being commonly diagnosed through small tumor biopsies or cytological samples, given its peculiar localization. Therefore, strategies for the optimal selection of patients for molecular testing are eagerly awaited,” Dr. Giordano concluded.

newswise release

About
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.

CITATIONS
Russo A, Franchina T, Ricciardi GR, Fanizza C, Scimone A, Chiofalo G, Giordano A, Adamo V. Influence of EGFR mutational status on metastatic behavior in non squamous non small cell lung cancer. Oncotarget. 2017 Jan 2. doi: 10.18632/oncotarget.14427.

pubmed abstract    Oncotarget publication page

Combination treatment may be valuable therapeutic option for HER2-negative metastatic breast cancer

Finding the ideal combination of targeted, hormonal and chemotherapeutic agents to treat HER2-negative metastatic breast cancer has been challenging researchers for decades. In tumors which lack expression of the human epidermal growth factor receptor 2 (HER2-), the use of regimens based on the administration of paclitaxel, a taxane, and bevacizumab, a humanized monoclonal antibody directed against VEGF-A, eventually integrated by maintenance therapy with bevacizumab and/or endocrine therapy may represent a valuable therapeutic option. In other words, an initial round of targeted chemotherapy to rapidly halt cancer progression, followed by maintenance therapy to prevent further metastases. The specific drug regimen analyzed in a recent study resulted in better control of disease progression and a higher overall survival rate.

The study, “A Real-World Multicentre Retrospective Observational Study of Paclitaxel-Bevacizumab and Maintenance Therapy as First-Line Treatment for HER2-Negative Metastatic Breast Cancer,” was recently published in the Journal of Cell Physiology an international, peer-reviewed journal focused on cancer-related issues.

Researchers identified 314 patients diagnosed with HER2-negative metastatic breast cancer at 12 Italian cancer centres. From that group, they identified a subgroup of about 180 hormone-receptor positive patients to administer maintenance endocrine therapy following paclitaxel discontinuation, which was eventually combined with bevacizumab maintenance therapy.

“Notwithstanding the overall improvement in the available therapeutic options, metastatic breast cancer is still considered incurable,” says Dr. Maddalena Barba, researcher at the Regina Elena National Cancer Institute of Rome, Central Italy, “with particularly low survival rates in some patient subgroups for whom novel treatment combinations and potential therapeutic targets are urgently needed.”

The authors belong to a multidisciplinary Italian-American team, which has long collaborated with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research, Temple University Philadelphia, USA

“In this study, we observed evidence of the efficacy of first-line paclitaxel-bevacizumab in metastatic HER2 negative breast cancer patients. In addition, both bevacizumab and endocrine maintenance therapy significantly improved slowing disease progression and the overall survival rate, compared to cases with no maintenance therapies,” says Dr Vici, clinical researcher at the division of Medical Oncology 2 of the Regina Elena National Cancer Institute.

“When addressing metastatic breast cancer, pathologists and oncologists work jointly to identify single therapeutic approaches to be used within a wider therapeutic strategy,” says Prof. Antonio Giordano, a scientist with widely recognized expertise in breast cancer with a specific focus on translational research. “Each step of the decision making process is driven by specific disease features, such as the lack or presence of therapeutic important targets, which may be exemplified by HER2 and hormone receptors, along with our patients specific needs. In addition, data collected from real world populations, likewise those commonly involved in our research pipeline on breast cancer, are closer to the routine clinical practice and patient needs compared to the evidence from randomized clinical trials, whose participants are generally highly selected,” Prof. Giordano concluded.

News-Medical Release        PubMed Abstract

New Study ‘Sheds Light’ On The Mechanisms Safeguarding The Genome

Newswise — Understanding the molecular mechanisms that exist for cells to safeguard their genome against cancer-causing defects is crucial not only to understand how cancer arises but also because these mechanisms can be targeted therapeutically. Researchers have identified a new net of molecular interactions occurring within cells upon exposure to DNA damaging UV radiation. The team lead by Antonio Giordano, MD, PhD, Director and Founder of the Sbarro Health Research Organization at Philadelphia, PA (www.shro.org), published their findings in Oncotarget.

The study explores the mechanisms underlying the expression of NONO, a protein with different functions correlated to melanoma development and progression. The authors found that UV radiations trigger the activation of a tiny RNA molecule (microRNA320a), the purpose of which is not fully understand. Scientists believe microRNA320a plays an important role in the process which allows cells to survive various forms of DNA damage, given that its removal sensitizes cancer cells to UV-induced death. At the same time, however, they found that microRNA320a can target NONO for degradation.

“This was puzzling because we had previously shown that the cellular response to UV radiations relies on NONO for the activation of a cell cycle ‘checkpoint’, necessary to allow DNA repair upon damage,” says Francesca Pentimalli, PhD at the National Cancer Institute of Naples and Adjunct Professor at Temple University, Philadelphia, and group leader of Dr Giordano’s team. Delving further into these mechanisms the researchers found that HUR, an RNA binding protein, which coordinates gene expression at the mRNA level upon stress cues, binds NONO mRNA, competing with microRNA320a and protecting NONO from degradation. “Whereas the crucial role of HUR in directing the cell response to stress was previously recognized, the role of microRNA320a in this context was not known and we found that its expression is under direct control of p53, the main player in the cell response to DNA damage, defined as the ‘guardian of the genome’, which is mutated in more than half of human cancers,” Pentimalli says.

“Considering that many studies have identified p53 and also HUR alterations in cancer, and other studies are reporting NONO andmicroRNA320a alterations too, our findings could help to shed light on the molecular mechanisms of tumorigenesis, especially in tumours like melanoma, in which exposure to UV radiations plays such a prominent part,” say authors Caterina Costa, PhD, and Luigi Alfano, PhD, of the National Cancer Institute of Naples Pascale Foundation, Cancer Research Center of Mercogliano, Italy (CROM).

“Also, it will be useful to assess whether targeting microRNA320a could be used as a synthetic lethal approach to sensitize cancer cells to a variety of drugs that cause DNA damage, such as common chemotherapy agents,” concludes Antonio Giordano, who is also Professor of Pathology at the University of Siena and Director of the Sbarro Institute for Cancer Research and Molecular Medicine, at Temple University, Philadelphia.

Newswise release     Oncotarget publication

Researchers slow glioblastoma by inhibiting tumor’s PPARα receptor

One of the most remarkable features of glioblastoma is the metabolic reprogramming of cancerous cells, resulting in uncontrolled cell proliferation, hypoxic conditions and angiogenesis. Metabolic reprogramming enables tumor cells with a faster way to produce energy and form new membranes. For this and other reasons, glioblastoma is presently incurable and the affected patients have a poor outcome.

One of the possible strategies for defeating brain tumors is to interfere with the pathways of nutrient supply. This may be achieved by blocking the utilization routes of glucose or lipids.

In a new study published in the Journal of Cellular Physiology, researchers examined the effects of a new inhibitor, AA452, of a transcription factor, PPARα, known to be involved in the control of energetic metabolism. The result obtained in this study indicates that blocking PPARα in glioblastoma cells affected a strong decrease of cell proliferation and migration, as well as induced a major sensitivity to radiotherapy.

The research is a collaboration from the Sbarro Health Research Organization (SHRO, Center for Biotechnology, Temple University, Philadelphia PA USA), the University of L’Aquila (Italy) and University of Siena (Italy).

This finding may have important implications for the design of new drugs and therapeutic interventions for this incurable tumor.

“Our studies point towards a possible way to counteract glioblastoma growth and recurrence by interfering with energetic metabolism by blocking PPARα,” says Annamaria Cimini of the University of L’Aquila, lead author of the study.

“The design of a new drug specifically directed against PPARα activity may provide new perspectives for glioblastoma therapies by counteracting its energy supply,” says Antonio Giordano, founder and director of the Sbarro Institute for Cancer Research and Molecular Medicine.

Journal Article         Pubmed Abstract

International Award Giovan Giacomo Giordano NIAF-Ethics and Creativity in medical research – Saturday, 9 A.M October 15th at the Marriot Wardman Park Hotel in Washington, D.C.

official-niaf-2016-flyerWomen Leaders in advanced Cancer Research

The Sbarro Health Research Organization (SHRO), in collaboration with Temple University’s College of Science and Technology, the National Italian American Foundation (NIAF), and the Giovan Giacomo Giordano Foundation will host the medical conference “Women Leaders in Advanced Cancer Research” 9 A.M on Saturday, October 15th at the Marriot Wardman Park Hotel in Washington, D.C.

The conference will feature an introduction on “Women Leaders in Advanced Cancer Research” presented by SHRO’s President Antonio Giordano who is also director of Temple’s Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology.  Temple and CST are leaders in biotech research and development, and recently launched masters programs in both bioinnovation and biotechnology.

Guest speakers include Maria Catherine Pietanza, Global Director of Scientific Affairs for Oncology Center Merck Research Laboratories, Francesca Pentimalli, Adjunct Faculty at Temple University, and Michele Masucci, Vice President for Research at Temple University.  Dr. Pietanza will address “Activating the Immune System Against Cancer: where are we?”. Dr. Pentimalli will discuss “Cancer and the Environment: What did we learn from the Mesothelioma Case?” and Dr. Masucci will report on “Strategies for meeting the needs of the 21st Century STEM Workforce in Academia”.  A special recognition will be given to Dr. Pentimalli for her work in the field of mesothelioma.

The conference will culminate in the presentation of the 2016 Giovan Giacomo Giordano NIAF Lifetime Achievement Award for Ethics and Creativity in Medical Research by Mrs. Dolores Del Raso and Dr. Giacomina Massaro to Dr. Pietanza and Dr. Masucci.  This award was established six year ago in honor of Dr. Giordano’s father, the late Professor Giovan Giacomo Giordano, renowned pathologist and former chair of the Department of Pathology, National Cancer Institute of Naples and professor at the Second University of Naples, who dedicated more than sixty years of his life to the study of cancer and the role of environmental factors in the onset of this disease.  Professor Giovan Giacomo Giordano was also a major advocate against corruption in the Italian medical community and driving force for the establishment of medical ethical standards among his colleagues.

An exclusive preview of the Carlo Fumo-directed documentary “Land of Poison”, on the ongoing environmental and health problems facing the Campania area of Italy, will also be shown.

New RNA stem cell editing reduces unintended genetic complications

Date: October 3, 2016

Source: Sbarro Health Research Organization (SHRO)

Summary:  An international collaboration of government, university, and industry resources showed the promise of using RNA as a safe way to both make and modify induced Pluripotent Stem Cells (iPSCs) from patient cells for clinical applications in regenerative medicine, tissue engineering, and personalized medicine.

For more info, see the ScienceDaily release.

The Complex Crosstalk Between Obesity & Breast Cancer

Figure-1.pngA new study published in the Journal of Cellular Physiology  (abstract) describes how inflammation that characterizes fatty tissue is one of the main microenvironment actors responsible for promoting cancer. The authors also describe the involvement of steroid hormones and others factors produced by adipose tissue in breast cancer development.

The study, “Multifaceted breast cancer: the molecular connection with obesity,” appeared in the July 1, 2016 edition of the international, per-reviewed journal focused on cancer-related issues. The authors belong to a multidisciplinary Italian-American-Tunisian team with a long and productive history of collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research, Temple University of Philadelphia, Pennsylvania, USA.

A novel approach was developed to analyze cell culture systems by professor Pietro Formisano from the University of Naples “Federico II” (NA, Italy), in order to study interactions between adipose tissue and tumors, and the molecular mechanism of insulin action. The contribution of professor Angelina Di Carlo, University of Rome “La Sapienza” (Rome, Italy), was to underline the role of matrix metalloproteinases in obesity-related mechanisms of breast carcinogenesis. The work by Professor Soumaya Kouidhi, of Manouba Thabet University (Aryanah,Tunisia), suggests that the small circulating RNA could be important in the diagnosis and prognosis of breast cancer. Finally, professor Marina Di Domenico from the Second University of Naples (Italy) and PI of IRCCS “La salute della donna” of “Malzoni Clinic ” (AV, Italy), describes the “non genomic” actions of estrogen receptors in relation to breast cancer, with particular reference to the main roles of p85 / PI3K, in differentiation and cell migration.

This publication, resulting from an excellent exchange of worldwide knowledge, represents an important contribution in the studies of molecular mechanisms regulating breast cancer pathogenesis.

See Science Daily release.

DECT trial shows combination of epirubicin and trastuzumab improves outcomes in breast cancer patients

The study entitled “A phase II neoadjuvant sequential regimen of docetaxel followed by high-dose epirubicin in combination with cyclophosphamide administered concurrently with trastuzumab. The DECT trial” has recently appeared in the Journal of Cell Physiology, an international, per-reviewed journal focused on cancer-related issues. The authors belong to a multidisciplinary Italian-American team with a long and productive history of collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research of Philadelphia, Temple University Pennsylvania, USA and the Department of Medicine Surgery and Neuroscience at University of Siena.

“The use of trastuzumab, a monoclonal antibody targeting the HER2 receptor, has dramatically improved the prognosis of the subgroup of breast cancer patients whose tumors overexpress this specific receptor. One of the greatest challenges in these patients has been combining trastuzumab with extremely effective drugs such as anthracyclines at the cost of an acceptable toxicity. Initial evidence seemed to discourage this approach due to the high-rate of cardiotoxicity, i.e., 27%, reported in the pivotal phase III trial of metastatic breast cancer from Slamon and colleagues. Subsequent studies have partly downsized these results. Yet, several doubts have remained concerning the combined use of these drugs. The DECT trial was design to further address this key question. We also used the data from this randomized trial to interpret treatment efficacy in light of hormonal and metabolic determinants, including the expression of estrogen and progesterone receptors and body mass index,” says Prof. Antonio Giordano.

For more information see the news-medical,net release or the PubMed abstract

Dr Antonio Giordano visits Medical Research institutions In Santiago Chile

Dr. Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University, was invited as an expert in scientific research to evaluate the Advanced Centers for Chronic Disease in Chile, one of the most important among centers of excellence in scientific research, established at the Catholic University in Chile and the University of Chile.  The program is funded by CONICYT, a Chilean government agency that is part of the Ministry of Education and is responsible for coordinating, promoting and aiding scientific research in the country. The name is an acronym for Comisión Nacional de Investigación Científica y Tecnológica, meaning “National Commission of Scientific Research and Technology”.  During his visit, Dr. Giordano was invited by  the Italian Ambassador in Santiago, the Honorable Marco Ricci, to meet several leaders from the Italian community in Chile.

schermata20160525alle14-29-47

Dr Antonio Giordano and Ambassador Marco Ricci in Santiago, Chile

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