Dr. Dario Marchetti - Member of Scientific

Professor, Departments of Pathology

and Molecular and Cellular Biology;

Director, Cell Search CTC Core Facility

Baylor College of Medicine, BCM

Email:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it

Specialty: Biology and Diagnostics of CTC ; Brain-metastatic melanoma; Heparanase; Heparan sulfate processing; Brain-metastatic breast cancer; Mechanisms of medulloblastoma invasion and tumorigenicity.

Research Interests: The biology and mechanisms of brain metastasis in melanoma and breast cancers. Heparanase (HPSE) and heparan sulfate proteoglycans (HSPG) as biological modulators of tumor angiogenesis and metastasis.  Roles of neurotrophins/neurotrophin receptors in invasive tumors of the nervous system, perineural invasion and HPSE/HSPG roles in interactions between tumor and CNS cells. The biology and prognostic utility of Circulating Tumor Cells (CTC) in metastatic cancers and Circulating Endothelial Cells (CEC) in Type2 Diabetes.

Prospectus: Focus of my laboratory is to investigate mechanisms and determinants underlying brain metastasis formation, and microenvironmental interactions between normal and nervous system-invading cells.

Possessing long-term interests and a multi-decade experience in the field of neurotrophic factors, my laboratories have studied roles and relevance of a family of neurotrophic factors, the neurotrophins (NT), and their receptors (NTR), and a NT-regulated extracellular matrix degradative enzyme, called heparanase (HPSE), uniquely involved in cancer invasion and metastasis, notably to brain. 

Brain metastases, which occur in 30-40% of all cancer patients, are an important cause of cancer morbidity and mortality, and their frequency is rapidly increasing.  Mechanisms responsible for malignant melanoma or breast cancer progression to highly aggressive brain-metastatic disease remain largely unknown. Main objective of our laboratory is to understand molecular determinants in these two cancer types, and to use this knowledge for developing novel therapies to prevent brain metastasis. We have demonstrated that the neurotrophin receptor p75NTR and neurotrophin - regulated HPSE are critical determinants of brain metastasis. HPSE represents the only functional mammalian endoglycosidase cleaving heparan sulfate (HS), the main polysaccharide constituent of the extracellular matrix and basement membranes as HS proteoglycans (HSPG). HPSE plays decisive roles in fundamental biological events associated with extracellular matrix remodeling, such as cancer metastasis, inflammation, modulation of HS-binding angiogenic growth factors and cytokines (which bound/are stored at high levels in ECM/BM HSPG) action and associated mechanisms and biological outcome.

HPSE relevance in cancer invasion and metastasis is established:  HPSE over-expression/upregulation significantly correlates with the metastatic phenotype, tumor vascularity (angiogenesis), and reduced post-operative survival of patients from several cancer types. The anti-cancerous effects of hpse silencing, HPSE inhibiting molecules, and the unexpected identification of a single functional heparanase, place this enzyme as a promising target for anticancer drug development. However, precise mechanisms of its action, e.g., nuclear presence/functionality, splice variants expression, gene regulation, post-transcriptional regulation, etc., are not fully understood nor is the “HPSE system” including, besides HPSE, heparanase-2 (a HPSE-related protein not possessing enzymatic activity or known function) and its isoforms, the HPSE processing enzyme and a cell - surface HPSE receptor.

Paolo Fiorentino is an Adjunct Professor at the Faculty of Medicine, University of Torino and Postgraduate Research and Clinic Fellow at the School of Medicine & Dentistry, University of Rochester.

His field of interests covers Craniomandibular Pain, Genetic Therapy of Pain, Development and Growth of the Face, Oral Physiology, Neuroscience, and  Orthodontics and Dentofacial Orthopedics. Paolo Fiorentino’s work on experimental gene therapy in the field of osteoarthritis has produced very exciting results and perhaps a whole new approach to the treatment of the disease, based on the “feedback-loop” theory of osteoarthritis. To read the full article click >>> - Spinal Interleukin-1 in a Mouse Model of Arthritis and Joint Pain

• An excellent summary of Fiorentino’s research and its promising developments can be read in “Contrordine: il dolore non ti rende piu’ forte,” an article published in TuttoScienze by Riccardo Lattanzi.

Monica Fornier


ISSNAF Member and medical oncologist
at the Breast Cancer Medicine Service of

Memorial Sloan-Kettering Cancer Center

in New York

This technology allows for the concomitant evaluation of hundreds of small molecules (metabolites) from blood samples of cancer patients. The tumor produces several types of metabolites that can be easily detected in the blood of cancer patients by the metabolomic technology. The researchers aim to identify a group of metabolites from the blood of breast cancer patients, associated with a high risk of tumor recurrence. To identify metabolites associated with the risk of cancer recurrence could be a major step forward in the fight against breast cancer and would allow the identification of patients who are still at risk of tumor recurrence although the cancer has been removed during breast cancer surgery.

This research will be the first worldwide to test the value of metabolomics as a tool defining breast cancer outcome in each individual patient. The project will be carried out thanks to the collaboration between the Breast Medicine Service of Memorial Sloan-Kettering Cancer Center in New York and the "Sandro Pitigliani" Medical Oncology Unit, Hospital of Prato - Istituto Toscano Tumori, Italy. Two hundred patients will participate in this project. First results will be available by the end of 2009. (Source BCRF)

By Valter Longo

ISSNAF member and Associate Professor of Gerontology and Biological Sciences
and the Hanson Chair of Biogerontology at the University of Southern California (USC)

Longo's Lab


Abstract

Strategies to treat cancer have focused primarily on the killing of tumor cells. Here, we describe a differential stress resistance (DSR) method that focuses instead on protecting the organism but not cancer cells against chemotherapy. Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2val19. Low-glucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/pro-oxidant cyclophosphamide. Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide. These studies describe a starvation-based DSR strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells. (Source PNAS)

VIDEO: Valter Longo GroundBreaking Discovery Cancer Research >>>