Branca, Jacopo Junio Valerio

Pacini, Stefania

Ruggiero, Marco

English

Branca, JACOPO JUNIO VALERIO

Florence Research

and especially about individualized therapy, we could suspectthat the protective effect of vitamin D on the prostate cancerdevelopment is also individual. It may for example result fromthe polymorphism of the receptor of this vitamin and activityof vitamin D-metabolizing enzymes. Conclusion: Theconcentration of vitamin D in blood of patients with prostatecancer is lower than in the blood of patients with benignprostate hyperplasia. 1 Apperly FL: The relation of solar radiation to cancermortality in North America. Cancer Res 194 1:19119-52 Bulathsinghala P, Syrigos KN and Saif MW: Role of vitamind in the prevention of pancreatic cancer. J Nutr Metab.2010;2010:721365. doi: 10.1155/2010/721365. Epub 2011Jan 9.3 Kang W, Lee S, Jeon E, Yun YR, Kim KH and Jang JH:Emerging role of vitamin D in colorectal cancer World JGastrointest Oncol 3: 123-127, 2011.4 Rollison DE, Cole AL, Tung KH, Slattery ML, BaumgartnerKB, Byers T et al: Vitamin D intake, vitamin D receptorpolymorphisms, and breast cancer risk among women livingin the southwestern U.S. Breast Cancer Res Treat 132: 683-691, 2012.5 Haghsheno MA, Mellström D, Behre CJ, Damber JE,Johansson H and Karlsson M: Low 25-OH vitamin D isassociated with benign prostatic hyperplasia. J Urol 190:608-614, 2013.83HSV1716 (SEPREHVIR): AN ONCOLYTIC HERPESVIRUS FOR CANCER THERAPYLynne BraidwoodVirttu Biologics Ltd, Dept of Neurology, Southern GeneralHospital, 1345 Govan Rd, Glasgow, G51 4TF, UKThe HSV-1 mutant HSV1716 has deletions in both copies ofthe gene encoding the neurovirulence factor ICP34.5.HSV1716 effectively kills tumor cell lines in vitro andoncolysis has induced tumor regression and increased survivaltimes in a wide range of solid tumor xenograft modelsincluding glioma, hepatocellular carcinoma, melanoma,medulloblastoma, mesothelioma, ovarian carcinoma andteratocarcinoma supporting translation into clinical studies. Incompleted safety studies, direct intratumoral injection ofHSV1716 has been used to treat patients with recurrentglioma, metastatic melanoma and squamous cell carcinoma ofthe head and neck. Phase I dose escalation studies of HSV1716 inpediatric/young adult patients with non-central nervous systemsolid tumors ( http://clinicaltrials.gov/ NCT00931931) and inpediatric patients with refractory or recurrent high gradegliomas (NCI Protocol #: PBTC-037) and a phase 1/2a studyin malignant pleural mesothelioma (http://clinicaltrials.gov/NCT01721018) are currently on-going. Regulatory approvalhas recently been obtained for a phase I/2a study inhepatocellular carcinoma. In total 88 patients have receivedHSV1716 and the virus is well-tolerated with no spread tosurrounding normal tissue or no shedding in patients. Theselectivity of HSV1716 for replication only in tumour cellsand intimations of efficacy have been demonstrated.The oncolytic biopotency of HSV1716 can be enhanced viathe incorporation of exogenous genes that generate novelfunctionalities or via combination with drugs that targetspecific pathways. For example, expression of the Inhibitor ofNew Growth 4 protein generates a more efficacious HSV1716variant with improved replication kinetics and datademonstrated that HSV1716 and mTOR inhibitors frequentlycombined to enhance cancer cell killing.. Therefore, HSV1716provides a platform with the potential to generate diversetherapeutic options.84FOCUSSED TRANSCRANIAL ULTRASOUNDS:APPLICATION TO THE DELIVERY OFGLYCOSYLATED OLEIC ACID/VITAMIN D-BINDING PROTEIN TO BRAIN TUMOURS AND METASTASESJacopo J.V. Branca1, Stefania Pacini1 and Marco Ruggiero2,3Departments of 1Experimental and Clinical Medicine and2Experimental and Clinical Biomedical Sciences, Universityof Firenze, Firenze, Italy;3Immuno Biotech Ltd., Guernsey, Channel Islands, UKGlycosylated oleic acid/vitamin D-binding protein, also knownas oleic acid/Gc protein-derived macrophage activating factor(OA-GcMAF), has proven effective in the immunotherapy ofsolid neoplasms and haematological malignancies. The limitedpermeability of the blood brain barrier (BBB), however, is anobstacle to its widespread use in primary brain tumours, aswell as in brain metastases. In order to overcome thislimitation, we developed a procedure involving the use offocussed ultrasounds that allow selective permeabilisation ofthe BBB and targeted delivery of OA-GcMAF. One day beforethe procedure, OA-GcMAF is injected in the proximity ofinguinal nodes; it is administered orally as a fermented milkproduct and with suppositories or enemas. The following day,OA-GcMAF is administered by nebulisation. Measurement ofblood pressure variations and assessment of splenic blood flowafter nebulisation are used to determine the individualresponse (1). Five minutes after nebulisation, transcranialultrasounds are applied through the temporal acoustic windowon the same side where the lesion is located. With propersetting, the cerebral cortex can be visualised, thus indicatingthat the ultrasound waves reach the gray matter (2). TheANTICANCER RESEARCH 34: 5761-6258 (2014)5844ultrasound could then be directed toward the anatomicalregions where the lesion is located. Most regions of the braincan be accessed through the temporal acoustic window, withthe exception of distal areas of the frontal and occipital lobes.Focussed ultrasounds are known to transiently increase thepermeability of the BBB (3) and, therefore, allow passage ofOA-GcMAF that is a relatively lipophilic molecule thanks tothe presence of oleic acid. The procedure lasts 5-15 min,causes no discomfort or side effects and can be repeatedcontinuously or in cycles. The procedure can be safelyperformed before, during or after other anti-neoplastictreatments.1 Ruggiero M et al: Oleic Acid, deglycosylated vitamin d-binding protein, nitric oxide: a molecular triad made lethalto cancer. Anticancer Res 34(7): 3569-3578, 2014.2 Bradstreet JJ et al: A new methodology of viewing extra-axial fluid and cortical abnormalities in children with autismvia transcranial ultrasonography. Front Hum Neurosci 7:934, 2014.3 Burgess A et al: Drug delivery across the blood-brain barrierusing focused ultrasound. Expert Opin Drug Deliv1 1(5):711-721, 2014.85GLYCOSYLATED OLEIC ACID/VITAMIN D-BINDING PROTEIN SUPPRESSES HER2 ONCOGENEEXPRESSION IN HUMAN BREAST CANCERMarco Ruggiero1,3, Jacopo J.V. Branca2, David Noakes3,Massimo Gulisano2, Gabriele Morucci2, Lynda Thyer3 and Stefania Pacini2Departments of 1Experimental and Clinical BiomedicalSciences and 2Experimental and Clinical MedicineUniversity of Firenze, Firenze, Italy;3Immuno Biotech Ltd; Guernsey, Channel Islands, UKA woman was diagnosed with mammary adenocarcinoma inthe right breast in 1985 at the age of 37, followed byquadrantectomy, lymphadenectomy and irradiation. In 1999, anadenocarcinoma was diagnosed in the left breast, followed byample resection and anti-oestrogen receptor treatment for 6years. In April 2014, an infiltrating adenocarcinoma wasdiagnosed in the right breast that had been operated in 1985.Pre-operative biopsy showed weak positivity for progesteronereceptor (PgR, <1%) and high positivity for the oncogeneHER2 (>10%, score 2+). With the goal of boosting herimmune system during the 3 weeks preceding surgery,glycosylated oleic acid/vitamin D-binding protein (OA-GcMAF) was administered by subcutaneous injections,nebulisation and with a fermented milk product rich in OA-GcMAF. No drug was administered in the 3 weeks precedingsurgery, nor had the patient received any treatment for theprevious 8 years. Following right mastectomy, analysis of thesurgical specimen showed no positivity for HER2 expression(negative, score 0) and significant increase in positivity of PgR,from <1% to 20%. These results indicate that OA-GcMAFtreatment suppressed oncogene expression and induceddifferentiation of cancer cells. Introduction: The healthyproperties of oleic acid (OA) in breast cancer have been knownfor centuries (1) and recent evidences suggest that theseproperties are amplified by association of OA with proteinssuch as α-lactalbumin and lactoferrins. These proteins formOA-protein complexes that exhibit highly selective anti-tumouractivity in vitro and in vivo (2). We recently demonstrated thatalso a serum protein with the capability to bind OA showsanticancer effects; this is the glycosylated vitamin D-bindingprotein also known as Gc-protein-derived macrophageactivating factor or GcMAF (3). This protein binds both OAand vitamin D and exerts its immune-stimulating andanticancer effects through cross-talk with the vitamin Dreceptor (4). Here we report a clinical observation suggestingthat OA-GcMAF, that is GcMAF-complexed with OA,suppresses the expression of a major oncogene involved inhuman breast cancer that is the human epidermal growth factorreceptor 2 (HER2). Patients and Methods: A woman wasdiagnosed with mammary adenocarcinoma in the right breast in1985 at the age of 37, followed by quadrantectomy,lymphadenectomy and irradiation. In 1999, an adenocarcinomawas diagnosed in the left breast, followed by ample resectionand anti-oestrogen receptor treatment for 6 years. In April2014, an infiltrating adenocarcinoma was diagnosed in the rightbreast that had been operated in 1985. With the goal ofboosting her immune system during the 3 weeks elapsingbetween biopsy and programmed surgery, OA-GcMAF(Goleic®, Immuno Biotech Ltd.) was administered bysubcutaneous injections (880 ng) and nebulisation (880 ng) asindicated in (3). The patient followed a nutritional regime basedon a low carbohydrate, high protein diet (5). To this end, thepatient was provided with food containing only 2%carbohydrates (Le Gamberi Foods, Forlì, Italy), and withessential aminoacids (Master Aminoacid Pattern®, dr. reinwaldhealthcare gmbh, Schwarzenbruck, Germany) (6). The patientwas also provided with a fermented milk product containingcolostrum and microorganisms known to produce OA-GcMAFfrom the Gc-protein present in milk (Bravo Probiotic®, LesAlpes, Wellington, NZ). No drug was administered or wasprogrammed in the 3 weeks preceding surgery, nor had thepatient received any treatment for the previous 8 years. Theanalyses on HER2 and other gene expression on the biopsy andsurgical specimens were performed by the laboratory of theUniversity Hospital of Careggi of the Italian Public HealthService, in Firenze, Italy. Analyses were performed accordingto the European standards of quality (UNI EN ISO 9001:2008)and were examined and countersigned by four differentprofessionals. The original documents are conserved in thearchives of the Department of Biomedicine of the CareggiAbstracts of the 9th International Conference of Anticancer Research, 6-10 October 2014, Porto Carras, Sithonia, Greece5845

Focussed transcranial ultrasounds: application to the delivery of glycosylated oleic acid/vitamin d-binding protein to brain tumours and metastases

https://flore.unifi.it/bitstream/2158/918538/1/84.Focussed%20transcranial%20ultrasounds.%20Application%20to%20the%20delivery%20of%20glycosylated%20oleic%20acidvitamin%20dbinding%20protein%20to%20brain%20tumours%20and%20metastases.pdf

Focussed transcranial ultrasounds: application to the delivery of glycosylated oleic acid/vitamin d-binding protein to brain tumours and metastases

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