ClinFomatrix Oncology, USA
Breast cancer is the most common cancer in women worldwide. It is also the principle cause of death from cancer among women globally. Despite the high incidence rates in western countries, 89% of women diagnosed with breast cancer are still alive 5 years after their diagnosis, which is due to detection and treatment. Breast cancer incidence has been increasing. In 2015, an estimated 231,840 new cases of invasive breast cancer are expected to be diagnosed in women, along with 60,290 new cases of non-invasive (in situ) breast cancer. About 2,350 new cases of invasive breast cancer are expected to be diagnosed in men in 2015. A manʼs lifetime risk of breast cancer is about 1 in 1,000. Breast cancer incidence rates in the U.S. began decreasing. One theory is that this decrease was partially due to the reduced use of hormone replacement therapy (HRT) after the results of a large study called the Womenʼs Health Initiative were published in 2002. These results suggested a connection between HRT and increased breast cancer risk. About 5-10% of breast cancers can be linked to gene mutations. Mutations of the BRCA1 and BRCA2 genes are the most common. On average, women with a BRCA1 mutation have a 55-65% lifetime risk of developing breast cancer. For women with a BRCA2 mutation, the risk is 45%. Breast cancer that is positive for the BRCA1 or BRCA2 mutations tends to develop more often in younger women. An increased ovarian cancer risk is also associated with these genetic mutations. In men, BRCA2 mutations are associated with a lifetime breast cancer risk of about 6.8%; BRCA1 mutations are a less frequent cause of breast cancer in men.
All drugs for breast cancer treatment developed and in market cause mild to several side effects and the safety, pharmacovigilance, signal detection a and risk management of breast cancer drugs are difficult to manage. A series of challenges of breast cancer therapy and the drug safety will be discussed at the meeting.
Biography:
Dr. Ashok Srivastava is Chief Executive Officer and Chief Medical Officer of Cure Pharmaceuticals and ClinFomatrix Oncology CRO, He was founder, CEO and CMO of CareBeyond - A Radiation Therapy Cancer Center, New Jersey. USA. He has more than 15 years of experience in drug development, medical affairs and commercialization of cancer drugs including radiopharmaceutical and supportive care; Phase 1–4 and marketing commercialization of Hematology, Oncology and radio-immuno-oncology drugs in USA, EU and Japan. He received his clinical, medical training & worked at renowned medical centers and pharmaceutical institutions worldwide. He received his Clinical, Medical & Business educations from All India Institute of Medical Sciences, New Delhi, India; Academy of Medical Sciences, Czechoslovakia; School of Medicine Nagasaki University, Japan and Pharmaceutical Business at Rutgers University Business Management, New Jersey and USA. He played key role in dramatic expansion of oncology drug – developed cancer drugs- Sutent (Sunitinib), Evoxac (Cevimeline HCl) and liposomal doxorubicin (Myocet) in combination with Herceptin & Paclitaxel for HER2 positive for metastatic breast cancer patients and Latuda (Lurasidone) for schizophrenia. He has published more than 85 papers in National and International Journals, more than 120 abstracts, 3 book chapters and 2 patents. He is recipient of numerous National & International prestigious medical awards and recognitions. He served as medical advisor to Poniard Pharmaceutical for small cell lung cancer and Taiho Oncology in USA, EU and India.
Dr. Srivastava is member of numerous prestigious organizations; Americaʼs Top Oncologist of the years 2017, Breast Cancer Foundation, Indian Society of Oncology, American Society of Clinical Oncology, American Society for Therapeutic Radiology & Oncology, American Association of Cancer Research and International Society of Lung Cancer. Recently He was awarded membership of Japan External Trade Organization, USA. He is a Leader in Drug Safety, pharmacovigilance of Oncology, hematology, immuno-oncology and built global drug safety and pharmacovigilance companies in USA and India. He was invited as an honorable speaker at drug safety & Pharmacovigilance congress in London, UK, India and Washington, DC, USA in 2017. He is the one who brought 2 cancer drugs & a vaccine in global market for approximately 3 – 3.5 billion $ in global sales. He serves as board of directors for oncology pharma companies in USA.
Dnipropetrovsk Medical Academy of Health Ministry of Ukraine, Ukraine
Effect of piracetam, thiocetam and interleukin-1 receptor antagonist (IL-1ra) (7.5 mg/kg) on the values of thiol-disulfide system (TDS) and protein oxidative modification (POM) was studied based on the rat alloxan diabetes model. It is established that postischemic damage to brain tissue of the experimental animals was followed by multidirectional thiol-disulfide imbalance (increase in levels of oxidized forms of glutathione and thiols on the background of sharp decrease in their reduced forms), decreased activity of TDS enzymes (glutathione peroxidase and glutathione reductase) and increased level of POM markers – APhH and KhH. It is proved that course introduction of piracetam, thiocetam and IL-1ra was beneficial in stabilizing TDS and POM values, normalizing activity of glutathione peroxidase and glutathione reductase, with maximum activity noted for IL-1ra.
Keywords: Interleukin-1, IL-1ra, experimental diabetes mellitus, thiol-disulfide system
Dnipropetrovsk Medical Academy of Health Ministry of Ukraine, Ukraine
Introduction: L-carnitine is a metabolite of C4 oil LC, which is involved in the transfer of palm-n-LC through the inner membrane into the mitochondrial matrix and is a substrate for the formation of ATP molecules. Carnitine is a trimethylated amino acid naturally synthesized in the liver, brain and kidneys from protein lysine and methionine. Several factors, such as sex hormones and glucagon, can influence the distribution and level of carnitine in tissues. It is generally believed that carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, where they can be broken down through β-oxidation to acetyl-CoA to obtain usable energy via the citric acid cycle. Therefore LC is required for the generation of metabolic energy in living cells.
As we know, malignant neoplasms have specific influence on the organism in general and on DNA in particular. So, in vitro studies in human tumor cell lines have shown a positive effect of L-Carnitine regarding the inhibition of apoptosis and DNAdamage. Using of L-carnitine in patients with cancer improves the metabolism of fatty acids in mitochondria, restores normal mitochondrial function and, thus, improves the general condition and quality of patientsʼ life. On the other hand, L-Carnitine is well known for its potential to modulate the inflammatory response mechanisms, which is known to play the predominant role in the generation of cancer cachexia. Increasing the effectiveness of antitumor therapy who received L-carnitine compared with patients who donʼt take it, served as a prerequisite for studying possible antitumor mechanisms of L-carnitineʼs action.
In this article presents epidemiological, preclinical and clinical studies information of the antitumor efficacy of L-carnitine.
The mechanism of L-carnitineʼs action:
Carnitine is synthesized from the amino acids lysine and methionine. The rate limiting step in carnitine biosynthesis is the availability of trimethyllysine at the intramitochondrial site of trimethyllysine hydroxylase activity. L-carnitine is absorbed in the intestine by a combination of active transport and passive diffusion. In the absence of L-carnitine, the inner membrane of the mitochondria becomes impermeable to fatty acids, which entails a chain of various metabolic disorders in the human body.
This medicine has many effects on the organism. One of them is a modulating effect on the function of acetylcholine excitatory neurotransmitter, glutamate excitatory amino acid, insulin growth factor-1 (IGF-1) and nitric oxide (NO). Also proved, that L-carnitine may have a dual protective effect by enhancing the energy dynamics of the cell and inhibiting cell membrane hyper excitability, which make it an ideal nutrient for cancer prevention and treatment. Carnitine may also mimic some of the biological activities of glucocorticoids, particularly immunomodulation, via suppressing TNF-α and IL-12 release from monocytes. L-carnitine as adjuvant therapy in cisplatin-treated cancer patients proved a beneficial effect in reducing the cisplatin-induced organ toxicity.
It is possible that, the extremely lipophilic nature of carnitine may be responsible for the decrease in EGF binding. Carnitine may insert in the cell membrane and/or interact with one of the many cellular enzymes having lipid substrates or cofactors. In addition, carnitine may interact directly with the EGFR. L-carnitine, via its free radical scavenging and antioxidant properties, may inhibit ROS-mediated EGFR phosphorylation. It has been found that palmitoyl-carnitine can inhibit the activity of heart and brain protein kinase C in a competitive manner and subsequent phosphorylation of the EGFR.
Studies on the role of L-carnitine for the prevention and treatment of cancer:
The efficacy of using L-carnitine for the prevention and treatment of malignant neoplasms has been proven in epidemiological, experimental and clinical studies.
Based on the data provided by Rania M. Khalil and co-authors (2013), we can prove the positive effect of this medicine on the course and outcome of breast cancer. The study showed that patients who received Tamoxifen with L-carnitine had significant decrease of Her-2 / neu and IGF-1 level (P <0.05) in the serum compared with patients who received only Tamoxifen. Using of L-carnitine led to significant decrease Her-2 / neu level in the serum (P <0.05) compared to each of the control patients namely, 59.5%. The effect of tamoxifen on IGF-1 (P <0.05) -decrease its level by 5.4%.
However, it has been proved that using of L-carnitine in the treatment of ER+ breast cancer does not significantly reduce the level of estradiol, but leads to decrease both tumor markers CEA and CA15.3 (P <0.05,% decrease by 80.9% and 67, 8%, respectively).
Matthias Kraft and co-authors (2012) have shown that using L-carnitine reduces chemotherapy related side effects of treatment of advanced pancreatic cancer.
Waldner et al. (2006) examined the effects of L-carnitine with a view to reducing cardiotoxicity of DOX-containing chemotherapy in 20 patients with Non-Hodgkin lymphoma. Patients were scheduled to receive 3g L-carnitine before each chemotherapy cycle, followed by 1g L-carnitine/day during the following 21 days. Carnitine-treated patients showed a rise in plasma carnitine which led to an increase of relative mRNA levels from CPT 1 and OCTN2. They concluded that biochemical and molecular analyses indicated a stimulation of oxidative metabolism in white blood cells through carnitine uptake.
Hongbiao Huang and co-authors (2012) compared the effects of LC on normal tissue and cancer growth in vivo. Normal Balb/c mice or Balb/c nude mice inoculated with HepG2 cancer cells were i.p. injected with a tolerated dose of the medicine. It was found that LC treatment inhibited more than 70% of cancer growth, while the same treatment decreased less than 20% of the normal organ development and body weight. Also they proved that LC treatment increased protein (histone) acetylation in cultured cells.
Biography:
Dr. Mohammad Hojouj presently is an Assistant Professor, Oncologist, research scientist, sub-investigator in clinical trials, Associate professor at the Oncology and Medical Radiology Department, (More than 340 trials & Principal Investigator Bondarenko Igor) from the Municipal Institution “Dnipropetrovsk City Multi-field Clinical Hospital #4”, Chemotherapy Department, State Institution “Dnipropetrovsk Medical Academy at the Ministry of Health of Ukraine”, Ukraine. He was a speaker at German Pharmaceutical Phytoneering Company “Bionorica”/Ukrainian representative office. In 2014 was a Specialist-oncologist from Territorial oncological hospital/Dnepropetrovsk, Ukraine.
He obtained his Doctor Philosophy, Ph.D. from Special Academic Council of Dnepropetrovsk state Medical Academy, Master of Medicine (oncology) degree, Medical Specialist of Oncology and Medical Doctor from Dnepropetrovsk State Medical Academy/Dnepropetrovsk, Ukraine
He is in association & a member in various organizations - ASCO; ESMO; ESGO; NCCN, EDS, certificate NCCN (September, 2015); AAPU; The Arab Medical Union in Europe (ARABMED) (Certificate ARAB MED, November, 2015); The Arab Medical Union in UKRAINE (AMUU), “Association of Arabic doctors in Ukraine”. He is a certified doctor-oncologist. And participated at many regional research and practical conferences, obtained maximum CME credits, 12 certificates from NCCN-national comprehensive cancer network to confirm the results of professional skills improvement. He is a Medical license holder.
He delivered some lectures about the prevention of breast and skin cancer on Ukrainian television and holds some publications. As a doctor-oncologist he took part in organization of cancer care to the population, made diagnosis and treatment of main localization tumors such as: Breast cancer (I, II, III, IV), Lung cancer, Ovarian cancer, Bone cancer, Lymphoma cancer, Kidneys cancer, Colorectal cancer, Skin cancer and minimally invasive skin operations, Malignant acrospiroma, Head and neck cancer, Hematology. He worked as assistant at tumourʼs surgical operations & performed minor surgeries.
1Northwest Minzu University, China
2Guizhou Normal University, China
3Southwest University of Science and Technology, China
The present study aimed to investigate FSH receptor binding inhibitor (FRBI) effects on relative factors (K-Ras, c-Myc and Vascular endothelial growth factor (VEGF)) to ovarian cancer and expression levels of FSH receptor (FSHR) mRNAs and proteins in the cumulus-oocyte complex (COCs), to determine changes of protein kinase A (PKA) in sheep granulosa cells, further to elucidate signaling pathway of FRBI action. COCs were cultured in vitro for 24h under supplementation of varying concentrations of FRBI (0, 10, 20, 30 and 40µg/mL) or FSH (10IU/mL). Concentrations of K-Ras, c-Myc, VEGF, cAMP and FSH were detected in IVM media fluids, respectively. The results showed that the concentrations of c-Myc, K-Ras and FSH of FRBI groups were gradually reduced with the increase of FRBI doses. VEGF level of the FRBI-4 group was significantly greater than control group (CG). Expression levels FSHR mRNA and protein and PKA of FRBI-3 and FRBI-4 groups were less than that of CG or FSH group (P<0.05 or P<0.01). Inositol trisphosphate (IP3) concentrations of FRBI-3 and FRBI-4 groups were less than FSH group (P<0.05). FRBI administration doses had significant negative correlations to levels or concentrations of K-Ras, c-Myc, VEGF, FSHR mRNA and protein and PKA protein. K-Ras had significant positive correlations with FSHR mRNA and protein and PKA protein. In conclusion, FRBI could promote the production of VEGF of sheep COCs. Higher doses of FRBI (30 and 40µg/mL) suppressed the production of c-Myc and K-Ras and declined FSH concentrations in the IVM medium fluid and decreased the expressions of FSHR at the gene and protein levels, additionally attenuated expression of PKA protein in the granulosa cells.
Keywords: FSH receptor binding inhibitor; Ovarian cancer; K-Ras; c-Myc; Protein expression; Signal pathway
Stanford University School of Medicine, USA
Introduction: Lack of specific targeting/insufficient genetic material delivery have hampered gene directed enzyme prodrug (GDEPT) therapies. We have developed “EXO-DEPT” exosomes that specifically target HER2+ breast cancer, delivering a gene (as mRNA) that encodes our improved bacterial enzyme, HChrR6 which activates the prodrugs CNOB and CB1954. Drug generated by CNOB is MCHB, which is fluorescent. Exosomes being ‘natureʼs own antigen delivery systemʼ are superior to other delivery vehicles, e.g., viruses and nanoparticles. mRNA is superior to DNA for gene delivery: It is directly translated upon delivery to the cytosol and eliminates the danger of insertional mutagenesis.
Methods: To direct the exosomes specifically to HER2+ cells/tumors, the chimeric protein, EVHB, was constructed composed of high-affinity anti-HER2 scFv antibody (ML39) and lactadherin C1-C2 domains, capable of tethering to exosome surface. Transfection of HEK293 cells with a new plasmid, generated mRNA-loaded exosomes (“plasmid exosomes”); their incubation with EVHB generated plasmid-EXO-DEPT exosomes. CNOB to MCHB conversion was measured from MCHB fluorescence, cell viability by MTT assay. To load exosomes with a plasmid-free method, in vitro transcribed (IVT) HChrR6 mRNA was used (“IVT-exosomes”) because CB1954 has already been in clinical trials, this prodrug was also used.
Results: Plasmid-EXO-DEPT treatment specifically enabled HER2+ BT474 cells to convert CNOB into MCHB (actinomycin D–independent), showing successful mRNA transfer. These EXO-DEPT+CNOB treatment caused complete growth arrest of orthotopic BT474 xenografts in mice. IVT-EXO-DEPTs proved more efficient; some two-log fewer number along with CB1954 resulted in complete inhibition of the tumor growth. Hematological analyses and pathological examination of several organs showed no signs of toxicity.
Conclusion: This is the first time that functional exogenous mRNA was delivered by exosomes. The EXO-DEPT prodrug regimen successfully treats HER2+ tumors in mice without offsite toxicity. Use of IVT-EXO-DEPTs eliminates the danger of introduction of potentially harmful plasmid genetic material during the treatment. Since the ML39 anti-HER2 scFv can be replaced by other similar targeting ligands, the approach is generic and can treat any cancer/disease in which a receptor is over-expressed. Since exosomes can cross the blood brain barrier, this regimen can be adapted to teat brain metastasized cancer/brain diseases.
Biography:
Dr. Matin has been a full professor at Stanford University for several years and is affiliated with several programs, including the Stanford Cancer Research Institute. He has contributed to many areas of biological research, including discovery of new drugs and therapeutic enzymes and their improvement as well as specific targeting of these to cancer. He did his Ph. D. at UCLA, spent some years in the Netherlands (State University of Groningen), where he directed a research group, before joining Stanford. He is recipient of numerous awards and honors.
University of Liverpool, UK
Cellular based therapeutic approaches for cancer rely on careful consideration of finding the optimal cell to execute the cellular goal of cancer treatment. Cell lines and primary cell cultures have been used in some studies to compare the in vitro and in vivo efficacy of autologous vs allogeneic tumour cell vaccines. This study examines the effect of γ-irradiation on a range of tumor cell lines in conjunction with suicide gene therapy of cancer. To determine the efficacy of this modality, a series of in vitro and in vivo experiments were conducted using genetically modified and unmodified tumor cell lines. Following co-culture of HSV-TK modified tumor cells and unmodified tumor cells both in vitro and in vivo we observed that the PA-STK ovariantumor cells were sensitive to γ-irradiation, completely abolishing their ability to induce bystander killing of unmodified tumor cells. In contrast, TK-modified human and mouse mesothelioma cells were found to retain their in vitro and in vivo bystander killing effect after γ-irradiation. Characterisation of tumor cell death showed that PA-STK cells underwent pyknosis (necrosis) after γ-irradiation. These results suggest that PA-STK cells are not suitable for clinical application of suicide gene therapy of cancer, as lethal γ-irradiation (100Gy) interferes with their bystander killing activity. However, the human mesothelioma cell line CRL-5830-TK retained its bystander killing potential after exposure to similarly lethal γ-irradiation (100Gy). CRL-5830 may therefore be a suitable vehicle for HSV-TK suicide gene therapy. This study highlights the diversity among tumor cell lines and the careful considerations needed to find the optimal tumor cell line for this type of whole cell tumour vaccination.
Biography:
Dr. Jehad Zweiri, lecturer in Cancer studies at the University of Liverpool Medical School, born and grew up in Jordan and received his Bachelorʼs degree from the University of Jordan in 1990. He obtained his master degree from London School of Hygiene and Tropical Medicine/University of London and then obtained his PhD degree in 2000 from Kings College Medical School/University of London, in the field of Immune Gene Therapy of Cancer under the supervision of Professor Farzin Farzaneh. He then started his work as Postdoctoral Associate at the department of Immunology and Medicine at the University of Liverpool in 2002. In 2010 he was appointed as a lecturer in the University of Liverpool Medical School and he is currently fellow of the British Higher Education Academy since 2012.
University of Pittsburgh, USA
Chromosome mutations and rearrangements are some of the hallmarks of human malignancies. Chromosomal rearrangement is frequent in human cancers. One of the consequences of chromosomal rearrangement is gene fusions in the cancer genome. We have identified a panel of fusion genes in aggressive prostate cancers. In the present study, we found that these fusion genes are present in 7 different types of human malignancies with variable frequencies. Among them, CCNH-C5orf30 and TRMT11-GRIK2 gene fusions were found in breast cancer, colon cancer, non-small cell lung cancer, esophageal adenocarcinoma, glioblastoma multiforme, ovarian cancer and liver cancer, with frequencies ranging from 12.9% to 85%. In contrast, four other gene fusions (mTOR-TP53BP1, TMEM135-CCDC67, KDM4-AC011523.2 and LRRC59-FLJ60017) are less frequent. Both TRMT11-GRIK2 and CCNH-C5orf30 are also frequently present in lymph node metastatic cancer samples from the breast, colon and ovary. Thus, detecting these fusion transcripts may have significant biological and clinical implications in cancer patient management. One of these fusion genes called MAN2A1-FER generated a constitutively activated tyrosine protein kinase. The fusion translocates FER kinase from the cytoplasm to Golgi apparatus. The fusion protein ectopically phosphorylates the N-terminal domain of EGFR and activates the EGFR signaling pathway in the absence of a ligand. MAN2A1-FER has been found in a variety of human malignancies. It transforms immortalized cell lines into highly aggressive cancer cells. Expression of MAN2A1-FER produces spontaneous liver cancer in animals. Cancer cells positive for MAN2A1-FER are highly sensitive to several tyrosine kinase inhibitors and can be targeted by genome therapy intervention. Thus, targeting at MAN2A1-FER or other oncogenic fusion genes may hold promise to treat human cancer effectively.
Biography:
Dr. Luo has been studying molecular pathology related to human malignancies in the last 28 years. Currently, he is a Professor of Pathology and Director of High Throughput Genome Center at University of Pittsburgh. In the last 17 years, Dr. Luo has been largely focusing on the genetic and molecular mechanism of human prostate and hepatocellular carcinomas. In this period, his group has identified and characterized several genes that are related to prostate cancer and hepatocellular carcinoma, including SAPC, myopodin, CSR1, GPx3, ITGA7, MCM7, MCM8, MT1h and GPC3. He has characterized several signaling pathways that play critical role in prostate cancer development, including Myopodin-ILK-MCM7 inhibitory signaling, myopodin-zyxin motility inhibition pathway, CSR1-CPSF3, CSR1-SF3A3 and CSR1-XIAP apoptotic pathways, MT1h-EHMT1 epigenomic signaling, ITGA7-HtrA2 tumor suppression pathway, GPx3-PIG3 cell death pathway, AR-MCM7, MCM7-SF3B3 and MCM8-cyclin D1 oncogenic pathways. He proposed prostate cancer field effect in 2002. He is one of the pioneers in utilizing high throughput gene expression and genome analyses to analyze field effects in prostate cancer and liver cancer. He is also the first in using methylation array and whole genome methylation sequencing to analyze prostate cancer. Recently, his group discovered several novel fusion transcripts and their association with aggressive prostate cancer. One of the fusion genes called MAN2A1-FER, was found present in 6 different types of human cancers. He later defined a critical MAN2A1-FER/EGFR signaling pathway that is essential for MAN2A1-FER mediated transformation activity. His group also developed a genome intervention strategy targeting at the chromosomal breakpoint of fusion gene to treat cancers. Overall, these findings advance our understanding of how cancer develops and behaves and lay down the foundation for better future diagnosis and treatment of human malignancies.
1Fox Chase Cancer Center, USA
2Drexel University, USA
Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease which is driven and supported by changes in its microenvironment, or stroma. This project dissects the intercellular communication that exists between the primary stromal component, Cancer-associated fibroblasts (CAFs) and PDAC. Specifically we focus on how CAF-secreted vesicles promote PDAC progression, with an additional goal to identify biomarkers suitable to generate a future “liquid biopsy” test for early PDAC detection. PDAC communicates with its microenvironment, in part through the exchange of specific types of extracellular vesicles (EVs), which include exosomes.
We observe distinct types of CAF-derived EVs containing unique surface receptors. One EV subpopulation of interest contains a novel surface protein, NetrinG1 (NG1), which is expressed on the plasma membrane of pancreatic CAFs, but not their normal/healthy counterparts. Further, PDAC cells, but not healthy pancreatic epithelial cells, upregulate NG1ʼs lone binding partner, NGL1, suggesting a role for these binding partners in PDAC-selective EV uptake. Functional assays designed to test PDAC viability suggest these NG1(+)-EVs protect PDAC cells from programmed cell death as a result of physiological stress. Pursuing our biomarker goal, we confirm stromal NG1 expression prior to tumor development and are currently seeking to validate NG1-postive EVs in blood of PDAC patients. Altogether, this research identifies a novel mechanism of tumor-stroma communication and introduces EV biomarkers capable of identifying both early PDAC occurrences and predicted efficacy of certain adjuvant interventions.
Biography:
Kris Raghavan is currently 4th year PhD student, conducting research on pancreatic cancer in the lab of Dr. Edna Cukierman at Fox Chase Cancer Center. He completed his MSc at Georgetown University with a degree in Tumor Biology, conducting breast cancer research in the lab of Dr. Robert Clarke. Kris is the primary author for two publications: a review article on caveolinʼs role in breast cancer and Springer textbook chapter on stress response pathways in mammalian cells. As he approaches the completion of his PhD, Kris seeks to make professional connections in both the academic and private biotechnology sectors.
University of São Paulo, Brazil
Background: TP53 p.R337H germline mutation is highly prevalent among individuals from South and Southeast Brazil; mainly in pediatric adrenocortical tumours (ACTs). The prevalence Li-Fraumeni Syndrome (LFS) spectrum, clinical outcomes and tumor occurrence in relatives carrying has not been fully investigated.
Patients and Methods: Medical records of all LFS and LFL patients with p.R337H were reviewed and tumor profile data, clinical characteristics and outcomes assessed. Tumor penetrance in familial carriers was also evaluated.
Results: 47 of 43 families, female (70%), with LFS due to TP53 p.R337H mutation. Maternal inheritance occurred in 72%. ACT in the pediatric group was diagnosed in 57%; (median age = 2 years), in adult group ACC in 23%; (median age= 29.5 years), breast cancer (11%; median age = 41 years), sarcoma (6%; median age = 50.3 years) and choroid plexus carcinoma (CPC) (2%; median age = 18 years). Children did not develop the second tumor and 11% (n=3) died due to complications related to the initial tumor (median follow-up time of 81.5 months, range= 3-378 months). Among adult with ACC all presented aggressiveness histologic and clinical criteria at diagnosis and 82% of patients died (median follow-up time of 19 months, range = 1-69 months). The adult patients that presented a second primary tumor (n = 4; 9%) have had breast cancer, sarcoma or ACC as their first syndromic manifestation. The second primary tumors were bronchi alveolar lung cancer, ACC, uterine cervical carcinoma and fibrosarcoma, diagnosed 8, 18, 26 and 36 months after diagnosis of first primary tumor, respectively. Among these 4 patients, two patients died (median follow-up time of 60 months, range= 8 to 218 months). Two cases of adrenocortical tumor in the same family were observed only once - they were second-degree cousins and one presented ACT in infancy and had an optimal evolution (overall survival = 378 months) and the other presented ACC in adulthood and had a poor outcome (overall survival =6 months). Cancer screening in familial asymptomatic carriers (n = 71) according to Toronto Protocol identified only three malignant neoplasms in three different carriers.
Conclusions: This study showed that TP53 p.R337H mutation is associated with ACT in the pediatric group but also brings new insights such as the occurrence of others tumors of LFS spectrum, the rare occurrence of multiple tumours, the predominance of maternal inheritance and mostly the difference in aggressiveness of adrenocortical tumours depending on the age group in which it was diagnosed. The pronounced intra and interfamilial phenotypic diversity raises the need to understand the other events that, added to the presence of this mutation justify these findings.
Biography:
Dr. Maria CandidaBarisson Villares Fragoso Professor of the Clinical Hospital of the Faculty of Medicine of the University of São Paulo, Head of the Suprarenal Unit of the Department of Endocrinology and Metabolism of HCFMUSP, Medical Researcher at the Laboratory of Hormones and Molecular Genetics LIM / 42, Graduated in Medicine from the Pontifical Catholic University of Campinas in 1989. Obtained her PhD in Endocrinology and Metabology, Faculty of Medicine, University of São Paulo in 1999. Post-doctorate in Endocrinology and Metabology, Faculty of Medicine, University of São Paulo in 2002. She was a Senior Researcher at University Hospital Center Research Center (CHUM) at the Laboratory of Endocrine Pathophysiology Montreal / Canada, CNPq Senior Scholarship in 2009. And was a Professor in Endocrinology and Metabology, Faculty of Medicine, University of São Paulo in 2011. CNPq Scholarship-Productivity in Research (2013-2019).
She is presently member of the Brazilian Society of Endocrinology and Metabology and Effective Member of the Endocrine Society (USA), European Network for the Study of Adrenal Tumors ENSAT and also for the A5Adrenal Network American Australian Asian Adrenal Alliance.
Bar-Ilan University, Israel
Gliomas are the most frequent brain tumors, making up about 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. Diagnosis of different glioma tumor types and their tumor grade is an essential step to suggest a right treatment for the glioma patients. Existing standard diagnostic technique for glioma tumor includes tissue biopsy, which is a highly invasive and hence a risky technique for the patientʼs survival. ‘Liquid biopsyʼ is a new and recently developed non-invasive cancer diagnostic technique. This technique includes collection of blood or urine samples and diagnosis of cancer based on analyzing molecular bits or cancer cells that are released from tumor tissue into the blood or urine system. Circulating cell-free DNA (cfDNA) fragments is one those molecular bits that are released into the bloodstream after rapid apoptosis or necrosis of the tumor cells in the cancer patients.
Our goal is to do comprehensive study between distinct types of glioma cancer tumors and cfDNA of the respective patients, to elucidate the scope of cfDNA in liquid biopsy technique for glioma diagnosis. We have successfully detected glioma specific mutations such as IDH1, IDH2, PDGFRA, NOTCH1, PIK3R1 and TP53, from cfDNA isolated from the plasma of glioma patients and could relate this mutations to the different tumor grades of glioma. We are also studying the dynamics of these mutations in response to glioma drug treatment by collecting blood samples at different time intervals. This study may help in developing liquid biopsy technique for glioma tumor diagnosis and in its prognosis for monitoring the glioma treatment by non-invasive approach and will eventually help physicians to decide the right treatment on appropriate time while bypassing the existing ‘wait-and-seeʼ approach of treatment monitoring.
Keywords: Liquid biopsy, glioblastoma, circulating cell free DNA, low burden tumors, gliomas.
Acknowledgements:
This research was supported by Israel Cancer Association (Cancer Diagnostics project 2017-2019), Israel.
Biography:
Dr. Milana Frenkel-Morgenstern has completed her Ph. D at the age of 32 years from Weizmann Institute of Science and postdoctoral studies from Spanish National Cancer Research Centre (CNIO). She has published more than 25 papers in reputed journals and serving as an editorial board member of repute. She is a founder of the Art in Science competition at the ISMB conference since 2008; a chair of the ISCB affiliated Israeli Bioinformatics group and a head of the Cancer Genomics and BioComputing group in the Azrieli faculty of Medicine, Bar-Ilan University. Her Research Interest includes the development of a Liquid Biopsy platform for brain cancers using unique biomarkers, particularly, fusion proteins. We expect to provide a proof-of-concept stage of our research for 50 patients in glioblastoma and the validation stage for 1000 patients in gliomas.
UTHSC Center for Cancer Research Memphis, USA
Triple negative breast cancers (TNBCs) evolve to highly chemoresistant subtypes in response to chemotherapy and that frequently metastasize to various organs simultaneously. TNBCs are devoid of a specific-targeted therapy and are active for a WNT10B-network that drives metastasis. Here we demonstrate that WNT inhibition decreased proliferation on multiple TNBC breast cancer cell lines and TNBC PDX tumor-derived cell lines, in vitro. The WNT inhibitor ICG-001/PRI-724 led to loss of protein expression of the WNT10B/β-CATENIN direct targets HMGA2, EZH2, AXIN2, MYC, PCNA and CYCLIN D1. In addition, ICG-001 decreased transwell migration assays, correlating with the loss EMT markers VIMENTIN and SNAIL and decreased wound healing capacity. In vivo, in chemoresistant patient-derived xenograft (PDX) models of TNBC and MDA-MB-231 cells, we observed similar frequencies of simultaneous visceral metastasis to the lymph node and lungs, but not to the brain, bone, ovaries and liver and WNT-therapy blocked whole body metastasis. Micro-computed tomography (μCT) analysis of bone metastasis from the TNBC PDX model demonstrated differential osteolytic properties than that of the MDA-MB-231 cells, in vivo. ICG-001 synergized with doxorubicin, but not with cisplatin-based therapy in the TNBC PDX-derived cells in vitro. Mechanistically, loss of protein expression of WNT10B-network genes and EMT-makers was observed in the primary tumors. Moreover, WNT-inhibition sensitized the doxorubicin response, preventing simultaneous visceral metastases to the bone, liver and ovaries in the TNBC PDX tumors. We suggest that WNT-inhibition can sensitize and lower dosages of FDA-approved anthracycline-based therapies to treat simultaneous visceral metastasis of TNBC.
Chulalongkorn University, Thailand
Purpose: This study was performed to assess cardiac, lung and left anterior descending (LAD) artery dose using deep inspiration breath hold (DIBH) technique comparing with free breath (FB) technique in left breast cancer irradiation with or without internal mammary lymph node (IMN) irradiation.
Material & Method: Twenty-four left breast cancer patients who had breast conserving surgery were prospectively included in this study. CT simulation image data were acquired in FB and DIBH. Respiratory management systems were performed by Varian Real-time Position Management (RPM) during simulation and Vision RT during treatment. Planning target volume of breast, chest wall, IMN and organ at risk (heart, lung, LAD) were contoured in both DIBH and FB CT images. Four treatment planning in each patient were conducted in tangential directions, covering whole breast alone or chest wall plus IMN, in FB images and DIBH images. Planning target volumes need to be covered by 95% isodose line in all plans. Dosimetric parameters including heart (mean heart dose (MHD), heart V25 and V40), lungs (mean left lung dose, left lung V20, mean bilateral lung dose, bilateral lung V20, V40) and mean LAD dose were compared using two tailed unpaired t test. In-field maximum heart distance, heart volume and breast size were evaluated and analyzed using Pearson correlation test to show correlation with mean heart dose.
Result: Comparing FB and DIBH techniques in whole breast irradiation, there is significant reduction in MHD (5.3 Gy vs 2.9 Gy respectively, p 0.006) and Heart V25 (8.2% vs 3.3% respectively, p 0.005). LAD dose has trend of dose reduction in DIBH, 18.3 Gy vs 12.5 Gy in FB, p 0.057. In wide tangent field, covering breast, chest wall and IMN, there were non-significantly better in MHD, 10.6 Gy in FB vs 8.5 Gy in DIBH, p =0.19 and mean LAD, 29.1 Gy vs 25.6 Gy in FB and DIBH respectively, p =0.33 However, Heart V40 and all lung parameters in all treatment plannings did not show significant difference between the 2 techniques. Reduction in MHD was significantly correlated with in-field maximum heart distance, heart volume and breast size. In the patients who had in-field maximum heart distance less than 1 cm, MHD had significantly better and within acceptable dose range. Patients with larger breast size tend to receive more heart dose than smaller breast.
Conclusion: DIBH in left breast cancer irradiation effectively reduce radiation exposure to the heart and LAD while achieving adequate target volume coverage. There were no significant different in lung dose between these 2 techniques. Optimal in-field maximum heart distance will help keeping acceptable MHD.
1Yong Loo Lin School of Medicine, National University of Singapore, Singapore
2National Cancer Centre Singapore, Singapore
3SingHealth Duke-NUS Head and Neck Centre, Singapore
4Singapore General Hospital, Singapore
Background: Regional failure in nasopharyngeal carcinoma (NPC) is managed by salvage treatment in the form of neck dissection. Radical neck dissection (RND) is preferred over modified radical neck dissection (MRND), since it is traditionally believed to offer better long term disease control. However, with the advent of more advanced imaging modalities like high-resolution Magnetic Resonance Imaging, Computed Tomography and Positron Emission Tomography-CT scans, earlier detection is achieved. Additionally, concurrent chemotherapy also contributes to reduced tumour burden. Hence, there may be a lesser need for a RND and a greater role for MRND. With this retrospective study, the primary aim is to ascertain whether MRND, as opposed to RND, has similar outcomes and hence, whether there would be more grounds to offer a less aggressive procedure to achieve lower patient morbidity.
Methods: This is a retrospective study of 66 NPC patients treated at Singapore General Hospital between 1994 to 2016 for histologically proven regional recurrence, of which 41 patients underwent RND and 25 who underwent MRND, based on surgeon preference. The type of ND performed, primary treatment mode, adjuvant treatment and pattern of recurrence was reviewed. Overall survival (OS) was calculated using Kaplan-Meier estimate and compared.
Results: Overall, the disease parameters such as nodal involvement and extranodal extension were comparable between the two groups. Comparing MRND and RND, the median (IQR) OS is 1.76 (0.58 to 3.49) and 2.41 (0.78 to 4.11) respectively. However, the p-value found is 0.5301 and hence not statistically significant.
Conclusion: RND is more aggressive and has been associated with greater morbidity. Hence, with similar outcomes, MRND could be an alternative salvage procedure for regional failure in selected NPC patients, allowing similar salvage rates with lesser mortality and morbidity.
Biography:
Sim Zi Hui Ralene is a fourth-year medical student at National University of Singapore, with an interest in head and neck cancer research.
University of Delhi, India
Over the past decade, the cancer incidence rate was stable in women and declined by approximately 2% annually in men, while the cancer death rate declined by about 1.5% annually in both men and women. Doctors and scientists are always looking for better treatment ways to cure people having cancer. Hence, they create and study new anticancer drugs. Moreover, they also look for new pathways to deliver drugs in tumor tissues that are already available. Drug discovery to drug delivery is a long development and approval process. During this process, researchers make sure that the drug should be safe for patients to take and effectively treats cancer. This process often takes many years and significant resources.
The armamentrum of chemotherapy is generally used to target specific cellular mechanisms in the malignant tissues. Chemotherapeutic agents usually disrupt the vital parts of the cancer cell that consequently prevent cell division. Treatment of cancer requires combination of both radiation and chemotherapy, respectively.
Our group had discovered the anticancer potential of Noscapine, a phthalideisoquinoline alkaloid obtained from the plant “Papaver somniferum”. Later, several potent analogues of noscapine such as 9-bromonoscapine, chloronoscapine, 9-aminonoscapine and reduced bromo-noscapine were synthesized and reported by our group. These potent analogues were collectively termed as “Noscapinoids”.
Recently, several preclinical analyses of noscapinoids against human or mouse tumor cells such as human cervical cancer (HeLa) cells, human non-small cell lung cancer (A549) cells and mouse melanoma cancer (B16F1) cells substantiated that noscapinoids exert potent anticancer activity against cancer cells and even tailored analogues are also toxic to resistant cancer cells. Apart from cancer, noscapine also exhibited potential in the treatment of experimental polycystic ovary syndrome and stroke. Hence, owing to encouraging preclinical consequences, noscapine is currently undergoing Phase I clinical trial against multiple myeloma.
Likewise other anticancer drugs, noscapinoids also exhibit poor physicochemical and biopharmaceutical chattels. The oral absolute bioavailability of noscapine is reported in the range of 40-50% that may be credited to low aqueous solubility. Nevertheless, these properties created both challenges as well as opportunities for formulation scientists to develop a clinically viable formulation for the treatment of cancer.
Thanks to era of nanoscaled drug delivery systems that are providing opportunities to young scientists for developing novel clinically viable formulations to fight cancer. Abraxane (Human serum albumin-paclitaxel conjugate) is one of the commercially successful formulations. Hence, our group reported the cyclodextrin complexes, nanoparticles, effervescent nanoparticles and silver nanoparticles for effectively delivering noscapinoids to tumor cells. In conclusion, noscapinoids may be transformed to clinically viable formulations by conquering existing challenges.
Ohio State University, USA
Small cell lung cancer (SCLC) treatment is a major clinical challenge at present as it is highly refractory to available drugs. The MDSCs/macrophages are known to help SCLC develop resistant to available therapies. S100A9 (Migration inhibitory factor-related protein 14 (MRP14) is an EF-hand calcium-binding protein that has been involved in cell migration, invasion, proliferation and tumor metastasis in various type of cancers. S100A9 has been shown that increases migration of macrophages in vitro and in vivo. The relationship between S100A9 and MDSC has not been studied in SCLC. In this study, we found that S100A9 protein is highly up-regulated in various type of pulmonary neuroendocrine carcinomas (NEC) tissues by tissue microarray. We also observed that SCLC patients with higher S100A9 expression have significantly increased the number of macrophage in the stroma. Additionally, furthermore pre-treatment of the cells with S100A9 inhibitor (Tasquinimod) suppressed in-vitro cell migration, invasion and colony formation. Furthermore, we analyzed the efficacy of S100A9 inhibitor in SCLC in vitro and in vivo. By using xenograft mouse model showed S100A9 inhibitor significantly reduces tumor growth and metastasis in SCLC. Here, we reported that S100A9 inhibitor suppressed MDSC populations and TAMs of the M2-polarized phenotype in SCLC. Moreover, we found myeloid cells sequestered from tumors of treated mice expressed higher levels of inducible nitric oxide synthase (iNos) and lower levels of arginase-1 were more immunosuppressive. Molecular analysis revealed that Tasquinimod decreases expression of IL6, IL10 and TGF-β1 in the cancer cells which helps inhibit macrophage activation to TAMs. Reduced proliferation and vascularization were observed in the tumors obtained from animals treated with S100A9 inhibitor. We also observed S100A9 inhibitor suppressed osteolytic bone formation in ex-vivo resorption assay. Overall, our studies, for the first time, we description here a unique immunotherapy Tasquinimod targets S100A9 signaling that decreases the immunosuppressive assets of myeloid cells and angiogenesis in mouse model of SCLC.
Dr. D. Y. Patil University, India
TransAbdominal Sonography of the stomach & duodenum can reveal following diseases: Gastritis & duodenitis, acid gastritis. An ulcer, whether it is superficial, deep with risk of impending perforation, perforated, sealed perforation, chronic ulcer & post-Healing fibrosis & stricture, polyps & diverticulum, benign intra-mural tumours, intra-mural haematoma, duodenal outlet obstruction due to annular pancreas, gastro-duodenal ascariasis, pancreatic or biliary stents, foreign body, necrotizing gastro-duodenitis, tuberculosis, lesions of ampulla of Vater like prolapsed, benign & infiltrating mass lesions. Neoplastic lesion is usually a segment involvement & shows irregularly thickened, hypoechoic & aperistaltic wall with loss of normal layering pattern. It is usually a solitary stricture & has eccentric irregular luminal narrowing. It shows loss of normal gut signature. Enlargement of the involved segment is seen. Shouldering effect at the ends of stricture is most common feature. Enlarged lymphnodes around may be seen. Primary arising from wall itself & secondary are invasion from peri-ampullary malignancy or distant metastasis. All these cases are compared & proved with gold standards like surgery & endoscopy.
Some extra efforts taken during all routine or emergent ultrasonography examinations can be an effective non-invasive method to diagnose primarily hitherto unsuspected benign & malignant Gastro-Intestinal Tract lesions, so should be the investigation of choice.
Biography:
Dr. Vikas Leelavati Balasaheb Jadhav has completed post graduation in radiology in 1994. He has a 24 Years of experience in the field of gastro-intestinal tract ultrasound & diagnostic as well therapeutic interventional sonography. He is the pioneer of gastro-intestinal tract sonography, especially gastro-duodenal sonography. He has delivered many guest lectures in Indian as well International Conferences in nearly 27 countries as an invited guest faculty, since March 2000. He is a consultant radiologist & the specialist in conventional as well unconventional gastro-intestinal tract ultrasound & diagnostic as well therapeutic interventional sonologist in Pune, India.
Dr. D. Y. Patil University, India
TransAbdominal Sonography of the small & large intestines can reveal following diseases: Bacterial & viral entero-colitis. An ulcer, whether it is superficial, deep with risk of impending perforation, perforated, sealed perforation, chronic ulcer, post-healing fibrosis, stricture, polyps & diverticulum, benign intra-mural tumours, intra-mural haematoma, intestinal ascariasis, foreign body, necrotizing entero-colitis, tuberculosis, intussusceptions, inflammatory bowel disease, ulcerative colitis, cronhs disease, complications of an inflammatory bowel disease – perforation & stricture.
Neoplastic lesion is usually a segment involvement, & shows irregularly thickened, hypoechoic & aperistaltic wall with loss of normal layering pattern. It is usually a solitary stricture & has eccentric irregular luminal narrowing. It shows loss of normal gut signature. Enlargement of the involved segment is seen. Shouldering effect at the ends of stricture is most common feature. Primary arising from wall itself & secondary are invasion from adjacent malignancy or distant metastasis. All these cases are compared & proved with gold standards like surgery & endoscopy. Some extra efforts taken during all routine or emergent ultrasonography examinations can be an effective non-invasive method to diagnose primarily hitherto unsuspected benign & malignant gastro-intestinal tract lesions, so should be the investigation of choice.
Biography:
Dr. Vikas Leelavati Balasaheb Jadhav has completed post graduation in radiology in 1994. He has a 24 Years of experience in the field of gastro-intestinal tract ultrasound & diagnostic as well therapeutic interventional sonography. He is the pioneer of gastro-intestinal tract sonography, especially gastro-duodenal sonography. He has delivered many guest lectures in Indian as well International Conferences in nearly 27 countries as an invited guest faculty, since March 2000. He is a consultant radiologist & the specialist in conventional as well unconventional gastro-intestinal tract ultrasound & diagnostic as well therapeutic interventional sonologist in Pune, India.
Dr. D. Y. Patil University, India
TransAbdominal Sonography of the gall bladder can reveal hepatic, extra hepatic & peritoneal perforations of the gall bladder, whether it is impending perforations, frank perforations, sealed perforations, concealed perforations & its complications. It can also demonstrate adhesions in the gall bladder fossa at the right upper quadrant. All these cases are compared & proved with gold standards like laparoscopic & open surgery & endoscopy.
Some extra efforts taken during all routine or emergent ultrasonography examinations can be an effective non-invasive method to diagnose primarily hitherto unsuspected gall bladder impending perforations, frank perforations, sealed perforations, concealed perforations & its complications, so should be the investigation of choice.
Biography:
Dr. Vikas Leelavati Balasaheb Jadhav has completed post graduation in radiology in 1994. He has a 24 Years of experience in the field of gastro-intestinal tract ultrasound & diagnostic as well therapeutic interventional sonography. He is the pioneer of gastro-intestinal tract sonography, especially gastro-duodenal sonography. He has delivered many guest lectures in Indian as well International Conferences in nearly 27 countries as an invited guest faculty, since March 2000. He is a consultant radiologist & the specialist in conventional as well unconventional gastro-intestinal tract ultrasound & diagnostic as well therapeutic interventional sonologist in Pune, India.
Dr. D. Y. Patil University, India
Sonography of the gastro-intestinal tract can reveal intra-mural tumours, intra-mural haematoma, lesions of Ampulla of Vater like benign & infiltrating mass lesions. Neoplastic lesion is usually a segment involvement & shows irregularly thickened, hypoechoic & aperistaltic wall with loss of normal layering pattern. It is usually a solitary stricture & has eccentric irregular luminal narrowing. It shows loss of normal gut signature. Enlargement of the involved segment is seen. Shouldering effect at the ends of stricture is most common feature. Enlarged lymphnodes around may be seen. Primary arising from wall itself & secondary are invasion from peri-Ampullary malignancy or distant metastasis. All these cases are compared & proved with gold standards like surgery & endoscopy.
Some extra efforts taken during all routine or emergent ultrasonography examinations can be an effective non-invasive method to diagnose primarily hitherto unsuspected benign & malignant gastro-intestinal tract lesions, so should be the investigation of choice.
Biography:
Dr. Vikas Leelavati Balasaheb Jadhav has completed post graduation in radiology in 1994. He has a 24 Years of experience in the field of gastro-intestinal tract ultrasound & diagnostic as well therapeutic interventional sonography. He is the pioneer of gastro-intestinal tract sonography, especially gastro-duodenal sonography. He has delivered many guest lectures in Indian as well International Conferences in nearly 27 countries as an invited guest faculty, since March 2000. He is a consultant radiologist & the specialist in conventional as well unconventional gastro-intestinal tract ultrasound & diagnostic as well therapeutic interventional sonologist in Pune, India.
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