SUMMARY REPORTS OF EXCHANGE SCIENTISTS
(1) Tatsuro Irimura
Division of Chemical
Toxicology and Immuno-chemistry,
Faculty of Pharmaceutical Sciences
The University of Tokyo
SPONSOR AND HOST INSTITUTION:
Olja J Finn
University of Pittsburgh School of Medicine
Department of Molecular Genestics and Medicine
DATES OF VISITS: November 7 - 19, 1994
SUMMARY OF ACTIVITIES:
The purpose of this visit was to exchange new information on four major categories, all of which are related to carcinoma- associated mucins. My special interest is the involvement of these molecules in carcinoma metastases. Dr. V. P. Bhavanandan is an expert on the biosynthetic regulation of mucin carbohydrate chains. Dr. Subhash Basu has continuously been studying the biosynthetic aspects of sialyl-Lex carbohydrate chains. Dr. Sandra Gendler is the only scientist who succeeded in the generation of MUCI mucin-gene targeting mice. Dr. Olja Finn is the only scientist who already performed a clinical trial of the use of MUC1 mucin in cancer immunotheraoy. I have collected significant information on the role of mucins in cancer biology and immunology. All these scientists and I have collaborated in the past. In this visit, we have reconfirmed that these collaborative efforts will continue and will be fruitful.
Gave a seminar entitled “Cancer Metastasis Determined by Carbohydrate-Mediated Cellular Recognition” between 10 and 11:30 a.m. Attended at the graduate student meeting of the Department of Biochemistry and Molecular Biology, Penn State University College of Medicine during lunch time. Discussed with Dr. Judith Bond, Chair of the Biochemistry Department, and her collegues in the afternoon on the biological roles and the specificity of serine proteases in cancer biology.
Discussed with Dr. Danny R. Welch, Department of Pathology and his collegues on the Biology of melanoma metastasis during the morning. This results in arrangement of new collaborative projects on the role of cell surface glycoproteins in melanoma metastasis.
Attended the 23rd Anual Meeting of the Society for Glycobiology. The sessions consisted of simposia, selected talks from abstracts, and poster sessions. Titles of the sessions were: 1. Structure and chemistry of glycoconjugates, 2. Cell surface glycoconjugates of normal and those under pathologic conditions including cancer, 3. Glycosyltransferases and their regulations, 4. Glycosylation of expressed protein, 5. Glycosydases and their mechanism of actions, 6. Mucin and proteoglycans in normal tissues and cancer cells, 7. Glycobiology, 8. Medical aspects of glycobiology. On November 11, I gave a talk entitled “Highly glycosylated MUCI mucins on highly malignant carcinoma cell” in the session 6.
Visited Dr. Subhash Basu’s Laboratory at the Department of Chemistry, University of Notre Dame, and discussed on the biosynthetic mechanism of the sialyl-Lex carbolydrate antigen. We came to a conclusion that Dr. Basu and I had different opinions on the regulation of sialy-Lex carbohydrate antigen. Particularly its upregulation during the tumor progression to the metastatic stages may be regulated by different mechanisms in different type of cancer.
Visited Mayo Clinic, Scottsdale. Gave a Seminar entitled “Mucins and Lectins: Determinants of Celluar Recognition and Trafficking.” Discussed with Drs. Riobrdan and Wu on the pathogenesis of cystic fibrosis in the morning. Attended to the graduate student meeting of Dr. Gendler’s group. Discussed with Drs. Kappen and Chang on the gene targetting methods to study the regulation of gene expression during the differentiation.
Discussed with Dr. Hideaki Tahara, University of Pittsburgh, on the use of the cytokine gene therapy in cancer treatment.
Visited Dr. Olja Finn, University of Pittsburgh. Discussed in the morning on the use of mucin and related compounds in cancer immunotherapy. Dr. Finn was involved with the Phase I clinical trial of MUCI mucin peptides. There was no toxicity but did no observe any effect, though this was a Phase I. Gave a seminar entitled “Mucins and Lectins: Determinants of Celluar Recognition and Cancer Metastasis.” All afternoon, discussed with the graduate students and Post Doctoral fellows of Dr. Finn’s laboratory. It was notable that everyone was engaged with basic research on the induction og cytotoxic T cells.
Discussed with Dr Elieser Gorelik, Department of Pathology, University of Pittsburgh, on the role of carbohydrates and carbohydrate-binding molecules in cancer metastsis in the morning. Dr. Gorelik and I shared the same research interest during the last 15 years. He showed interesting observations on the effect of lectins on the growth of metastatic tumor cells. Dr. Tahara showed his new facility to prepare vectors and other tools to perform cytokine-based gene therapy. Discussed with Dr. Finn in the afternoon on possible collaborative projects to elucidate the biological roles of MUC1 mucins.
(2) Kozo Morita
Research Center of Charged Particle Therapy,
National Institute of Radiological Sciences,
Director
SPONSOR AND HOST INSTITUTION:
Luka Milas
Department of Experimental Radiotherapy, Univ of Texas
M.D. Anderson Cancer Center,
Chairman
DATES OF VISIT: December 2 - 21 1994
SUMMARY OF ACTIVITIES :
In 1960 the “conformation radiotherapy technique” was reported by Prof. Takahashi. This technique was an improved type of coplanar moving field technique. Supporting several technical improvement such as (a) introduction of the computer techniques, (b) introduction of CT/MRI, this technique is at present almostly accomplished as a kind of standard dynamic conformal technique.
On the other hand, since 1985 various kinds of so-called static conformal technique has been developed chiefly in U.S.A. At present, conformal technique can be defined as ‘radiotherapy technique to coincide the high dose region to the target volume, while keeping the dose to the neighboring healthy tissues as low as possible’. From this definition, the heavy particle therapy such as proton or heavy-ion therapy also considered as a kind of conformal radiotherapy technique. The purpose of my visit to several university hospitals is to show our conformation technique and to discuss the difference of each conformal technique using photon beam, and at the same time, to observe the proton and heavy-ion facilities in U.S.A.
(1) In Massachusetts General Hospital, the history and present activity of our dynamic conformal technique was demonstrated. Discussion after my presentation was summarized that routine use of serial CT images and 3D-dose calculation is necessary, in order to become this conformal technique into wide use. Conformal treatment using proton beam from horizontal beam line was performed in every work day. Obtained data at this clinic is no yet sufficient to conclude whether proton beam therapy will be able to substitute for conformal photon therapy in curative intent, because the cyclotron was not constructed for medical use alone.
(2) In M.D. Anderson Cancer Center Dr. Milas and I discussed chiefly several predictive factors indicating radiosensitivity of tumors such as SF-2, micro-nucleoles and apoptosis. In order to obtain the good clinical result using conformal technique, the selection of suitable patients for this technique is very important, because the local control rate dose not increase significantly in spite of 30% dose escalation, probably due to Inhomogeneity of tumor cells. Prof. Milas showed me several promissing data, but these data are no yet sufficient to use clinically.
(3) In Loma Linda Univ. Medical Center, I observed the clinical study chiefly for prostate cancer using proton beam. Every day about 60 patient are irradiated routinely in 3 treatment rooms. The proton beam facility at LLUMC is the first facility for medical use alone. As would be expected, the proton beam facility can become one of the main radiotherapy facility for radical treatment, instead of photon beam facility such as linear accelerator/micritron in future. But it is clear that the lack of man-power in Japan might be one of the essential problem to introduce this proton beam facility.
(4) In Lawrence Bereley Laboratory at Univ. of California in San Francisco, I visited Prof. Castro and discussed several problems about heavy-ion therapy with him. As the most useful beam for heavy-ion therapy, he recommended me carbon-ion instead of neon-ion, that he used for about 600 patients in U.S., because of its better dose-distribution. At the same time, we discussed about the fractionation schedule. I could not completely agreed with hirecommendation, because the biological behavior of carbon beam is considerably different with that of neon beam. I agreed with his opinion that the clinical trialusing carbon beam should be performed carefully about the dose escalation problem.
(3) Takashi Takahashi
Laboratory of Chemotherapy,
Aichi Cancer Research Institute
SPONSOR AND HOST INSTITUTION:
John D Minna
Harold Simmons Comprehensive Cancer Center,
University of Texas, Southwestern Medical Center
DATES OF VISIT: February 13 - 26, 1995
SUMMARY OF ACTIVITIES:
The US-Japan (NCI-JSPS) Cooperative Cancer Research Program for Scientist Exchange made it possible for me to visit independent laboratories in the United States. First, I visited Dr. B. Tycko in Columbia University to exchange information about altered genomic imprinting in human cancers. I also gave a talk on our recent progress on this matter. Dr. Tycko’s group has been focused on epigenetic alterations in Wilms’ tumors in the H19 gene, which is known to be imprinted in man. Since we have been working on altered imprinting in lung cancer, we could discuss its functional significance in the development of human cancers. It was especially Interesting for both of us that our recent data on H19 overexperssion in lung cancer appears to be in direct conflict with his hypothesis in that H19 might be a tumor suppressor gene for Wilm’s tumors. Our consensus was that we need to pursuit this matter more vigorously and that we may see differential roles of H19 depending on the cellular context.
I next visited Dr. S. Tighman in Princeton University to exchange information on basic mechanism of genomic imprinting and its relation to cancer development. Their laboratory has been a leading one in this field and recent data on H19 knock-out mice was quite interesting. In addition, an additional gene was recently discovered by them to be included in the imprinted domain of the H19/IGF2 region. It will be interesting for us to examine whether or not its imprinting status Is also altered in lung cancer as observed in the H19 and IGF2 genes.
Dr. J. Minna has been working on various aspects of molecular pathogenesis of lung cancer for many years and his recent major interest is to identify the putative tumor suppressor gene at 3p21.3. We are also trying to clone the gene and I presented our data in a seminar in his cancer center. Therefore, my visit to his laboratory was quite informative for both of us to exchange our recent information with regard to possible overlap between homozygous deletions we are working on separately using different cell lines established in each laboratory.
Lastly, I visited Dr. R. Namikawa with whom we have been collaborating on SCID-hu mice model for metastasis of lung cancer. After an informative discussion, we agreed to continue our collaboration using transfectans of a novel integrin a subunit gene which we cloned from the region of the homozygous deletion at 3p21 3 in a lung cancer cell line.