Research

The key research accomplishments achieved by this program include:

• 35 Peer-reviewed Publications
• 25 Presentations with Student Co-authors
• $3.8+ million in NIH research grant funding including an R01, a P01 project, and two R21s
• $2.5+ million in other research grant funding (RIMI, SCORE, NSF, ACS)

• NDGA Analogs and Breast Cancer
  
• Lay Health Workers and Colorectal Cancer Screening among Chinese Americans in San Francisco
  
• Development of a Culturally Appropriate Colorectal Cancer Educational Video for Latinos
  
• Combinatorial Approaches for Studying Substrate Recognition and Developing Inhibitors of PSMA
  
• Quality of Life Among Breast Cancer Survivors from Diverse Populations
  

NDGA Analogs and Breast Cancer

This project is a collaboration of Jack Youngren, PhD (UCSF) and Clifford Berkman, PhD (SFSU).

There is considerable clinical and experimental data that the IGFs and the IGF-1R play a major role in breast cancer initiation, growth, and proliferation. Clinical studies suggest that serum IGF-1 levels are increased in postmenopausal patients with breast cancer, and IGF-1 levels correlate with a poor prognosis. Both in vivo and in vitro, in a variety of breast cancer cell lines, the IGF-1R is overexpressed. In cultured breast cancer cells and animals with breast cancers, reducing IGF-1 levels decreases breast cancer growth. The HER2/neu (c-erbB-2) protooncogene plays an important role in the development and progression of breast and other cancers. HER2 overexpression occurs in 20-30 percent of breast cancers, most commonly via gene amplification, and is associated with poor prognosis for these patients. Much experimental evidence indicates that HER2 overexpression directly contributes to transformation and tumor progression. An antibody to HER2/neu is used clinically to treat certain patients with breast cancer.

Nordihydroguaiaretic acid (NDGA) has been identified as a major component of a tea made from resinous extracts of the creosote bush Larrea divaricatta. It has been used for centuries by Native North Americans as a remedy for diverse illnesses, including tumors. Although NDGA has been reported to inhibit the growth of tumors both in vitro and in animals, the mechanism of this anti-cancer effect is not well understood. Preliminary studies suggest that NDGA acts on cultured cells and in animals with breast tumors to inhibit tumor growth via inhibition of the IGF-1R and HER2/neu. However, the studies in animals suggest that relatively high concentrations of NDGA are needed to achieve efficacy.

We hypothesized that novel NDGA analogues with enhanced potency and specificity for HER2/neu and the IGF-1R will become new drug candidates for breast cancer. The project aimed to develop potent, receptor-specific analogs of NDGA to serve as lead compounds for new drugs to inhibit the IGF-1R and HER2/neu in breast and possibly other cancers. This project produced two abstracts and three publications. Dr. Youngren submitted an R01 grant with a subcontract to Dr. Berkman to study diarylurea derivatives as IGF-1 receptor inhibitors which has been funded. Drs. Berkman and Youngren have written a full research project for the U54 application.

Publications:

Youngren, J.F., Gable, K., Penaranda, C., Maddux, B.A., Zavodovskaya, M., Lobo, M., Campbell, M., Kerner, J., Goldfine, I.D. Nordihydroguaiaretic acid (NDGA) inhibits the IGF-1 and c-erbB2/HER2/neu receptors and suppresses growth in breast cancer cells. Breast Cancer Res Treat. 2005 Nov;94(1):37-46.

Gable, K.L., Maddux, B.A., Penaranda, C., Zavodovskaya, M., Campbell, M.J., Lobo, M., Robinson, L., Schow, S., Kerner, J.A., Goldfine, I.D., Youngren, J.F. Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth. Mol Cancer Ther. 2006 Apr;5(4):1079-86.

Anderson, M.O., Yu, H., Penaranda, C., Maddux, B.A., Goldfine, I.D., Youngren, J.F., Guy, R.K. Parallel synthesis of diarylureas and their evaluation as inhibitors of insulin-like growth factor receptor. J Comb Chem. 2006 Sep-Oct;8(5):784-90.

Lay Health Workers and Colorectal Cancer Screening among Chinese Americans in San Francisco

This project is a collaboration of Tung Nguyen, MD (UCSF) and Mary Beth Love, PhD (SFSU).

Colorectal cancer is the second leading cause of cancer-related deaths and the fourth most common cancer in the United States. Among California Chinese men and women, it is the third and second leading cancer in incidence and mortality, respectively. Colorectal cancer screening reduces mortality. Current guidelines recommend that everyone age 50 and older should have regular screening, which include an annual fecal occult blood test (FOBT), a sigmoidoscopy every 5 years, or a colonoscopy every 10 years. In California in 2001, the rates of ever having been screened for FOBT, sigmoidoscopy, or colonoscopy were 40%, 43%, and 59% for Chinese compared to 58%, 57%, and 75% for non-Latino Whites.

The project builds upon the potential of lay health workers as ideal health educators in minority communities where they know the barriers specific to the community based on life experiences, possess culturally appropriate knowledge and skills, and have earned the trust of the community due to their presence within it. Lay health workers have been effective in increasing breast and cervical cancer screening in several ethnic groups. Two studies by the UCSF investigators at the Vietnamese Community Health Promotion Project have shown that interventions through lay health workers were effective in increasing breast and cervical cancer screening.

This study aimed to identify barriers to and facilitators of colorectal cancer screening among Chinese Americans with limited English proficiency in San Francisco, to evaluate the feasibility of training lay health workers (LHWs) to deliver education on colorectal cancer among Chinese Americans with limited English proficiency, and to understand how to conduct LHW intervention in Chinese community and what qualities exemplify an effective LHW. The study was completed in December 2006. Results showed that lay health worker outreach (LHWO) was feasible and effective among Chinese Americans. An abstract was accepted for roundtable presentation at American Public Health Association annual meeting Nov. 5-7, 2007 in Washington, D.C., and a manuscript is currently in preparation.

Development of a Culturally Appropriate Colorectal Cancer Educational Video for Latinos

This project is a collaboration of Rene Salazar, MD, Judith Walsh, MD, Regina Otero-Sabogal, PhD (UCSF), and Lena Zhang, PhD (SFSU)

Rates of colorectal cancer screening are lower among ethnic minorities and colorectal cancer (CRC) is an important problem among Latinos. In the 1997 Behavioral Risk Factor Surveillance Survey, only 13% of Latinos had a fecal occult blood testing during the preceding year and only 20% had sigmoidoscopy or proctoscopy during the preceding five years. These rates were significantly lower than those of non-Latino whites, which were 20% and 31%, respectively.

Dr. Otero-Sabogal has found that low participant in cancer control programs among ethnically diverse communities can be explained by limited access, low literacy and cultural values and attitudes, all of which much be better understood in order to develop more effective interventions. We hypothesed that the exposure to a culturally appropriate CRC educational video will improve knowledge and attitudes toward CRC screening, which will improve colorectal cancer screening rates among Latinos.

The specific aims of the study were to develop intervention messages to address facilitators and barriers toward CRC screening among socioeconomically disadvantaged Latinos, to develop and pilot test a Spanish language, culturally tailored CRC educational video aimed at improving CRC screening knowledge and addressing attitudinal barriers among Latinos, and to use the educational video in a future trail to improve CRC screening behavior, knowledge, and attitudes in Latino patients. The project results have been presented at a meeting of the American Association for Cancer Education and other national meetings. Dr. Salazar received an American Cancer Society Career Development Award to test the effectiveness of the video.

Combinatorial Approaches for Studying Substrate Recognition and Developing Inhibitors of PSMA

This medicinal chemistry project was a collaboration among three laboratories: R. Kip Guy, PhD (UCSF), Charles Craik, PhD (UCSF), and Clifford Berkman, PhD, SFSU. The project developed and tested a library of putative inhibitors of the enzyme, prostate specific membrane antigen (PSMA), leading to a subsequent two-year award to Dr. Berkman from the DOD (Inhibitor-Directed Imaging of Prostate Cancer, for $112,469). The overall objective of the DOD project is to elaborate the design of competitive PSMA inhibitors to selectively deliver fluorescent terbium ions Tb(III) to prostate cancer cells so that the prostate cancer cells expressing PSMA will be selectively labeled with fluorescent inhibitors and consequently detectable by fluorescence microscopy. The investigators presented 7 abstracts and published 11 articles. Dr. Berkman also established a new collaboration with Dr. Benjamin Franc (UCSF) and obtained funding for a R21 project to prove the concept that potent inhibitors of PMSA will selectively tag prostate cancer cells for single photon emission computed tomography (SPECT).

Publications:

Lu, H., Berkman, C.E. Organophosphorus Derivatives of Glutamic Acid and 2-HHydroxyglutaric Acid. Recent Res. Dev. Org. Chem. 2002; 6: 41-55.

Barrios, A.M. and Craik, C.S. Scanning the Prime-Site Substrate Specificity of Proteolytic Enzymes: A Novel Assay Based on Ligand-Enhanced Lanthanide Ion Fluroescence. Bioorg. Med. Chem. Lett. 2002; 3619-3623.

Kamga, I., Ng, R., Hoaska, M., Berkman, C.E. High Performance Liquid Chromatography Method for Detecting Prostate-Specific Membrane Antigen Activity. Anal. Biochem. 2002; 310: 125-127.

Lu, H., Ng, R., Shieh C.C., Martinez, A.R., Berkman, C.E. Inhibition of Glutamate Carboxypeptidase by Phosphoryl and Thiophosphoryl Derivatives of Glutamic and 2-Hyroxyglutraic Acid. Phosphorus, Sulfur, and Silicon. 2003; 178: 17-32.

Maug, J., Campbell, T.Y., Shieh, C.C., Berkman, C.E. Synthesis of N-Thiophosphoryl amino acids via phosphoramidite amine-exchnage. Synth. Comm. 2004; 34: 571-577.

Mallari, J.P., Choy, C.J., Hu, Y., Martinez, A.R., Hoaska M., Toriyabe, Y., Maoung, J., Blecha, J.E., Packovic, S.F., Berkman, C.E. Stereoselective Inhibition of Glutamate Carboxypeptidase by Organophosphorus Derivatives of Glumtamic Acid. Bioorg. Med. Chem. 2004; 12: 6011-20.

Maung, J., Mallari, J.P., Girtsman, T.A., Wu, L., Rowley, J., Santiago, N. , Brunelle, A., Berkman, C.E. Probing for a Hydrophobic Binding Site in Prostate-Specific Membrane Antigen with Phenylakylphosphonamidates. Bioorg. Med. Chem. 2004; 12: 4969-79.

Maung, J., Mallari, J.P., Choy, C.J.; Berkman, C.E. Alternatives to 1-H-Tetrazole in the Preparation of Phosphonate Diesters and Phosphonamidates from Phosphonyl Dichlorides. Tetrahedron Lett. 2004; 45: 6497-99.

Mallari, J. P., Choy, C.J., Hu, Y.; Martinez, A.R., Hosaka, M., Toriyabe, Y., Maung, J., Blecha, J.E., Pavkovic, S. F., Berkman, C. E. Stereoselective Inhibition of Glutamate Carboxypeptidase by Organophosphorus Derivatives of Glutamic Acid. Bioorg. Med. Chem., 2004; 12: 6011-20.

Wone, D.W.G., Rowley, J.A., Garofalo, A.W., Berkman, C.E. Optimizing Phenethylphosphonamidates for the Inhibition of Prostate-Specific Membrane Antigen. Bioorg. Med. Chem. 2006; 14: 67-76

Wu, L., Berkman, C.E. Synthesis of N-Phosphoryl Amino Acids Using Bis(9-fluorenylmethyl) Phosphite. Tetrahedron Lett. 2005; 46: 5301-03.

Quality of Life Among Breast Cancer Survivors from Diverse Populations

This project led by Cheryl Ewing, MD (UCSF), Caryn Aviv, PhD (UCSF), Grace Yoo, PhD (SFSU), and Ellen Levine, PhD (SFSU) investigated health disparities in survivorship among women in the San Francisco Bay Area who were diagnosed with breast cancer. The U56 mechanism enabled the researchers to develop a RIMI subproject proposal that was funded in 2003 and subsequently expanded to support a survey of at least 200 breast cancer survivors from various communities. Preliminary results of the study show that the type of social support used differed at diagnosis, during treatment, and after treatment among individuals from different groups. In 2003, this project received a 5-year grant for $900,000 from the RIMI Program from the National Center on Minority Health and Health Disparities (NCMHD). This pilot project has produced 2 publications and12 abstracts and conference presentations.

Publications:

Levine, E., Yoo, G., Aviv, C., Ewing, E., Au, A. Spirituality and coping with breast cancer across ethnic groups. Journal of Cancer Survivorship: Research and Practice; in press.

Yoo, G., Lam, M., Levine, E., Aviv, C., Ewing, C., Au, A. An exploratory, qualitative study of Asian American breast cancer survivors and support groups. In Darlene Yee-Melcihar and Andrea Boyle, Minority Women's Health: Best Practices in Education and Research. New York: Springer; in press.