Faculty Talks

Qiao-Hong Chen, CSU Fresno

Zampanolide-Inspired Anti-Prostate Cancer Agents

(-)-Zampanolide is a marine microtubule stabilizing macrolide and has been evidenced by in vitro experiments as a promising anti-cancer lead compound. Through a unique covalent-binding with tubulin, zampanolide possesses superior cytotoxic potency towards multi-drug resistant cancer cells, as compared with paclitaxel. However, the limited availability of zampanolide prevents its further in vivo evaluation as a viable drug candidate. Additionally, we envision that zampanolide will become more drug-like if its chemically fragile side chain can be optimized. This project thus aims to develop simplified mimics of (-)-zampanolide with a stable side chain as well as manageable synthetic methods. To this end, each of twelve new zampanolide mimics with a stable side chain has been successfully synthesized through a 24-step transformation, using commercially available 2-butyn-1-ol as starting material. The Horner-Wadsworth-Emmons reaction has been successfully used for incorporating the stable side chain and for closing the core ring. Our WST-1 cell proliferation assay in three human prostate cancer cell models indicated that the stable side chain can serve as the bioisostere for the N-acetyl hemiacetal side chain in Zampanolide. This presentation will report the full details of the synthesis and antiproliferative activities of the zampanolide mimics.

Crystal Rogers, CSU Northridge

Cadherin-11 is required for the specification and cell survival of neural crest cells

The neural crest (NC) is an embryonic population of stem-like cells that form various tissues in vertebrates. Abnormal NC cell development leads to congenital defects as well as NC-derived cancers such as neuroblastoma and melanoma. Programs used by NC cells during embryonic development are often re-used by cancer cells during tumor formation and metastasis. During development, NC cells express cell adhesion molecules, including cadherin proteins, which control their specification, EMT, and migration. Here, we identify the role of Cadherin-11 (CDH11) in early chicken NC development. CDH11 is a type II cadherin protein that regulates cell migration in amphibian embryos and cancer cells. We determined that CDH11 protein has previously unreported dynamic expression in all neuroectodermal progenitor cells and subsequently becomes restricted to pre-migratory and migratory NC cells. Electroporation of a translation-├é┬Čblocking CDH11 morpholino reduces NC cells, but has no effect on more ventral neural tube cells, suggesting that CDH11 is required specifically for NC specification. We determined that CDH11 is required for NC cell survival, loss of CDH11 increases p53-mediated programmed-cell death, and blocking the p53 pathway can rescue the neural crest phenotype. Our findings demonstrate a new requirement for CDH11 in NC cell survival, and may increase our understanding of early developmental defects. Our future efforts will focus on the role of CDH11 in cancer cell survival.

Elva Arrendondo, SDSU

Strategies for building transdisciplinary cancer research capacity at Minority Serving Institutions

Increasing the cancer research capacity of Minority Serving Institutions (MSIs) requires strong institutional commitment, faculty involvement, and extramural funding. We describe key strategies that an MSI has taken to strengthen the cancer research portfolio in basic, clinical, translational, and population based research to address cancer health disparities. Institutional support was instrumental in the hiring of new faculty who conduct cancer research and in supporting Early Stage Investigators. Extramural funding has provided pilot funds to faculty to conduct cancer research, supported the training of undergraduate and graduate students from under-represented backgrounds in STEM, and stimulated translational research collaborations. Inter-institutional faculty retreats have promoted collaboration between community partners and university researchers. Recently, an interdisciplinary group of researchers from five colleges has formed to build on these concerted efforts and conduct a needs assessment to determine next steps. The presentation will outline the process and impact of the various efforts that our campus has undertaken over the past three years to increase SDSU's transdisciplinary cancer research capacity.

Jason Bush, CSU Fresno

Metabolomic Analysis of HER2-positive Breast Cancer Cells

HER2-positive breast cancer accounts for more than 20% of diagnosed cases and is characterized by aggressive growth, increased disease recurrence, and poor prognosis. While much of the signaling mechanism(s) have been elucidated, the impact of HER2 positivity on cellular metabolism is not well understood. We examined (1) gene expression profiles of mammalian breast cancer cell lines with increasing HER2 expression levels and correlated changes to metabolic expression profiles and (2) the effect of pervanadate treatment on the metabolic profiles of these HER2-expressing cell lines. Our study used a combination of NMR, multivariate analyses, and protein expression validation in human breast cancer cell lines. We found that both gene and metabolic expression profiles of HER2-positive cell lines correlated with leucine and isoleucine biosynthesis. Comparative analyses of profiles from untreated and pervanadate-treated cell samples revealed that lactate concentration dropped significantly with serum starvation and pervanadate treatment consistent with reduced glycolytic metabolism and potentially mediated through suppression of tyrosine phosphatase activity. This study highlights important metabolites that are potential biomarkers of HER2-positive breast cancer and suggests alternate/novel pathways to consider for future understanding and targeting.