Basic Research

Southern Research scientists are currently engaged in the following basic research initiatives in cancer:

Anticancer Drug Discovery, William Parker, Ph.D.

Dr. Parker is a member of a research team at Southern Research that designs, synthesizes, and evaluates nucleoside analogs in an effort to create new anticancer compounds. A new drug resulting from these efforts, clofarabine, was approved by the FDA in 2004 for the treatment of childhood acute lymphocytic leukemia. Another agent, 4'-thio-arabinofuranosyl cytosine, is currently being evaluated in clinical trials for antitumor activity.

Gene Therapy of Cancer, William Parker, Ph.D.

Dr. Parker is involved in the development of a gene therapy strategy to treat solid tumors. Specifically, this strategy exploits the substrate differences between human and E. coli purine nucleoside phosphorylase to selectively generate toxic purine analogs in tumor cells. This approach to the treatment of solid tumors has led to the creation of PNP Therapeutics, Inc. An IND was approved by the FDA in March of 2010, and a Phase I clinical trial to evaluate the safety and efficacy of this strategy in head and neck cancer patients is expected to begin in January of 2011.

Antiestrogen Resistance in Breast Cancer, Jaideep Thottassery, Ph.D.

A primary focus of Dr. Thottassery's work at Southern Research is to elucidate mechanisms of antiestrogen resistance in breast cancer patients. In the two-thirds of breast cancer patients who have estrogen receptor positive (ER+) disease, estrogen plays a critical role in the growth of tumor cells. Tamoxifen, an ER agonist/antagonist, and aromatase inhibitors are used routinely in treatment in ER+ disease, although progression after an initial response remains a significant problem. ICI 182780 (Faslodex), a pure antiestrogen, inhibits the growth of tamoxifen-resistant lines and has also shown effectiveness in tamoxifen-resistant patients, although there were no complete responses. Dr. Thottassery's research seeks to understand the mechanisms of antiestrogen resistance, which could lead to strategies that might either restore or prolong sensitivity to such therapies.

Molecular Mechanisms of Nucleoside Anticancer Agents, Jaideep Thottassery, Ph.D.

Dr. Thottassery is a member of a research team at Southern Research that investigates newer nucleosides and the mechanisms by which their effects are elicited in tumor cells. Southern Research has maintained a nucleoside drug discovery program for several years, and two FDA-approved drugs - Fludarabine and Clofarabine - have resulted from these efforts. Clofarabine was approved by the FDA in 2004 for the treatment of childhood acute lymphocytic leukemia. Another agent, 4'-thio-arabinofuranosyl cytosine, is currently being evaluated for antitumor activity in clinical trials. Southern Research investigates the role of cellular pathways in the effects mediated by these agents.

Angiogenesis and Tumor-Stromal Cell Interactions, Zhican Qu, Ph.D.

Angiogenesis is a fundamental biological process. Clinical research in recent years has revealed that angiogenesis imbalance is involved in many human diseases. A specific finding from this research is that the progression of human malignant tumors depends on angiogenesis. Tumor growth is not determined solely by tumor cells but is governed by interactions between tumor and host stromal cells, including endothelial and fibroblastic stroma cells. Tumor stroma profoundly influences tumor growth, metastasis, and angiogenesis and promotes anticancer drug resistance. Dr. Qu's laboratory is involved in studying angiogenesis and tumor microenvironments with both in vitro and in vivo approaches and exploring possibilities of targeting tumor angiogenesis and stroma compartments for effective cancer therapeutic development. Current projects include:

• Targeting tumor angiogenesis for anticancer therapeutic development
• Defining the roles of VEGF, IGF, and PDGF signaling pathways in tumor-stromal
interactions and their effects on cancer progression and treatment resistance
• Developing clinically relevant animal tumor models for translational cancer research

Wnt Signaling in Cancer, Yonghe Li, Ph.D.

The canonical Wnt signaling pathway is important in stem cell biology and embryonic development and can lead to tumor formation when aberrantly activated. Dr. Li's research interests center around the canonical Wnt signaling pathway in cancer. Current projects in this area include:

• Defining the roles of Wnt co-receptor LRP6 and its regulators in cancer tumorigenesis and metastasis
• Exploring cancer chemopreventive and therapeutic effects of Wnt signaling inhibitors including natural compounds, synthetic agents, recombinant proteins, and peptides
• Identifying small molecule inhibitors of the canonical Wnt signaling pathway