carla finkielstein's lab  

 

RESEARCH INTERESTS

Most of the cancer malignancies arise from malfunction of genes that control the cellular responses to DNA-damage as well as cell growth and division. The fact that cancer results from the combined action of multiple oncogenic alterations argues that single-agent therapies will remain the exception. The identification of appropriate targets is based on a detailed understanding of the molecular changes underlying tumor growth and progression. Recent preclinical studies have suggested that radiotherapy in combination with other targeting agents enhances the therapeutic ratio of ionizing radiation alone. However, resistance of tumor cells to chemotherapeutic drugs and radiotherapy represents a major obstacle in anti-cancer therapy. Our research will precisely define why some tumors fail to respond to radiotherapy in the first place, and how to interfere with this resistance pathway so that more effective treatment modalities can be developed. My previous work showed that the cell cycle is arrested and cell death (apoptosis) prevented in Xenopus embryos treated with high doses of ionizing radiation at anytime after the mid-blastula transition. This phenotype results from the activation of a concerted number of mechanisms that lead to cell cycle arrest at the G1/S boundary, as observed for most radiation resistant tumors as well. Thus, our research takes advantage of the simplicity of this model organism to define key players in the ionizing radiation response.

 Early embryo Xenopus development


Movie taken from
 http://www.xenbase.org/atlas/movies.html
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In a second area, we are investigating the role of circadian clock genes as important endogenous factor that contributes to cancer development and progression. Core circadian clock genes are defined as genes whose protein products are necessary components for the generation and regulation of circadian rhythms (from the latin circa diem, "about a day"). Several studies have shown that about 7% of all circadian-controlled genes regulate either cell-cycle progression or apoptosis. These observations made scientists wonder whether the circadian and cell cycle systems operating within an individual cell might be interlocked by sharing some critical elements. Specifically, our laboratory explores the means by which loss of circadian function impairs apoptosis in response to ionizing radiation, leading to genomic instability and accumulation of damaged cells. The methodologies we plan to use are primarily cellular and molecular biology along with structure-based analysis.

The core feedback loops of the mammalian clock (left) and the clock-controlledpathways (right). Casein kinase 1 epsilon (Ck1e); Chrypochrome 1 and 2 (Cry1 and Cry2); Period 1,2,3 (Per1, Per2, Per3); circadian locomotor output cycles kaput protein (Clock);and brain-muscle-ARNT-like protein (Bmal1), and the orphan nuclear receptor rev-erb alpha genes.

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