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Faculty Affairs: Faculty Interests Database Erik Knudsen, PhD

Cancer Biology
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Mailing Address Contact Information
233 South 10th St. BLSB Room 1002
Philadelphia, Pennsylvania 19107
United States
Phone: 215-503-8578
Erik.Knudsen@jefferson.edu
Expertise and Research Interests
RB Tumor Suppressor Pathway Involvement in Cancer Etiology and Therapeutic Response

Research Foci: Research is focused on the retinoblastoma tumor suppressor (RB). This tumor suppressor is lost or functionally inactivated in the majority of human cancers. The Knudsen laboratory takes a multi-disciplinary approach to understanding how RB functions to inhibit tumorigenesis and to devise new means to effectively target the RB-pathway in the treatment of cancer.

RB-mediated transcriptional regulation: The retinoblastoma tumor suppressor can bind to numerous cellular proteins and assemble large multi-protein complexes. Many of the complexes participate in transcriptional repression. This function is requisite for RB-mediated cell cycle control. Specifically, our group showed that SWI/SNF chromatin remodeling activity is required RB-mediated effects on transcription and cell cycle control. In contrast, other co-modulators such as HDAC activity are responsible for only a subset of transcriptional repression events. Ongoing studies are focused on defining how SWI/SNF activity is required for assembly of RB-repressor complexes on gene promoters. In parallel, the impact of pathological RB loss on transcriptional regulatory programs has been evaluated. Using microarray analyses a signature of RB loss has been defined and has been shown to have utility in predicting disease outcome and defining how loss of RB and other components of the repressor complexes function in concert to restrict tumorigenesis.

Influence of RB on DNA replication machinery and cell cycle control: The laboratory has identified three distinct means through which RB inhibits DNA replication and believe that relief of this multi-fold regulation is one of the reasons why RB loss is targeted at such high frequency in human cancers. Current investigation has revealed that other tumor suppressors can target DNA replication control, but through mechanisms that are distinct from that of RB. In model systems, loss of RB can either enhance proliferation or lead to genomic instability. Currently, we are defining how RB dysfunction leads to these distinct outcomes and are modeling their relevance to human cancers.

Role of RB in liver tumorigenesis and other environmentally-induced cancers: Liver cancer is a major health concern. Currently, this disease is the 3rd leading cause of cancer deaths worldwide with over 400,000 new diagnoses each year. One of the key genetic lesions found in liver cancer is inactivation of RB. However, the role of RB loss in tumor etiology and progression remains largely undefined. To determine the mechanism(s) by which RB prevents tumor formation in the liver, a number of mouse model of liver specific RB deletion were interrogated. These studies revealed a novel mechanism of RB function, indicating that RB action in this tissue is distinct from its ability to prevent unchecked cellular proliferation. Rather, our data support the hypothesis that RB loss cooperates with hepatic carcinogens to induce genomic instability and promote liver tumorigenesis. Liver cancer is just one of many human cancers that has a strong environmental component. Therefore, in addition to specific studies dissecting the action of RB loss in the liver, we have also begun to model bladder cancer, which is induced by carcinogens from cigarettes and other toxic materials.

Action of RB in modifying response to therapy: Given the high frequency of RB loss in human cancers we have postulated that RB-status could be an important determinant of therapeutic outcomes. Approaches currently used to treat breast cancer include hormonal, cytotoxic, and targeted therapeutic agents. Interestingly, diverse therapeutic agents function through common down-stream pathways that effect cellular proliferation--particularly, they all impinge upon the cell cycle machinery. One component of cell cycle control, which is compromised in breast cancer at high frequency, is the RB-pathway. We have found that RB is a critical determinant of hormonal therapies, such that RB-deficient tumors fail to effectively respond to tamoxifen. Additionally, we have found that deregulation of the RB-pathway is associated with early relapse in breast cancer patients treated with tamoxifen. In contrast, loss of RB enhances sensitivity to specific cytotoxic agents. Ongoing studies are dissecting additional agents utilized in the treatment of breast cancer and other tumor types (e.g. lung cancer), wherein RB status may be equally important in modifying therapeutic response.

p16ink4a and Cyclin D1 aberrations in human cancer: RB functions in a pathway which is controlled by the functional interplay between upstream regulators: particularly the tumor suppressor p16ink4a and proto-oncogene cyclin D1. Interestingly, overproduction of cyclin D1 or loss of p16ink4a have distinct effects on cell cycle control and suggest that intrinsic differences between components of the RB-pathway impact tumor behavior. Using a combination of pharmacological and genetic interventions these differences are being explored. Furthermore, tumor associated variants in cyclin D1 (e.g. cyclin D1b) as key drivers of malignant transformation and indicators of disease outcome.

Last Updated by KT Ferrera: Tuesday, December 18, 2012 11:58:42 AM

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