Our laboratory's major efforts are centered on identification and characterization of molecular alterations in human cancers that are responsible for clinically relevant features of the disease. We have focused on alterations in transcription factors and transcriptional regulation that contribute to the biology of cancer, and the use of genomic approaches to achieve an understanding of the biologic and clinical heterogeneity of human cancer. The major projects include:
Outcome Prediction in Early Stage Prostate Cancer Using Molecular and Clinical Variables
Most early stage PCA are curable with local therapy, however, many are relatively indolent such that some men do not require aggressive therapy. On the other hand, between 20 and 40% of men undergoing supposedly curative therapy for early stage disease will nonetheless relapse. A critical challenge is to develop means to distinguish indolent cancers from those that are potentially lethal so that therapeutic procedures can be tailored to an individual patient. We have used a combination of clinical and molecular variables to develop models that more accurately predict the likelihood of disease progression than current standard models. We continue to search for and test additional predictive molecular variables in an effort to improve on model performance.
In an effort to more fully define the molecular events that are critical to prostate cancer clinical biology, we are carrying out an integrated genomic analysis of genes and biological pathways involved in the development and progression of prostate cancer and resistance to hormonal therapy. This data set will include high resolution, genome-wide, array comparative genomic hybridization for gene copy number assessment, genome wide, exon level expression analysis, microRNA expression analysis and select full coding region sequencing for 250 high priority candidate prostate cancer related genes in 188 prostate cancer samples. This database will provide for a comprehensive catalog of molecular events in prostate cancer that are likely relevant to disease progression and will be used to direct future efforts in exploring this disease.
Mechanisms of Androgen-Independent Prostate Cancer
The androgen signaling pathway is critical to the development and progression of prostate cancer and androgen ablation is a mainstay of therapy for this disease. Response is variable and virtually all patients so treated eventually develop androgen ablation resistant prostate cancer, a serious clinical problem for which no consistently effective therapy exists. The mechanisms of resistance are largely unknown. Previous data and our initial studies have produced evidence that reactivation of androgen signaling is a critical event in therapy resistance and several biological pathways may play a role. Resistance is often associated with a marked increase in the androgen receptor (AR) and altered expression of several genes in pathways that potentially regulate AR transcription. Our hypothesis is that increased expression of AR plays a critical role in AARPC and is due to altered transcriptional regulatory mechanisms involving specific transcription factors and signaling pathways. We are attempting to define and characterize the critical elements that contribute to the increase of androgen receptor expression in hormone resistant prostate cancer using genomic evaluation of tumor samples, bioinformatic analysis and traditional cell biology and mouse models.
Pathway Integration in A Unique Subset of Estrogen Receptor Negative Breast Cancer
Estrogen receptor negative breast cancer represents approximately 25 to 30% of all breast cancers and generally has a more aggressive clinical course. With the exception of Herceptin, targeted therapies for ER(-) breast cancer remain elusive. In an effort to identify potential therapeutic targets in this tumor class, we defined a unique subset of ER(-) breast cancer that over express the AR and are responsive to androgens in an AR dependent, ER independent manner. We have also determined that this subset of tumors is enriched for phosphoinositide 3-kinase (PI3K) pathway activation through PI3KCA mutation or HER2 amplification suggesting this subset may be dependent on signal integration through PI3K signaling to enhance AR activity, contributing to breast cancer growth. This represents a new paradigm in breast cancer and the potential for targeted therapeutic strategies directed at the biological signal integration
EWS-WT1 Gene Fusion in Desmoplastic Small Round Cell Tumor
Desmoplastic Small Round Cell Tumor (DSRCT) is characterized by a unique chromosomal translocation involving the EWS gene on chromosome 22 and the WT1 gene on chromosome 11. This particular translocation creates a novel transcription factor with unique transcriptional targets. The functional significance of the altered transcription is unknown. We are attempting to define the direct and downstream targets of this tumor specific transcription factor and establish their functional relevance. In related efforts, we are using high throughput screening to identify active agents for treatment of this unique tumor and to define biological mechanisms that represent legitimate therapeutic targets.
Molecular Classification and Pathogenesis of Neuroblastoma
Neuroblastoma is the most common solid cancer in childhood and displays a remarkable clinical diversity. In collaboration with the Neuroblastoma Service in the Department of Pediatrics, we have carried out an extensive characterization of molecular genetic alterations in neuroblastoma and a carefully controlled assessment of associations between genetic alterations and clinically relevant aspects of this unique tumor. Our studies have defined molecular subsets of neuroblastoma that are clinically distinct and can be identified using molecular approaches. Our further efforts include identification of therapeutically relevant active pathways in specific molecular neuroblastoma subclasses.
Molecular Characterization of Lung and Colon Cancer
In recent years, we have contributed to the high throughput comprehensive genomic analysis of lung and colon cancer in collaborative efforts. These studies are designed to provide a careful assessment of associations between molecular alterations and clinical features of these tumors in order to provide information useful for diagnosis, prognosis and therapeutic design. These rich data sets are leading to the identification of clinically relevant genomic profiles and individual genes that will require extensive validation and functional analysis to fully establish their role in neoplastic disease. They also provide for cross tumor exploration of clinically relevant molecular events. These collaborations are ongoing.
