Philadelphia University + Thomas Jefferson University


Highlighted Publications

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis. Goodwin JF, Kothari V, Drake JM, Zhao S, Dylgjeri E, Dean JL, Schiewer MJ, McNair C, Jones JK, Aytes A, Magee MS, Snook AE, Zhu Z, Den RB, Birbe RC, Gomella LG, Graham NA, Vashisht AA, Wohlschlegel JA, Graeber TG, Karnes RJ, Takhar M, Davicioni E, Tomlins SA, Abate-Shen C, Sharifi N, Witte ON, Feng FY, Knudsen KE. Cancer Cell. 2015 Jul 13;28(1):97-113. doi: 10.1016/j.ccell.2015.06.004.

Mechanisms underlying metastatic development remain incompletely defined, and few therapeutic regimens effectively target the metastatic process. Studies here identify DNA-PKcs as a master driver of pro-metastatic signaling and tumor metastasis through transcriptional regulation, thus shifting paradigms with regard to DNA-PKcs activity and illuminating critical functions in human malignancy. Preclinical findings are strongly supported by clinical observations that demonstrate that DNA-PKcs is significantly upregulated in advanced disease and predicts for tumor metastases, recurrence, and poor survival. Moreover, DNA-PKcs was shown to be highly activated in metastatic tumors, independent of DNA damage indicators. These collective findings transform understanding of DNA-PKcs function, establish clinical relevance, and nominate DNA-PKcs as a therapeutic target to suppress metastases.

A hormone-DNA repair circuit governs the response to genotoxic insult. Goodwin JF, Schiewer MJ, Dean JL, Schrecengost RS, de Leeuw R, Han S, Ma T, Den RB, Dicker AP, Feng FY, Knudsen KE. Cancer Discov. 2013 Nov;3(11):1254-71. doi: 10.1158/2159-8290.CD-13-0108. Epub 2013 Sep 11.

The present study identifies for the first time a positive feedback circuit linking hormone action to the DNA damage response and shows the significant impact of this process on tumor progression and therapeutic response. These provocative findings provide the foundation for development of novel nodes of therapeutic intervention for advanced disease.

Dual roles of PARP-1 promote cancer growth and progression. Schiewer MJ, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL, Liu F, Planck JL, Ravindranathan P, Chinnaiyan AM, McCue P, Gomella LG, Raj GV, Dicker AP, Brody JR, Pascal JM, Centenera MM, Butler LM, Tilley WD, Feng FY, Knudsen KE. Cancer Discov. 2012 Dec;2(12):1134-49. doi: 10.1158/2159-8290.CD-12-0120. Epub 2012 Sep 19.

These studies introduce a paradigm shift with regard to PARP-1 function in human malignancy, and suggest that the dual functions of PARP-1 in DNA damage repair and transcription factor regulation can be leveraged to suppress pathways critical for promalignant phenotypes in prostate cancer cells by modulation of the DNA damage response and hormone signaling pathways. The combined studies highlight the importance of dual PARP-1 function in malignancy and provide the basis for therapeutic targeting.

Recent Publications

Detection of activating estrogen receptor gene (ESR1) mutations in single circulating tumor cells

Posttranscriptional regulation of PARG mRNA by HuR facilitates DNA repair and resistance to PARP inhibitors

Analysis of circulating cell-free DnA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

PARP Inhibitors in Prostate Cancer

Sigma1 targeting to suppress aberrant androgen receptor signaling in prostate cancer

Not So Fast: Cultivating miRs as Kinks in the Chain of the Cell Cycle

Cell cycle-coupled expansion of AR activity promotes cancer progression

RB loss promotes prostate cancer metastasis

Potential Impact on Clinical Decision Making via a Genome-Wide Expression Profiling: A Case Report

There and back again: The middle earth of DNA repair

Linking DNA Damage and Hormone Signaling Pathways in Cancer

Patient-level DNA damage and repair pathway profiles and prognosis after prostatectomy for high-risk prostate cancer

Downregulation of critical oncogenes by the selective SK2 Inhibitor ABC294640 hinders prostate cancer progression

Development and Validation of a Scalable Next-Generation Sequencing System for Assessing Relevant Somatic Variants in Solid Tumors

Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- And tissue-specific microRNAs

Novel actions of next-generation taxanes benefit advanced stages of prostate cancer

Models of neuroendocrine prostate cancer

Cell-cycle-dependent regulation of androgen receptor function

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function