Publications

Karen E Knudsen, MBA, PhD

Contact

Name: Karen E Knudsen, MBA, PhD
Position: Executive Vice President, Oncology Services Enterprise Director, Sidney Kimmel Cancer Center Chair, Cancer Biology

233 South 10th Street
Bluemle Life Science Building, Suite 1050
Philadelphia, PA 19107

Telephone: 215-503-5692

Highlighted Publications

Schiewer MJ, Mandigo AC, Gordon N, Huang N, Gaur S, de Leeuw R, Zhao SG, Evans J, Han S, Parsons T, Birbe R, McCue P, McNair C, Chand SN, Cendon-Florez, Gallagher P, McCann JJ, Neupane NP, Shafi AA, Dylgjieri A, Brand LJ, Visakorpi T, Raj GV, Lallas CD, Trabulsi EJ, Gomella LG, Dicker AP, Kelly WK, Leiby BE, Knudsen B, Feng FY, and Knudsen KE (2018) PARP1 regulates DNA repair factor availability.  EMBO Mol Med, 2018 Dec;10(12). pii: e8816. doi: 10.15252/emmm.201708816.

PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity. Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1-mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP-1 inhibition reduced HR factor availability and thus acted to induce or enhance "BRCA-ness". These observations bring new understanding of PARP-1 function in cancer and have significant ramifications on predicting PARP-1 inhibitor function in the clinical setting.

McNair C, Xu K, Mandigo A, Benelli M, Leiby B, Rodrigues D, Lindberg J, Gronberg H, Crespo M, De Laere B, Dirix L, Visakorpi T, Li F, Feng F, De Bono J, Demichelis F, Rubin MA, Brown MA, and Knudsen KE (2017) Differential impact of RB status on E2F1 reprogramming in human cancer.  J Clin Invest, Jan 2;128(1):341-358. doi: 10.1172/JCI93566. Epub 2017 Dec 4.

The tumor suppressor protein retinoblastoma (RB) is mechanistically linked to suppression of transcription factor E2F1-mediated cell cycle regulation. For multiple tumor types, loss of RB function is associated with poor clinical outcome. RB action is abrogated either by direct depletion or through inactivation of RB function; however, the basis for this selectivity is unknown. Here, analysis of tumor samples and cell-free DNA from patients with advanced prostate cancer showed that direct RB loss was the preferred pathway of disruption in human disease. While RB loss was associated with lethal disease, RB-deficient tumors had no proliferative advantage and exhibited downstream effects distinct from cell cycle control. Mechanistically, RB loss led to E2F1 cistrome expansion and different binding specificity, alterations distinct from those observed after functional RB inactivation. Additionally, identification of protumorigenic transcriptional networks specific to RB loss that were validated in clinical samples demonstrated the ability of RB loss to differentially reprogram E2F1 in human cancers. Together, these findings not only identify tumor-suppressive functions of RB that are distinct from cell cycle control, but also demonstrate that the molecular consequence of RB loss is distinct from RB inactivation. Thus, these studies provide insight into 

Dylgjeri E, McNair C, Goodwin JF, Raymon HK, McCue PA, Shafi AA, Leiby BE, de Leeuw R, Kothari V, McCann JJ, Mandigo AC, Chand SN, Schiewer MJ, Brand LJ, Vasilevskaya IA, Gordon N, Laufer TS, Gomella LG, Lallas CD, Trabulsi EJ, Feng FY Filvaroff EH, Hege K, Rathkopf, D, and Knudsen KE(2019) Pleiotropic impact of DNA-PK in cancer and implications for therapeutic strategies.  Clinical Cancer Research, Sep 15;25(18):5623-5637. doi: 10.1158/1078-0432.CCR-18-2207.

DNA-dependent protein kinase catalytic subunit (DNA-PK) is a pleiotropic kinase involved in DNA repair and transcriptional regulation. DNA-PK is deregulated in selected cancer types and is strongly associated with poor outcome. The underlying mechanisms by which DNA-PK promotes aggressive tumor phenotypes are not well understood. Here, unbiased molecular investigation in clinically relevant tumor models reveals novel functions of DNA-PK in cancer. DNA-PK function was modulated using both genetic and pharmacologic methods in a series of in vitro models, in vivo xenografts, and patient-derived explants (PDE), and the impact on the downstream signaling and cellular cancer phenotypes was discerned. Data obtained were used to develop novel strategies for combinatorial targeting of DNA-PK and hormone signaling pathways.

Key findings reveal that:

A.      DNA-PK regulates tumor cell proliferation
B.      pharmacologic targeting of DNA-PK suppresses tumor growth both in vitro, in vivo, and ex vivo
C.      DNA-PK transcriptionally regulates the known DNA-PK-mediated functions as well as novel cancer-related pathways that promote tumor growth
D.      Dual targeting of DNA-PK/TOR kinase (TORK) transcriptionally upregulates androgen signaling, which can be mitigated using the androgen receptor (AR) antagonist enzalutamide
E.       Cotargeting AR and DNA-PK/TORK leads to the expansion of antitumor effects, uncovering the modulation of novel, highly relevant protumorigenic cancer pathways
F.       Cotargeting DNA-PK/TORK and AR has cooperative growth inhibitory effects in vitro and in vivo

These findings uncovered novel DNA-PK transcriptional regulatory functions and led to the development of a combinatorial therapeutic strategy for patients with advanced prostate cancer, currently being tested in the clinical setting.

Recent Publications

Urine Extracellular Vesicle GATA2 mRNA Discriminates Biopsy Result in Men with Suspicion of Prostate Cancer

Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019

The DNA methylation landscape of advanced prostate cancer

Prospective study to define the clinical utility and benefit of Decipher testing in men following prostatectomy

Cellular rewiring in lethal prostate cancer: the architect of drug resistance

Double trouble: Concomitant RB1 and BRCA2 depletion evokes aggressive phenotypes

Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer

USP22 functions as an oncogenic driver in prostate cancer by regulating cell proliferation and DNA repair

The role of lineage plasticity in prostate cancer therapy resistance

The AR-DNA repair axis: insights into prostate cancer aggressiveness

Introduction to the 2019 Philadelphia Prostate Cancer Consensus Program: 'Implementation of Genetic Testing for Inherited Prostate Cancer'

SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors

Pleiotropic impact of DNA-PK in cancer and implications for therapeutic strategies

DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway

Expanding Role of Germline DNA Repair Alterations in Prostate Cancer Risk and Early Onset

Cancer and the circadian clock

Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing

An analysis of a multiple biomarker panel to better predict prostate cancer metastasis after radical prostatectomy

Rb1 heterogeneity in advanced metastatic castration-resistant prostate cancer

DNA damage response in prostate cancer

Novel Rb1-loss transcriptomic signature is associated with poor clinical outcomes across cancer types

PARP-1 regulates DNA repair factor availability

Erratum: Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer (Cell (2018) 174(3) (758–769.e9), (S0092867418308420) (10.1016/j.cell.2018.06.039))

Control of CCND1 ubiquitylation by the catalytic SAGA subunit USP22 is essential for cell cycle progression through G1 in cancer cells

Patient-derived Models Reveal Impact of the Tumor Microenvironment on Therapeutic Response