Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Deborah A. Knee is active.

Publication


Featured researches published by Deborah A. Knee.


Cancer Cell | 2004

Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway

Yan Wang; Ingo H. Engels; Deborah A. Knee; Marc Nasoff; Quinn L. Deveraux; Kim C. Quon

The genetic concept of synthetic lethality provides a framework for identifying genotype-selective anticancer agents. In this approach, changes in cellular physiology that arise as a consequence of oncogene activation or tumor suppressor gene loss, rather than oncoproteins themselves, are targeted to achieve tumor selectivity. Here we show that agonists of the TRAIL death receptor DR5 potently induce apoptosis in human cells overexpressing the MYC oncogene, both in vitro and as tumor xenografts in vivo. MYC sensitizes cells to DR5 in a p53-independent manner by upregulating DR5 cell surface levels and stimulating autocatalytic processing of procaspase-8. These results identify a novel mechanism by which MYC sensitizes cells to apoptosis and validate DR5 agonists as potential MYC-selective cancer therapeutics.


European Journal of Cancer | 2016

Rationale for anti-GITR cancer immunotherapy

Deborah A. Knee; Becker Hewes; Jennifer Brogdon

Over the past decade, our understanding of cancer immunotherapy has evolved from assessing peripheral responses in the blood to monitoring changes in the tumour microenvironment. Both preclinical and clinical experience has taught us that modulation of the tumour microenvironment has significant implications to generating robust antitumour immunity. Clinical benefit has been well documented to correlate with a tumour microenvironment that contains a dense infiltration of CD8+CD45RO+ T effectors and a high ratio of CD8+ T cells to FoxP3+ regulatory T cells (Tregs). In preclinical tumour models, modulation of the Glucocorticoid induced TNF receptor (GITR)/GITR ligand (GITRL) axis suggests this pathway may provide the desired biological outcome of inhibiting Treg function while activating CD8+ T effector cells. This review will focus on the scientific rationale and considerations for the therapeutic targeting of GITR for cancer immunotherapy and will discuss possible combination strategies to enhance clinical benefit.


Cancer Biology & Therapy | 2003

Activation and suppression of the TRAIL death-receptor pathway in chemotherapy sensitive and resistant follicular lymphoma cells.

Klaus Wagner; Fred King; Ken Nomoto; Deborah A. Knee; Garret M. Hampton; Marc Nasoff; Quinn L. Deveraux

Aberrant expression of the apoptosis inhibitor bcl-2 provides a survival advantage throughout oncogenesis and can facilitate chemotherapeutic resistance in a variety of human cancers. Follicular lymphoma (FL) for example, is characterized by the chromosomal translocation t(14;18), which results in bcl-2 over-expression and initiates lymphomagenesis. Although FL cells possess ample amounts of bcl-2, they respond remarkably well to standard first-round chemotherapy. However, the vast majority of patients relapses and becomes progressively resistant to therapy. We obtained cell lines derived from chemosensitive and chemoresistant FL patients, that are characterized by the chromosomal translocation t(14;18) and expression of bcl-2, to investigate how chemotherapeutic drugs can circumvent bcl-2 anti-apoptotic function and to identify alterations in those pathways that may facilitate resistance to DNA damaging drugs. In chemosensitive FL cells, we found that DNA damaging drugs promote apoptosis through p53-dependent up-regulation of the TRAIL-DR5 receptor, resulting in activation of caspase-8 and downstream executioner caspases—thereby evading bcl-2 mediated suppression of apoptosis. Examination of drug resistant FL cell lines revealed that at least two defects in this pathway can contribute to chemotherapeutic resistance; (1) p53 gene mutations that disable the transcriptional response to DNA damaging drugs, including expression of the TRAIL-DR5 receptor, and (2) transcriptional repression of the cell-death executioner enzyme caspase-3.


PLOS ONE | 2013

IL-2 Immunotherapy Reveals Potential for Innate Beta Cell Regeneration in the Non-Obese Diabetic Mouse Model of Autoimmune Diabetes

Yaiza Diaz-de-Durana; Janet Lau; Deborah A. Knee; Christophe M. Filippi; Marco Londei; Peter McNamara; Marc Nasoff; Michael DiDonato; Richard Glynne; Ann E. Herman

Type-1 diabetes (T1D) is an autoimmune disease targeting insulin-producing beta cells, resulting in dependence on exogenous insulin. To date, significant efforts have been invested to develop immune-modulatory therapies for T1D treatment. Previously, IL-2 immunotherapy was demonstrated to prevent and reverse T1D at onset in the non-obese diabetic (NOD) mouse model, revealing potential as a therapy in early disease stage in humans. In the NOD model, IL-2 deficiency contributes to a loss of regulatory T cell function. This deficiency can be augmented with IL-2 or antibody bound to IL-2 (Ab/IL-2) therapy, resulting in regulatory T cell expansion and potentiation. However, an understanding of the mechanism by which reconstituted regulatory T cell function allows for reversal of diabetes after onset is not clearly understood. Here, we describe that Ab/IL-2 immunotherapy treatment, given at the time of diabetes onset in NOD mice, not only correlated with reversal of diabetes and expansion of Treg cells, but also demonstrated the ability to significantly increase beta cell proliferation. Proliferation appeared specific to Ab/IL-2 immunotherapy, as anti-CD3 therapy did not have a similar effect. Furthermore, to assess the effect of Ab/IL-2 immunotherapy well after the development of diabetes, we tested the effect of delaying treatment for 4 weeks after diabetes onset, when beta cells were virtually absent. At this late stage after diabetes onset, Ab/IL-2 treatment was not sufficient to reverse hyperglycemia. However, it did promote survival in the absence of exogenous insulin. Proliferation of beta cells could not account for this improvement as few beta cells remained. Rather, abnormal insulin and glucagon dual-expressing cells were the only insulin-expressing cells observed in islets from mice with established disease. Thus, these data suggest that in diabetic NOD mice, beta cells have an innate capacity for regeneration both early and late in disease, which is revealed through IL-2 immunotherapy.


Molecular Biology of the Cell | 2004

Differential Regulation of the TRAIL Death Receptors DR4 and DR5 by the Signal Recognition Particle

Yan-Guo Ren; Klaus Wagner; Deborah A. Knee; Pedro Aza-Blanc; Marc Nasoff; Quinn L. Deveraux


Archive | 2003

Methods and compositions for inducing apoptosis in cancer cells

Marc Nasoff; Quinn Deveraux; Deborah A. Knee; Pedro Aza-Blanc; Garret M. Hampton; Klaus Wagner


Drug Development Research | 2008

LBY135, a novel anti‐DR5 agonistic antibody induces tumor cell–specific cytotoxic activity in human colon tumor cell lines and xenografts

Jing Li; Deborah A. Knee; Youzhen Wang; Qingxiu Zhang; Jennifer A. Johnson; Jane Cheng; Helen He; Christine Miller; Zhifang Li; Colleen Kowal; Joseph Eckman; Betty Tang; Jing Yuan; Liqing Chen; Quinn L. Deveraux; Marc Nasoff; David Stover


Cancer Research | 2007

Antitumor efficacy of LBY135, an anti-DR5 monoclonal antibody, alone or in combination with chemotherapy in human colon tumor cell lines and xenografts

Jing Li; Betty Tang; Jean Cheng; Joseph Eckman; Christine Miller; Jing Yuan; Youzhen Wang; Deborah A. Knee; Quinn L. Deveraux; Marc Nasoff; David Stover


Cancer Research | 2007

Tumor-cell specific cytotoxic activity of LBY135, a novel anti- DR5 agonistic antibody

Jing Li; Qingxiu Zhang; Jennifer Johnson; Deborah A. Knee; Quinn L. Deveraux; Marc Nasoff; David Stover


Archive | 2006

Methods and compositions for inducing apoptosis in cancer cells with an anti-DR5 antibody

Marc Nasoff; Quinn Deveraux; Deborah A. Knee; Pedro Aza-Blanc; Garrett M. Hampton; Klaus Wagner

Collaboration


Dive into the Deborah A. Knee's collaboration.

Top Co-Authors

Avatar

Marc Nasoff

Genomics Institute of the Novartis Research Foundation

View shared research outputs
Top Co-Authors

Avatar

Klaus Wagner

Genomics Institute of the Novartis Research Foundation

View shared research outputs
Top Co-Authors

Avatar

Quinn L. Deveraux

Genomics Institute of the Novartis Research Foundation

View shared research outputs
Top Co-Authors

Avatar

Garret M. Hampton

Genomics Institute of the Novartis Research Foundation

View shared research outputs
Top Co-Authors

Avatar

David Stover

Genomics Institute of the Novartis Research Foundation

View shared research outputs
Top Co-Authors

Avatar

Jing Li

Genomics Institute of the Novartis Research Foundation

View shared research outputs
Top Co-Authors

Avatar

Ann E. Herman

Genomics Institute of the Novartis Research Foundation

View shared research outputs
Top Co-Authors

Avatar

Betty Tang

Genomics Institute of the Novartis Research Foundation

View shared research outputs
Top Co-Authors

Avatar

Christine Miller

Genomics Institute of the Novartis Research Foundation

View shared research outputs
Researchain Logo
Decentralizing Knowledge