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Full-Text Articles in Molecular Biology

Tumor Interferon Signaling Initiates And Sustains A Multigenic Resistance Program To Immune Checkpoint Blockade, Joseph Lawrence Benci Jan 2017

Tumor Interferon Signaling Initiates And Sustains A Multigenic Resistance Program To Immune Checkpoint Blockade, Joseph Lawrence Benci

Publicly Accessible Penn Dissertations

Therapeutic blockade of the CTLA4 and/or PD1 immune checkpoint pathways has resulted in significant anti-tumor responses in broad variety of cancer types, but resistance is common. Using mouse models of metastatic melanoma and breast cancer in combination with CRISPR/Cas9 to selectively delete genes in our tumor cells, we demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Furthermore, we show that this interferon driven resistance mechanism primarily occurs in ICB resistant tumors and not in ICB responsive tumors. Persistent type II interferon signaling allows ...


Modulation Of Antitumor Immunity By The Mek Inhibitor Trametinib: Implications For Targeted Therapy Of Cancer, Michael J. Allegrezza Jan 2016

Modulation Of Antitumor Immunity By The Mek Inhibitor Trametinib: Implications For Targeted Therapy Of Cancer, Michael J. Allegrezza

Publicly Accessible Penn Dissertations

Through rational drug design, much progress has been made to develop small molecules that specifically inhibit the oncogenic signaling pathways driving malignant growth. However, the normal function of immune cells depends upon many of the same pathways inhibited by such targeted cancer therapies. Because the immune system can influence the growth of many cancers, I hypothesized that most small molecule inhibitors would have activity on leukocytes relevant in cancer, and this activity would contribute to their antitumor mechanisms. In order to test this hypothesis, I first screened a panel of over 40 small molecule inhibitors for their activity on proliferating ...


Interplay Between P53 And Epigenetic Pathways In Cancer, Jiajun Zhu Jan 2016

Interplay Between P53 And Epigenetic Pathways In Cancer, Jiajun Zhu

Publicly Accessible Penn Dissertations

The human TP53 gene encodes the most potent tumor suppressor protein p53. More than half of all human cancers contain mutations in the TP53 gene, while the majority of the remaining cases involve other mechanisms to inactivate wild-type p53 function. In the first part of my dissertation research, I have explored the mechanism of suppressed wild-type p53 activity in teratocarcinoma. In the teratocarcinoma cell line NTera2, we show that wild-type p53 is mono-methylated at Lysine 370 and Lysine 382. These post-translational modifications contribute to the compromised tumor suppressive activity of p53 despite a high level of wild-type protein in NTera2 ...


Adeno-Associated Viral Vector-Driven Expression Of Coagulation Proteins For Treatment Of Hemophilias And Cancer, Julie Marie Crudele Jan 2015

Adeno-Associated Viral Vector-Driven Expression Of Coagulation Proteins For Treatment Of Hemophilias And Cancer, Julie Marie Crudele

Publicly Accessible Penn Dissertations

Treatment of hemophilia, which involves infusion of the missing clotting factor, is often hindered by the development of neutralizing antibodies to the replaced clotting factor. We utilized liver-directed AAV gene therapy to tolerize outbred hemophiliac dogs with pre-existing anti-factor VIII and IX antibodies and to treat their underlying hemophilia. Additionally, we sought to shed light on the immunologic mechanisms responsible for this tolerization. Staining for CD4+CD25+FoxP3+ T cells and cytokine profiles of treated dogs suggest that induced Tregs are at least partially responsible for inducing and maintaining tolerance.

The second part of the dissertation attempts to determine the ...


Proliferation And Survival Mechanisms In Soft Tissue Sarcoma And Glioblastoma Tumors, Vera Mucaj Jan 2014

Proliferation And Survival Mechanisms In Soft Tissue Sarcoma And Glioblastoma Tumors, Vera Mucaj

Publicly Accessible Penn Dissertations

Soft tissue sarcomas and glioblastomas are two deadly tumors that are characterized by aggressive overproliferation, and regions of severe intratumoral nutrient and oxygen deprivation. The mechanisms by which tumors evade proliferation control signals and survive in a hostile microenvironment are active areas of investigation. This work describes two projects investigating loss of proliferation control in soft tissue sarcoma, as a result of Hippo pathway deregulation, and mechanisms of survival under stress in glioblastoma, as a result of decreased microRNA-124 (miR-124) levels. First, we demonstrate that the Hippo pathway is deregulated in soft tissue sarcoma patient samples, leading to overexpression of ...


Control Of The Tumor Suppressor P53 By Regulating Mdm2 Activity And Stability, Ruchira S. Ranaweera Jan 2013

Control Of The Tumor Suppressor P53 By Regulating Mdm2 Activity And Stability, Ruchira S. Ranaweera

Publicly Accessible Penn Dissertations

p53 is a tumor suppressor that is widely mutated or deleted in cancer cells. Mdm2, an E3 ubiquitin ligase, is the master regulator of p53. It targets p53 for proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. There are complex regulatory mechanisms balancing the activity and stability of Mdm2 in a cell. Mdm2 has an extremely short half-life in the unstressed cell and its regulation is not well understood. Like most E3 ligases, Mdm2 can autoubiquitinate. Previously, the sole function of autoubiquitination was thought to be to signal Mdm2 degradation. Here I show that ...


The Multifunctional Protein Daxx: Studies Of Its Biology And Regulation, And Discovery Of A Novel Function, Trisha Agrawal Jan 2013

The Multifunctional Protein Daxx: Studies Of Its Biology And Regulation, And Discovery Of A Novel Function, Trisha Agrawal

Publicly Accessible Penn Dissertations

Daxx, a multifunctional protein with a diverse set of proposed functions, is ubiquitously expressed and highly conserved through evolution. A primarily nuclear protein, Daxx is able to regulate apoptosis, transcription, and cellular proliferation. Despite many studies into the function of Daxx, its precise role in the cell remains enigmatic. Herein, evidence is presented to expand upon the known anti-apoptotic function of Daxx, to establish Daxx as a novel molecular chaperone, and to further its repertoire of transcriptional targets. As an apoptotic inhibitor, Daxx is known to regulate p53 by stabilizing its main negative regulator, Mdm2, via formation of a ternary ...