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Recent Submissions

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Reclaiming our voice: activism as antidote
(2023-09-22) Bornstein, Sue S.
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UT Southwestern Medical Center Ethics Grand Rounds - 2023/2024
(2023)
This document lists the schedule of Ethics Grand Rounds events for September 2023 through May 2024.
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A Cytokine Receptor Masked IL-2 Prodrug Selectively Activates Tumor-Infiltrating Lymphocytes for Potent Antitumor Therapy
(August 2021) Hsu, Eric Jonathan; Zhang, Chengcheng "Alec"; Farrar, J. David; Malladi, Srinivas; Yan, Nan; Fu, Yang-Xin
Cancers are very difficult to treat, and many cancer patients fail to respond to numerous standard of care therapies. Many of these tumors have been observed to lack functional CD8 T cells, which have been observed to be correlated with improved patient prognosis. One of the main strategies to combat the lack of functional tumor infiltrating immune cells is to treat patients with immune stimulating cytokines such as interleukin-2 (IL-2). As a potent lymphocyte activator, IL-2 is an FDA approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, limitations of both recombinant IL-2 and these next generation IL-2 variants are addressed through the engineering of a novel IL-2 prodrug (ProIL2). Numerous designs of ProIL2 were designed, engineered, and tested until a final optimal construct was synthesized. The activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein is masked with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Furthermore, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Lastly, ProIL2 can also synergize with radiation therapy to more effectively control both primary and metastatic cancer. Further protein engineering strategies are being implemented to overcome potential limitations of ProIL2. Taken together, this approach presents an effective tumor targeting therapy with reduced toxicity.
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Compensation Between Foxp Transcription Factors Maintains Proper Striatal Function
(August 2023) Ahmed, Newaz Ibrahim; Tsai, Peter; Chahrour, Maria; Roberts, Todd; Konopka, Genevieve
Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors Foxp1 and Foxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs. Paralogous transcription factors are thought to have the ability to compensate for each other and previous work published by the lab supports the hypothesis that Foxp1 and Foxp2 have compensatory roles in D1 SPNs as well. For my dissertation work, I utilized mice with a D1-SPN specific loss of Foxp1, Foxp2, or both and a combination of behavior, electrophysiology, and cell type specific genomic analysis to address if there was compensation occurring. It is only upon the loss of both genes that motor behavior was impaired whereas Foxp1 mediated social behavior impairments were exacerbated upon the further loss of Foxp2 (Chapter Two). I also found that while loss of Foxp1 resulted in KLeak mediated hyperexcitability of D1-SPNs, this too was further impaired with the additional loss of Foxp2 (Chapter Three). Viral mediated re-expression of Foxp1 in the double knockouts was sufficient to restore both behavioral and electrophysiological impairments to baseline. I further studied the contribution of Foxp1 and Foxp2 to regulation of downstream targets genes using single-nuclei RNA-seq and found that in both juvenile and adult D1-SPNs, loss of both transcription factors resulted in differential expression of hundreds of genes (Chapter Four). I was able to use these experiments to also investigate how loss of these transcription factors from the D1-SPNs impacted gene expression in other cell-types (Chapter Five). I also utilized single-nuclei ATAC-Seq and again found that loss of both genes resulted in large scale dysregulation of chromatin state not seen in the single knockouts, including in regions enriched for Fox motifs (Chapter Six). I also began to address the open question of what the direct binding targets of Foxp1 and Foxp2 are using the newly developed CUT&RUN technique (Chapter Seven). The findings from my experiments point towards a form of compensation between Foxp1 and Foxp2 where one transcription factor maintains striatal function upon the loss of the other, which I discuss more in depth (Chapter Eight). I also discuss my involvement in a project where we further study the role of Foxp1 in D1- and D2-SPNs, which I am working on in collaboration with Dr. Nitin Khandelwal (Chapter Nine). I conclude by discussing the implications of my findings and suggest recommendations for further study (Chapter Ten).