BME Summer Seminar Series

Wednesday, June 29^th, 2022

9:30-10:30AM EST

Via Zoom Meeting – link below*

Evaluation links:

Anna Alford: https://purdue.ca1.qualtrics.com/jfe/form/SV_3yYMKwlzjH9hBvE

Brenna Vaughn: https://purdue.ca1.qualtrics.com/jfe/form/SV_3ltS5zv62XhPERo

The Role of Acrolein for Influencing Disease Severity in EAE Mice

Anna Alford (R. Shi, advisor)

Abstract: Acrolein, a pro-inflammatory and pro-oxidative neurotoxin, has previously been demonstrated to contribute to demyelination and axonal injury, two key pathological hallmarks of multiple sclerosis (MS) in preclinical models. Acrolein scavengers such as hydralazine have therefore recently shown therapeutic promise in mitigating symptom severity in mice with experimental autoimmune encephalomyelitis (EAE), a widely utilized animal model of MS. However, the extent to which targeting acrolein can combat MS pathology has yet to be fully investigated. Our lab is the first to explore the effects of influencing both exogenous and endogenous mechanisms of regulating acrolein on EAE disease severity. To bolster the clinical relevance of acrolein scavenging as a therapeutic approach, we investigate the effects of pre-symptomatic and post-symptomatic applications and confirm the effectiveness of both in alleviating motor deficits and neuropathic pain in EAE mice. Additionally, we observe a strong correlation between levels of acrolein and myeloperoxidase, an established inflammatory marker, in response to acrolein scavenging treatments in EAE mice. Furthermore, we demonstrate heightened disease severity resulting from genetically weakening aldehyde dehydrogenase 2 (ALDH2), a means of endogenous acrolein scavenging, in a clinically relevant ALDH2*2 mouse variant. In contrast, pharmacologically enhancing ALDH2 using Alda-1 is capable of lowering acrolein and providing motor and sensory benefits to EAE mice. Current efforts are focused on utilizing the ALDH2*2 variant to further investigate the mechanisms by which acrolein contributes to enhanced disease severity in Multiple Sclerosis.

Antibody-Drug Conjugate Resistance in HER2+ Breast Cancer

Brenna Vaughn (M. Wendt/L. Solorio, advisor)

Abstract: One in eight women will develop breast cancer in their lifetime. Approximately 20-25% of these cases overexpress human epidermal growth factor 2 (HER2), a receptor tyrosine kinase that defines an aggressive subtype of breast cancer. HER2-targeted therapies have been developed

over the past two decades and have improved overall survival in HER2+ breast cancer patients.

One of the more recently developed HER2-targeted therapies is T-DM1. T-DM1 is an antibodydrug

conjugate comprised of a HER2-specific antibody, trastuzumab, conjugated to a cytotoxic

agent, emtansine, by a stable linker. However, metastatic recurrence remains an immediate

threat to survival as most patients with metastatic disease will develop resistance to such

therapies. In fact, when the disease recurs as distant metastasis rather than local disease, the 5-

year survival rate drops to only 25%. Significant gaps in knowledge remain in the understanding

of how breast cancer cells gain resistance to HER2-targeted therapies and result in lifethreatening

metastatic disease. Here, we investigate the potential involvement of a protein

crosslinking enzyme, tissue transglutaminase 2 (TG2), as a driver of resistance to antibodybased

therapies in HER2+ breast cancer. Preliminary results suggest that TG2 overexpression in

HER2-transformed human mammary epithelial (HMLE) cells may be important in acquiring

resistance to the HER2-targeted antibody-drug conjugate T-DM1. We hypothesize that TG2

overexpression may reduce the efficacy of T-DM1 through the occlusion of antibody binding

sites or crosslinking free T-DM1. Current work has included the derivation of a TG2

overexpressing HER2-transformed HMLE strain using a lentiviral stable transduction approach,

establishing an IC50 value for T-DM1 in these cells, and validation of TG2 overexpression by

western blot. Planned studies include imaging of trastuzumab penetration into tumors through

organ-clearing techniques as well as time until recurrence of disease studies with T-DM1

resistant HER2+ cells. Successful completion of this work will aid in identifying strategies to

overcome resistance to HER2-targeted therapies.

*Join Zoom Meeting

https://purdue-edu.zoom.us/j/92168739019?pwd=cnBOaFBxN3FWVVVTWC8wWWhaekdIdz09

Meeting ID: 921 6873 9019

Passcode: biomedical

Liz Rowen

She/Her

Graduate Program Assistant
Weldon School of Biomedical Engineering

Martin C. Jischke Hall of Biomedical Engineering
206 S. Martin Jischke Drive
West Lafayette, IN 47907-2032

o: 765-494-1197