Bethany Hannafon, PhD
2024 Collaborative Research Development Grant Recipient
University of Oklahoma Health Sciences Center
Development of a novel DCLK1-targeted CAR-T to prevent ovarian cancer metastatic recurrence
Project Summary
Ovarian cancer (OvCa) is characterized by disease recurrences due to the persistence of drug-resistant cancer cells known as cancer stem cells (CSCs). CSCs retain the ability to self-renew, propagate new tumors, and drive resistance to chemotherapy. Doublecortin-like kinase 1 (DCLK1) is a CSC-related protein and a regulator of programs that drive tumor metastasis and drug resistance. We show that in OvCa, DCLK1 is associated with poor survival, is highly expressed in chemo-resistant (compared to sensitive) cells, and that inhibition of DCLK1 enhances sensitivity to chemotherapy.
Chimeric antigen receptor T (CAR-T) is a type of immunotherapy whereby a patient’s T cells are engineered to attack specific tumor surface antigens. DCLK1 is increased on the surface of ovarian cancer cells, thus providing a novel tumor antigen. We hypothesize that engagement of CSCs that express DCLK1 with a novel CAR-T will overcome chemoresistance, reduce tumor growth, and metastasis, and prevent recurrence. In this study, we will systematically design, optimize, and investigate a DCLK1-targeted CAR-T therapy.
At completion, we will have identified a CAR-T with superior efficacy and persistence for the treatment of metastatic chemo-resistant OvCa that will ultimately provide safe and effective repression of recurrent metastases without the massive comorbidities associated with prolonged traditional chemotherapy, thus fulfilling a major unmet medical need.
This grant was made possible in part by generous donations from an anonymous donor in memory of Julia Skillman, Andrew Berger in memory of Sharon Berger, and Mike McLeod in memory of Christine Monzon.
Bio
Bethany Hannafon, PhD is an Assistant Professor of Gynecologic Oncology at the Stephenson Cancer Center, University of Oklahoma Health Sciences Center (OUHSC). Dr. Hannafon earned a dual PhD in the Program in Molecular Medicine and Cell and Molecular Biology from Boston University School of Medicine and completed postdoctoral training in cancer biology/pathology at Dana-Farber Cancer Institute and OUHSC.
Dr. Hannafons’ research aims to understand the cellular and molecular mechanisms that drive ovarian cancer development, progression, and therapeutic resistance and to discover novel treatment strategies to overcome resistance, prevent recurrences, and improve patient outcomes. Her recent efforts have focused on evaluating the role of doublecortin-like-kinase 1 (DCLK1) in promoting platinum resistance and cancer-stem-cell phenotypes in ovarian cancer. Novel treatment strategies, such as targeting DCLK1, that can overcome platinum resistance are urgently needed to reduce chemotherapy resistance and positively impact ovarian cancer patient outcomes.