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.