Evaluation of combination CLK/DYRK (Cirtuvivint) inhibition with PARP inhibition (Olaparib) in BRCA/HRD platinum resistant ovarian cancer

PROJECT SUMMARY/ABSTRACT Approximately 50% of patients with ovarian cancer harbor deficiencies in DNA damage repair with either a germline/somatic mutation in BRCA1/2 or homologous recombination deficiency (HRD), and benefit from maintenance therapy with a poly (ADP-ribose) polymerase inhibitor (PARPi) following adjuvant platinum-

based chemotherapy. Unfortunately, most of these patients will have a disease recurrence and develop resistance to PARP therapy for an ultimately non-curable disease. However, innovative combination strategies can be utilized to overcome resistance as well as provide therapeutic benefit, improving the lives of our

patients. We have identified a novel first in class agent, cirtuvivint, that demonstrates single agent activity in ovarian cancer, potentiates a unique mechanism to overcome PARP resistance, and synergizes with PARP therapy in PARP resistant ovarian cancer models. Cirtuvivint is a CDC-like kinase (CLK) and dual specificity

tyrosine kinase (DYRK) inhibitor with suspected multiple anti-tumor mechanisms of action. Our preclinical work has demonstrated three distinct mechanisms of activity of cirtuvivint by 1) increasing alternative splicing events, 2) inhibiting Wnt transcriptional activity, and 3) increasing R-Loop formation.

Alternative splicing is a normal physiologic function that allows cells to change isoform-specific protein production in response to extracellular and intracellular stimuli. Alterations are implicated in tumorigenesis and metastasis. Cirtuvivint alters alternative splicing in the Wnt genes. Our work established that PARP resistant

high grade serous ovarian cancer cells display hyperactivation of Wnt signaling and increased TCF transcriptional activity, leading to PARP resistance. We therefore established rationale for combination Wnt inhibition with PARP therapy to overcome Wnt driven resistance. Additionally, we demonstrate that cirtuvivint

induces DNA damage and R-Loop formation in ovarian cancer cell lines. R-Loops are the DNA-RNA hybrids created in DNA damage repair. Increased formation of R-Loops lends to susceptibility to PARP independent DNA damage. Finally, a synergy with PARP inhibition and cirtuvivint was demonstrated in a panel of PARP

resistant ovarian cancer cell lines. Based on this rationale Aim 1 will evaluate a Phase I clinical trial of combination cirtuvivint and olaparib (PARP inhibitor) in platinum resistant ovarian cancer patients with a germline or somatic BRCA/HRD deficiency who have previously been treated with a PARPi. We will evaluate the safety and tolerability of this combination

with the goal of establishing a recommended phase 2 dosing. Aim 2 will be focused on the evaluation of CLK/DYRK inhibition induction of R-Loop DNA damage and the subsequent susceptibility to PARP inhibition. We strive to elucidate the mechanism for synergy of these two drugs and introduce them as a viable

therapeutic strategy for a significant portion of ovarian cancer patients.