40: Pre-clinical and clinical evaluation of tivozanib for Exportin 7/Ste20-like-kinase (XPO7/SLK)-expressing cholangiocarcinoma

Thursday, March 23, 2023

10:46 AM – 10:56 AM

Location: Ballroom B

Abstract Presenter(s)

Tahsin M. Khan, MD

Surgical Oncology Research Fellow
National Cancer Institute
New York, New York, United States

Disclosure(s): No financial relationships to disclose

First Author(s)

Tahsin M. Khan, MD

Surgical Oncology Research Fellow
National Cancer Institute
New York, New York, United States

Disclosure(s): No financial relationships to disclose

Author(s)

Reed I. Ayabe, MD

Complex General Surgical Oncology Fellow
MD Anderson Cancer Center
Houston, Texas, United States

Disclosure(s): No financial relationships to disclose
PT

Pedro Torres-Ayuso, PhD

Post-doctoral Fellow
National Cancer Institute, United States

Disclosure information not submitted.
CR

Christina Robinson, BS

Scientist
Laboratory Animal Sciences Program, National Cancer Institute, United States

Disclosure information not submitted.
Amber Leila Sarvestani, MD

Surgical Oncology Clinical Research Fellow
Surgical Oncology Program, Center for Cancer Research, National Cancer Institute
Bethesda, Maryland, United States

Disclosure information not submitted.
SL

Stephanie Lux, BS

Post-Baccalaureate
National Institutes of Health, National Cancer Institute, United States

Disclosure information not submitted.
EV

Emily Verbus, MD

Surgical Oncology Research Fellow
National Cancer Institute, United States

Disclosure information not submitted.
AR

Alexander Rossi, MD

Surgical Oncology Research Fellow
National Cancer Institute, United States

Disclosure information not submitted.
SR

Shahyan Rehman, MD

MSRP Research Fellow
National Cancer Institute, United States

Disclosure information not submitted.
CH

Cathleen Hannah, RN

Research Nurse
National Institutes of Health, National Cancer Institute, United States

Disclosure information not submitted.
KS

Kathleen Smith, RN

Research Nurse
National Cancer Institute, United States

Disclosure information not submitted.
SS

Surajit Sinha, PhD

Post-doctoral fellow
National Cancer Institute, United States

Disclosure information not submitted.
KR

Kirsten Remmert, PhD

Staff Scientist
National Cancer Institute | National Institutes of Health, United States

Disclosure information not submitted.
SD

Simone Difilippantonio, PhD

Principal Scientist
Laboratory Animal Sciences Program, National Cancer Institute, United States

Disclosure information not submitted.
AB

Andrew M. Blakely, MD

Program Director
Surgical Oncology Program, National Institutes of Health, United States

Disclosure information not submitted.
Jeremy L. Davis, MD

Surgical Oncology
National Cancer Institute
Bethesda, Maryland, United States

Disclosure information not submitted.
CT

Craig Thomas, PhD

Leader, Division of Preclinical Innovation
National Center for Advancing Translational Sciences, United States

Disclosure information not submitted.
MY

Michael B. Yaffe, MD, PhD

Director, Surgical Oncology Program
National Cancer Institute, United States

Disclosure information not submitted.
JB

John Brognard, PhD

Senior Investigator
National Cancer Institute, United States

Disclosure information not submitted.
Jonathan M. Hernandez, MD

Principal Investigator
National Institutes of Health
Bethesda, Maryland, United States

Disclosure information not submitted.

Disclosure(s):

Tahsin M. Khan, MD: No financial relationships to disclose

Reed I. Ayabe, MD: No financial relationships to disclose

Introduction: Cholangiocarcinoma (CCA) is a deadly malignancy with an evolving but limited therapeutic landscape. We have discovered that a subset of patients (~30%) with CCA develop cytoplasmic accumulation of the nuclear export protein XPO7, which interacts with Ste20-like kinase (SLK) to activate downstream oncogenic signaling leading to abbreviated overall survival. Here, we present our preclinical and clinical experience targeting SLK using a small molecule kinase inhibitor, tivozanib.

Methods: A small molecule kinome screen was performed to identify inhibitors of SLK. X-ray crystallography was performed to confirm target specificity for the top hit, tivozanib. Tivozanib was evaluated in vivo using CCA cell line xenografts and two established patient-derived xenografts (PDX). CCA tumor fragments from two patients were treated with tivozanib in an ex vivo platform for 4 days. All tumors were evaluated using Ki67, cleaved caspase 3, and TUNEL immunohistochemistry. Finally, patients with advanced CCA were treated with tivozanib as part of a prospective Phase I/II clinical trial (NCT04645160).

Results: Tivozanib treatment led to a dramatic reduction in tumor burden in XPO7/SLK-expressing CCA cell line xenografts (Figure 1A) with reduced tumor cell proliferation and increased apoptosis (Figure 1B). A similar reduction in tumor volume was observed in both PDX models (Figure 1C), which translated into extended overall survival for mice treated with tivozanib (Figure 1D). In the ex vivo system, tivozanib significantly increased tumor cell apoptosis in XPO7/SLK-expressing tumors but not in tumors without this expression pattern (Figure 1E). Lastly, of the three patients treated to date on NCT04645160, one patient experienced disease stabilization by RECIST criteria after two cycles of Tivozanib monotherapy (Figure 1 F-G).

Conclusions: Robust pre-clinical data and early, encouraging clinical data supports the utilization of tivozanib as a therapeutic agent for XPO7/SLK expressing CCA.

Learning Objectives:

Upon completion, participant will be able to discuss emerging biomarkers in cholangiocarcinoma.
Upon completion, participant will be able to describe pre-clinical tool and clinical trials evaluating targeted therapies in cholangiocarcinoma.
Upon completion, participant will be able to define the efficacy of tivozanib monotherapy in cholangiocarcinoma.