CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients

Abstract

Purpose: CD44, a cell surface glycoprotein, plays important roles in the development, progression, and metastasis of various tumor types. The aim of this study was to investigate how the expression of CD44 isoforms influences the interaction with hyaluronic acid (HA) and how differential isoform expression impacts antitumoral responses in vivo to treatment with RG7356, a humanized anti-CD44 antibody inhibiting CD44-HA interaction.Experimental Design: CD44 isoform expression on various tumor cell lines was analyzed by RNASeq while data on patients with different tumor types were obtained from the publicly available TCGA RNASeq dataset as well as a phase I clinical study (NCT01358903). We analyzed the link between HA production and CD44 isoform expression as well as the consequences of blocking the CD44-mediated cell adhesion to HA using RG7356.The correlation between CD44 isoform expression and antitumor response to RG7356 treatment was investigated in the corresponding murine xenograft in vivo models as well as in a subset of patients treated with RG7356 from a recently completed phase I clinical trial.Results: CD44 isoform expression, in particular expression of CD44s, is associated with HA production and predicts response to treatment with RG7356 in tumor xenograft models. Furthermore, patient data suggest that CD44 isoform status is a potential predictive biomarker for clinical response to treatment with RG7356.Conclusions: We provide new insights into the close interplay between CD44 and HA and a potential biomarker to enrich patient responses to RG7356 in the clinic.

Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes

“…CD44 isoform status may also be predictive of response to anti-CD44 treatment in several solid tumor types. 93 Further, a splicing variant of the androgen receptor, AR-V7, has received much attention for its potential value as a prediction marker. 94 In a prospective study, expression of AR-V7 in circulating tumor cells from patients with metastatic castration-resistant prostate cancer was shown to be predictive for resistance to androgen deprivation therapy with the drugs enzalutamide and abiraterone.…”

First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors

“…CD44 encompasses a diverse family of molecules originating from alternative splicing and posttranslational modifications in different cells [1, 2]. CD44 standard (CD44s) and variant (CD44v) isoforms are aberrantly expressed in various cancers [3] and their interaction with HA influences cell migration and homing [4]. CD44, also expressed on cancer stem cells (CSC) in various tumors, is associated with chemoresistance and tumor regrowth following standard therapy [5].…”

“…Preclinical studies suggest that higher levels of HA and expression of CD44s versus CD44v on cells are important for RG7356 activity [4]. RG7356 has also demonstrated growth inhibition of several CD44-expressing tumor xenografts (Roche internal data).…”

Phase I clinical study of RG7356, an anti-CD44 humanized antibody, in patients with acute myeloid leukemia

“…By blocking the interaction between CD44 and HA, RG7356 inhibits cell adhesion to HA-coated plates at nanomolar concentrations in vitro [10]. In vitro , the RG7356-mediated disruption of the tumor microenvironment triggers the release of specific chemo-attractants (e.g.…”