# Non-canonical Wnt-Receptor Signaling and Targeted Therapies

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $638,151

## Abstract

ROR1 is a receptor for Wnt5a, which can induce non-canonical Wnt-signaling, activate Rho GTPases, and
enhance leukemia-cell migration, proliferation, and survival. High-level expression of ROR1 can accelerate
development and progression of leukemia in transgenic mouse models and associates with more aggressive
disease and shorter survival of patients (pts) with CLL. CLL cells also express other developmentally-restricted
Wnt5a-receptors, namely ROR2 and RYK, which can contribute to non-canonical Wnt-signaling in CLL. We
hypothesize that elucidation of the structure-function-relationships involved in signaling by ROR1, ROR2, and
RYK will define clinically relevant biomarkers for non-canonical Wnt-signaling and identify novel targets for
therapy. Moreover, inhibition of non-canonical Wnt-signaling could have therapeutic applications, either alone
or in combination with other newly developed targeted therapies that inhibit B-cell-receptor-signaling or BCL2.
For this, we have the following specific aims: (AIM 1) Interrogate the signaling-pathways of non-canonical
Wnt receptors in CLL - We will define the proteins recruited to ROR1/2 in response to Wnt5a and determine
the structural domains required for signaling. We will examine the contribution of RYK to Wnt5a-signaling in
CLL, determine the role of SH3-binding proteins, 14-3-3ζ, or Ca2+/calmodulin (CaM)-dependent protein kinase
II (CaMKII) in ROR1-dependent signaling, and examine the contribution and function of ROR1 kinase to non-
canonical Wnt-signaling. (AIM 2) Examine CLL cells for co-expression of non-canonical Wnt-receptors
and determine the relative levels of Wnt-signaling - We will examine the blood samples of pts with CLL
cells that have high, low, or negligible expression of ROR1 for plasma Wnt5a, leukemia-cell expression of
ROR2 and RYK, and for leukemia-cell activation of canonical and non-canonical Wnt signaling. We also will
examine the transcriptomes of selected CLL samples and cell lines for the newly described stemness index,
which is dependent on ROR1-signaling. We also will examine for cross-talk between the canonical β-catenin-
dependent Wnt-signaling pathway and the non-canonical, β-catenin-independent pathway, which may be
influenced by the relative expression of ROR1, ROR2, or RYK, or by treatment with newly generated mAbs
specific for ROR2 or RYK. (AIM 3) Examine the contribution of ROR1-signaling to the development of
resistance to targeted therapies in CLL - We will examine expression-levels and function of ROR1, ROR2,
and RYK in serial CLL samples collected from pts before, during, and after development of resistance to
targeted therapies and evaluate the potential for synergy between cirmtuzumab and the BCL2 antagonist,
venetoclax.

## Key facts

- **NIH application ID:** 10133546
- **Project number:** 5R01CA236361-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Thomas J Kipps
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $638,151
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133546

## Citation

> US National Institutes of Health, RePORTER application 10133546, Non-canonical Wnt-Receptor Signaling and Targeted Therapies (5R01CA236361-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133546. Licensed CC0.

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