ROR-1 Antagonist Combination Therapy for Chemoresistant Breast Cancer

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Solution Overview

Problem

Current breast cancer treatments are ineffective against chemoresistant cancer cells, particularly those with high expression of ROR1, which contribute to chemotherapy resistance and poor prognosis due to their role in self-renewal, metastasis, and drug resistance.

Innovation Solution

Administering a therapeutically effective amount of a chemotherapeutic agent in combination with a tyrosine kinase-like orphan receptor 1 (ROR-1) antagonist, such as a ROR-1 antagonist or anti-ROR-1 antibody, to target and inhibit ROR1-positive breast cancer cells, enhancing the sensitivity of these cells to chemotherapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If chemotherapeutic agents are administered alone, then treatment is simple, but chemoresistant cancer cells remain effective and patient survival is poor

Engineering Contradiction:

Improvechemotherapy effectivenessVSAvoidtreatment complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent combines chemotherapeutic agents with ROR1 antagonists into a dual treatment regimen. The ROR1 antagonist (either monoclonal antibody or small molecule inhibitor) is administered concurrently with chemotherapy to target cancer stem cells expressing ROR1, thereby enhancing overall treatment effectiveness against chemoresistant tumors while managing complexity through coordinated delivery of two therapeutic modalities

Inventive Principle:

Principle #5Merging (Combining)

2Reliability

If ROR1-positive cancer cells are targeted with ROR1 antagonist, then self-renewal and metastasis are inhibited, but treatment specificity must be maintained to avoid affecting normal tissues

Engineering Contradiction:

Improveanti-CSC activityVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent exploits the localized expression of ROR1 on cancer stem cells and ROR1-positive tumor cells while normal tissues either lack ROR1 expression or express it at lower levels. The ROR1 antagonist is designed to selectively bind and inhibit ROR1 signaling in the tumor microenvironment, achieving anti-CSC activity and metastasis inhibition with minimal off-target effects on normal tissues through this expression differential

Inventive Principle:

Principle #3Local quality

3Reliability

If combination therapy with ROR1 antagonist and chemotherapeutic agent is used, then treatment outcomes improve, but manufacturing and administration complexity increases

Engineering Contradiction:

Improvepatient survivalVSAvoidtherapy formulation

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent segments the combination therapy into two independently developable and manufacturable components: the ROR1 antagonist (available as monoclonal antibody or small molecule inhibitor) and the chemotherapeutic agent. Each component can be manufactured, stored, and administered separately, then combined at the point of administration. This segmentation maintains manufacturing simplicity for each individual therapy while achieving the synergistic benefits of combination treatment

Inventive Principle:

Principle #1Segmentation

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The combination of chemotherapeutic agents with ROR-1 antagonists effectively treats chemoresistant breast cancer by reducing ROR1-dependent signaling, inhibiting self-renewal, metastasis, and enhancing the sensitivity of breast cancer cells to chemotherapy, thereby improving treatment outcomes.

Implementation Method 1

ROR1 is a receptor for Wnt5a, which can induce non-canonical Wnt-signaling in chronic lymphocytic leukemia (CLL), leading to activation of Rho-GTPases and enhanced tumor-cell proliferation and survival.

Methodology Applied

Scientific EffectTyrosine kinase-like orphan receptor 1 (ROR-1) signaling inhibition:

Implementation Method 2

administering to the subject a therapeutically effective amount of a chemotherapeutic agent and a therapeutically effective amount of a tyrosine kinase-like orphan receptor 1 (ROR-1) antagonist

Methodology Applied

Scientific EffectChemotherapy-induced cell death:

Implementation Method 3

enhancing the sensitivity of these cells to chemotherapy... reducing ROR1-dependent signaling

Methodology Applied

Scientific EffectROR1-dependent signaling reduction:

Data Source

PatentUS11883492B2Combination treatment of chemoresistant cancers

Publication Date: 2024.01.30 RGT UNIV OF CALIFORNIA

AI summary

There are provided, inter alia, compositions and methods for treatment of chemoresistant cancer (breast cancer). The methods include administering to a subject in need a therapeutically effective amount of a chemotherapeutic agent and a ROR-1 antagonist. Further provided are pharmaceutical compositions including chemotherapeutic agent, ROR-1 antagonist and a pharmaceutically acceptable excipient. In embodiments, the chemotherapeutic agent is paclitaxel and the ROR-1 antagonist is cirmtuzumab.