Related Experiment Video

Updated: Sep 3, 2025

A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
05:29

A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells

Published on: March 28, 2021

2.9K

A potent tumor-selective ERK pathway inactivator with high therapeutic index

Zehua Zuo1, Jie Liu1, Zhihao Sun1

  • 1Aging Institute of University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA.

PNAS Nexus
|July 28, 2022
PubMed

Insights

Researchers reengineered anthrax toxin to create a tumor-selective MEK inactivator. This engineered toxin shows high efficacy and a superior therapeutic index for treating solid tumors, including those with BRAF mutations.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • FDA-approved BRAF and MEK inhibitors for metastatic melanomas have limited therapeutic index due to side effects on normal cells.
  • Existing targeted therapies face challenges with toxicity and efficacy in cancer treatment.

Purpose of the Study:

  • To reengineer the anthrax toxin delivery system to create a potent and tumor-selective MEK inactivator.
  • To develop a therapeutic agent with an improved therapeutic index for solid tumors, particularly those with BRAF mutations.

Main Methods:

  • Reengineering the anthrax toxin protein delivery system to create a MEK inactivator.
  • Evaluating the in vitro and in vivo activity of the engineered toxin against various solid tumors.
  • Assessing the specificity and therapeutic index of the MEK inactivator, focusing on its dependence on tumor-associated factors.

Main Results:

  • The toxin-based MEK inactivator demonstrated potent activity against a broad spectrum of solid tumors, with enhanced efficacy in BRAFV600E-mutated tumors.
  • The engineered inactivator exhibited a high therapeutic index (>15), dependent on tumor-associated proteases and receptors.
  • Specificity was improved, targeting only the ERK pathway to minimize off-target toxicity.

Conclusions:

  • Engineered bacterial toxins can be modified to create effective therapeutic agents with high therapeutic indices.
  • This approach offers a promising strategy for developing targeted cancer therapies with reduced side effects.
  • The tumor-selective MEK inactivator represents a novel therapeutic candidate for solid tumors, especially those driven by BRAF mutations.
Keywords:
CMG2ERK signalinganthrax lethal toxinintermolecular complementationtumor targeting

More Related Videos

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies09:29

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies

Published on: September 30, 2016

13.9K
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays13:22

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

8.0K

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.8K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.6K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.9K
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
2.7K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.1K