We are delighted to congratulate Dr. Rodrigo Leite de Oliveira on receiving this prestigious grant, which will support his pioneering work in the SCAR-F project. His dedication and innovative research are set to make significant strides in the fight against aggressive cancers.

A New Approach to Combat Aggressive Cancers

Aggressive cancers, such as pancreatic cancer, present a significant challenge due to the presence of extensive fibrotic scar tissue, known as stroma. This fibrotic tissue not only supports tumor progression but also diminishes the effectiveness of current treatments. Consequently, there is an urgent need for innovative therapeutic strategies to tackle these stubborn and deadly cancers.

Portrait of Rodrigo Leite de Oliveira

Proposed Solution: SCAR-F Project
The SCAR-F (Stroma-Targeted Cancer Therapy for Fibrotic Tumors) project aims to revolutionize the treatment of fibrotic tumors by targeting the key contributors to fibrotic scar tissue—cancer-associated fibroblasts (CAFs). These fibroblasts exhibit diverse phenotypes, some promoting tumor growth and others inhibiting it. The objective of the SCAR-F project is to selectively inhibit the tumor-promoting CAFs while preserving or enhancing the tumor-limiting ones.

Central to this approach is the exploration of the autotaxin (ATX)-lysophosphatidic acid (LPA) pathway. The project employs the ATX inhibitor IOA-289 to manipulate this pathway, aiming to normalize fibrosis and enhance the efficacy of combination therapies.

Research Questions and Hypothesis
The primary research question focuses on improving the efficacy of stroma-targeted therapies by selectively altering CAF phenotypes. The hypothesis is that by manipulating specific signaling pathways, such as the ATX-LPA pathway, it is possible to normalize fibrosis, thereby inhibiting tumor development and making the tumor more susceptible to treatment.

Research Design and Plan of Action
The research plan is divided into two main work packages:

  1. Conduct a CRISPR-Cas9 screen to identify genes that influence CAF phenotypes. This screening aims to pinpoint genetic targets that could be modulated to inhibit tumor-promoting CAFs while sparing tumor-limiting ones.
  2. Optimize the therapeutic activity of the ATX inhibitor IOA-289. This involves examining its impact on both tumor-promoting and tumor-limiting CAFs, ensuring the inhibitor effectively targets the desired fibroblast phenotypes.

Expected Outcomes and Relevance
The SCAR-F project is expected to yield several significant outcomes, including:

  1. Identification of novel targets for modulating CAF activity.
  2. Enhanced understanding of the efficacy of ATX-LPA pathway inhibitors.
  3. Discovery of potential biomarkers for patient stratification, enabling more personalized and effective treatment strategies.

These results aim to deepen our understanding of the complex interactions between CAFs and cancer cells, paving the way for more effective stroma-targeted therapies, particularly for cancers characterized by fibrotic tumors.

Next Steps and Implementation
Currently, the ATX inhibitor IOA-289 is undergoing clinical phase 1b development for pancreatic cancer. The insights gained from the SCAR-F project will be instrumental in identifying promising combination therapies. These findings will subsequently be tested in follow-up laboratory studies and clinical trials, ultimately aiming to translate this innovative approach into tangible benefits for cancer patients.

This article was created for Cancer Center Amsterdam.

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