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Publications of the Week

The PI3K/mTOR Inhibitor Gedatolisib Eliminates Dormant Breast Cancer Cells in Organotypic Culture, but Fails to Prevent Metastasis in Preclinical Settings

By June 23, 2021No Comments

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This week, we profile a recent publication in Molecular Oncology from Ryann Shor (pictured, 5th from right) in the lab of Cyrus Ghajar (3rd from right) at Fred Hutch.

Can you provide a brief overview of your lab’s current research focus?
Our lab studies breast cancer metastasis and the biology of disseminated tumor cells (DTCs) and their microenvironments. We are exploring the role of the microenvironment in the biology of the four “hallmarks” of DTCs: long-term survival, reversible growth arrest, immune evasion, and therapeutic resistance. Through interrogating these hallmarks, we hope to uncover treatment modalities, novel or recycled, to eradicate DTCs and prevent metastasis.

What is the significance of the findings in this publication?
Our previous research uncovered Integrin-β1 as a key driver of DTC chemoresistance. Since there are currently no clinically approved Integrin-β1 blocking antibodies, we looked downstream of Integrin-β1 to identify druggable targets. We identified PI3K as a key downstream signaling hub and demonstrated significant chemosensitization of tumor cells in organotypic culture using the dual PI3K/mTOR inhibitor Gedatolisib. Despite promise in organotypic culture, Gedatolisib failed to reduce DTC burden or improve metastasis-free survival in ER+ or triple-negative breast cancer mouse models. Our results suggest that PI3K is not likely a key regulator of chemoresistance and survival in vivo and that other targets should be explored. More broadly, our results cast doubt on the efficacy of PI3K inhibition in reducing minimal residual disease.

What are the next steps for this research?
We are using a multi-pronged approach to identify treatment modalities that allow for DTC eradication with the long-term goal of reducing and ultimately preventing delayed metastasis. While this publication indicates that PI3K does not effectively chemosensitize DTCs, we will continue working to identify druggable targets downstream of Integrin-β1 that do confer chemosensitivity in DTCs, including combinations with PI3K inhibitors in case signaling is re-routed upon this pressure. We will also develop inhibitors to integrin-β1 to pursue translational studies.

This work was funded by:
This research was supported principally by the Breast Cancer Research Foundation (IIDRP-16-001), the Department of Defense Breast Cancer Research Program (W841XWH‐15‐1‐0201 W81XWH‐19‐1‐0071 W81XWH‐19‐1‐0617 W81XWH‐20‐1‐0229 W81XWH‐18‐1‐0028), and the National Cancer Institute (R01 CA249528‐01).

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