Miguel Bronchud, Co-Founder at Regenerative Medicine Solutions, shared on LinkedIn:
“Prostate cancers – ‘maybe lost in translation’? New hopes for more effective treatments
‘This is the first time anyone’s ever shown that the identity of the cell can be regulated by inhibiting translation’
said at the Fred Hutch Institute in Seattle Dr Hsieh, who holds the Larry and Virginia Gordon Endowed Chair in Prostate and Bladder Cancer Research.
Fred Hutch researchers publish that they have discovered a molecular switch not at transcriptional levels but at ribosome translational level (from RNAm to Proteins) that helps prostate cancer quickly change its biology to evade therapy?
Drs. Andrew Hsieh and Rashmi Mishra identify a key step in the protein-making process that turns a treatable form of prostate cancer into a more lethal, drug-resistant subtype – and a way to switch it back?
Of course we are probably several years away from clinical trials but these results open up unexpected opportunities like making cancers resistant to therapy again vulnerable to treatments.
Despite advances in early detection and treatments, therapy resistance continues to drive poor outcomes, particularly in castration-resistant prostate cancer (CRPC).
A common denominator of therapy resistance in CRPC is the transition between lineage states from androgen receptor – dependent (AR-dependent) to AR-independent phenotypes.
These transitions may involve shifts to stem-like, progenitor, or multilineage intermediates, followed by either redifferentiation or transdifferentiation into alternative lineage identities .
AR-driven prostate cancers are often classified as luminal subtypes, characterized by strong AR signaling, expression of luminal keratins (e.g., keratin 8 and 18), and responsiveness to AR pathway inhibitors (ARPI).
In contrast, AR-independent tumors are typically classified as basal, exhibit limited AR signaling, express basal keratins (e.g., keratin 5, 6B, and 14), and are poorly responsive to ARPIs .
Recent studies have broadened our understanding of ‘cell lineage plasticity’, documenting transition into diverse phenotypic states – including neuroendocrine, gastrointestinal, Wnt-dependent, stem-cell like, and club – and hillock-like states
Title: Therapeutic targeting of the eIF4E cap-binding domain reveals control of lineage fate in prostate cancer
Authors: Rashmi Mishra, Sihyeon Song, Dhruv Choradia, Dmytro Rudoy, Cynthia L Wladyka, Patrick Hoang, Jin Yeong Kim, Ilsa M Coleman, Sonali Arora, Stephanie Dobersch, Alexander E Orellana, Chenwei Lin, Philip R Gafken, Eva Corey, Peter S Nelson, Sita Kugel, Haolong Li, Arnab Sengupta, Andrew C Hsieh
Fred Hutch prostate cancer expert Andrew C. Hsieh, and postdoctoral researcher Rashmi Mishra, recently published the Hsieh Lab’s first contribution to this growing genre of scientific literature.
These researchers in Seattle USA demonstrate that the eukaryotic initiation factor 4E no(eIF4E) cap-binding domain is a critical regulator of lineage plasticity in prostate cancer.
Using a first-in-class cap-binding domain inhibitor, they found that plasticity is driven by translational repression of basal keratins through a shared cis-regulatory element enciphered in their 5’ untranslated regions (UTRs).
Notably, prostate cancers resistant to AR blockade regained sensitivity upon eIF4E cap-binding domain inhibition, which reprogrammed them toward a luminal state.
In patients with castration-resistant prostate cancer (CRPC), elevated eIF4E expression was associated with a basal phenotype, reduced luminal differentiation, and accelerated resistance to AR pathway inhibitors (ARPIs).
These discoveries uncover a role for the eIF4E cap-binding domain in lineage plasticity and highlight that targeting this domain offers a promising strategy to overcome treatment resistance in prostate cancer.
In short, cancer hijacks a process called translation, which happens much further down the gene line in the production of proteins, the complex molecules that do the cell’s work.
Hsieh and Mishra discovered that the same mechanisms that aggressive prostate cancer cells manipulate to elude therapy can be used against them, forcing them to shapeshift back into their more treatable form.”
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