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Ronit Satchi-Fainaro: Target Therapies in P-selectin-expressing cancers

Ronit Satchi-Fainaro/LinkedIn

Dec 24, 2024, 18:16

Ronit Satchi-Fainaro: Target Therapies in P-selectin-expressing cancers

Ronit Satchi-Fainaro, Visiting Full Professor at University of Lisbon, shared a post on LinkedIn:

“Thrilled to share our new study, which was published in Science Advances!

Following the publication of our findings elucidating the key role of P-selectin in cancer progression, which led to an ongoing clinical trial exploring the use of its antibody in melanoma brain metastasis and glioblastoma patients (NCT05909618), we set to exploit it for selective targeting of therapeutics.

This is the first report to describe an anti-cancer P-selectin-targeted PLGA-PEG-GLY-(OSO3Na)2-based nanomedicine platform encapsulating a combination of two synergistic drugs. We demonstrate two optional drug combinations: (i) the BRAF inhibitor dabrafenib, and the MEK inhibitor trametinib, encapsulated in a single Two-in-One nanoparticle (2-in-1 NP) for BRAF-mutated cancers; (ii) the PARP inhibitor talazoparib, and our newly-developed small molecule PD-L1 inhibitor SM56 for BRCA-mutated cancers.

In comparison to our previously published drug delivery platform based on non-targeted polyglutamic acid (PGA) conjugated to modified dabrafenib and the MEK inhibitor selumetinib, we have encapsulated the FDA-approved SoC treatment for patients with unresectable or metastatic BRAF-mutant melanoma as well as pediatric low-grade glioma within the 2-in-1-NP.

While the lack of a functional group available for conjugation in trametinib challenged the use of PGA-based nanoconjugates, and therefore, replacing it with selumetinib, here, we have successfully encapsulated it together with dabrafenib through hydrophobic interactions.

This approach also ensured biocompatibility and biodegradability, as PLGA is an FDA-approved polymer for parenteral administration. Similarly, here we exploited this platform for the co-delivery of talazoparib and SM56 in an elegant and simple “plug-and-play” manner.

The distinct physicochemical properties, pharmacokinetics, and pharmacodynamics of two free drugs present challenges that limit their synergistic activity. To overcome these limitations, we designed P-selectin-targeted 2-in-1 NP, after we found that patient-derived samples overexpressed P-selectin in primary and brain metastatic melanomas compared to healthy brain and skin tissues; and in parallel, in primary and brain metastatic BRCA-mutated breast cancers compared to healthy breast and brain tissues.

Our P-selectin-targeted NPs exhibited superior anti-tumor efficacy and safety compared to the combination of free drugs or non-targeted NPs, at equivalent, and even higher, concentrations, allowing a true synergistic combination therapy enabling a thirty-times reduction in free drugs dosing schedules, in comparison to their dosing in pre-clinical studies.

This concept considerably promotes our knowledge of the rational design of targeted therapeutics as it can potentially be exploited in any P-selectin-expressing malignancy or neurodegenerative disease to allow co-delivery of drugs that would not otherwise reach their target.”

Ronit Satchi-Fainaro