Tumor Immune Microenvironment of Brain Metastases: Toward Unlocking Antitumor Immunity, page-3

Very good information R&P.


The 2 trials mentioned ((NCT03994796 and NCT04192981) BELOW are both GDC 0084 ( Paxalisib) -  Memorial  Sloan Pax with radiation and Priscilla's own ALLIANCE trial. Very deep into trials, this is therefore a very positive research note.

At Fiqure 5, an arrow and shading seems to highlight GDC 0084 response, to cancer inflamed tumor associated macrophages , known as TAMS's

Blazquez mentioned by PB is in fact this 2018 German study with PI3K buparlisib mentioned......but its the GDC 0084 FDA studies that are referred to in this detailed study.(at very bottom)
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Blazquez and colleagues found a cohort of human breast cancer–derived BrM to be enriched in PI3K signaling activity and that PI3K was a master regulator of metastasis promoting microglia/macrophages (146). BrM outgrowth in mice was impaired when using a CNS-penetrant small molecule inhibitor of PI3K. The promise of targeting PI3K in the CNS is further supported by the high frequency of PI3K alterations observed in human BrM and the availability of CNS-penetrant PI3K inhibitors (76, 147). Clinical trials investigating PI3K as a putative target in patients with BrM are ongoing (NCT03994796 and NCT04192981).








PI3K: A master regulator of brain metastasis-promoting macrophages/microglia

Raquel Blazquez,Darius Wlochowitz,Alexander Wolff,Stefanie Seitz,Astrid Wachter,Julia Perera-Bel,Annalen Bleckmann,Tim Beißbarth,**riela Salinas,Markus J. Riemenschneider,Martin Proescholdt,Matthias Evert,Kirsten Utpatel,Laila Siam,Bawarjan Schatlo,Marko Balkenhol,Christine Stadelmann,Hans-Ulrich Schildhaus,Ulrike Korf,Eileen Reinz,Stefan Wiemann,Elena Vollmer,Mathias Schulz,Uwe Ritter,Uwe K. Hanisch,Tobias Pukrop … See fewer authors
First published: 25 October 2018

https://doi.org/10.1002/glia.23485
Citations: 26
Funding information Bundesministerium für Bildung und Forschung, Grant/Award Number: 0316173C; Deutsche Forschungsgemeinschaft, Grant/Award Number: INST 89/341-1 and PU 355/5-1


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Abstract

Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis-promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan-PI3K Class I inhibitor with a good blood-brain-barrier penetrance, reduced their metastasis-promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re-educates the metastasis-promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.