Address

Dominik-Laurentius Candea

Targeting CCR7-PI3Kg axis to eradicate persistent lymphoma cells in ALK+ ALCL

Università di Torino

Supervisor: Claudia VOENA, Roberto CHIARLE

 

Research objectives:

To eradicate long-term persister cells by co-targeting of the CCR7-PI3Kγ axis.

We previously demonstrated that the CCL19/21-CCR7-PI3Kγ axis drives resistance to ALK tyrosine kinase inhibitors (TKIs) and promotes survival of ALK+ ALCL persister cells in the perivascular niche during TKI treatment.

We hypothesize that blockade of PI3Kγ during ALK TKI treatment would reduce primary resistance as well as the survival of residual lymphoma cells;

  1. To disrupt PI3Kg signalling by the PI3Kγ/δ inhibitor duvelisib as a single agent or in combination with other TKIs in the 3D microvessel cell culture system that we have developed to mimic the lymphoma perivascular niche and in vivo (sub cutis or intravenous grafts of ALK+ ALCL cell lines and ALK+ ALCL patient derived xenografts, PDX);
  2. To develop new nanomedicines for targeted treatment of persistent lymphoma cells. Precision nanomedicine may allow targeted treatment of persister lymphoma cells with new emerging drugs, increasing their efficacy and reducing systemic toxicity and off-target effects:
    •  To design and develop polymer-lipid nanoparticles releasing a PROTAC compound degrading ALK. Nanoparticles will be functionalized with clinically approved anti-CD30 antibodies to specifically recognize ALCL cells;
    • 1. To combine ALK degrader-nanoparticles with duvelisib to disrupt the CCL19/21-CCR7-PI3Kγ

Expected results:

We expect that blocking the CCR7/PI3Kγ axis will impair lymphoma persistence and the development of ALK TKI resistance. We expect that combinations of ALK TKIs with duvelisib will reach a superior cure rate than ALK TKIs alone leading to eradication of the disease. We expect to develop efficient nanoparticles to deliver the ALK-targeting degraders to lymphoma cells. In addition, we expect that a combination of ALK-degrader nanoparticles with blockade of PI3Kγ signalling with duvelisib will eradicate ALK+ lymphoma cells.

Planned secondments:

Year 1: Masters Chancellors and Scholars of the university of Cambridge, Milner Thearpeutics Institute: Drug screens conducted at the host institute that has significant experience and expertise in conducting such screens and also has established collaborations with multiple drug companies widening the network of the DC (4 months)

Year 2: Masters Chancellors and Scholars of the university of Cambridge: Treatment of PDX with novel therapeutics providing access to this resource uniquely available in the host lab (4 months)