Dimitris N. Chorafas Foundation Award - 2023 - Agnieszka Chryplewicz
Therapeutic co-targeting strategies for efficacious immune attack and tumor response
Thesis director: Prof. D. Hanahan
For elucidating mechanistic vulnerabilities in the tumor microenvironment of glioblastoma brain cancer that, when co-targeted therapeutically, elicit unprecedented anti-tumor immunity in an otherwise intractable cancer.
Tumors are heterogeneous and composed of multiple interacting cell types, ranging from organ-resident to peripherally-derived cells. This dynamic interplay poses a challenge for cancer treatment as tumors are able to evade immune destruction. In my Ph.D. thesis, I have focused on elucidating how to overcome the almost inevitable resistance that develops to existing standard-of-care cancer drugs as well as to the new dimension of immunotherapies by identifying critical mediators in the tumor microenvironment that contribute to immunosuppression.
We, therefore, undertook the approach of co-targeting and disrupting distinct features of this pro-tumoral microenvironment, aiming to elicit a sustained therapeutic response. As such, we assessed this concept by combining a tricyclic antidepressant – imipramine (IM) – with a drug targeting the dysfunctional vasculature (anti-VEGF) in a transgenic mouse model developing de novo brain tumors. While neither drug was efficacious as monotherapy, the combination of IM + anti-VEGF significantly delayed tumor growth. Investigation of the basis for the therapeutic efficacy revealed that the combo synergistically improved the vascular and immunological parameters in the tumor microenvironment beyond that achieved by monotherapies. As such, these hallmark co-targeting combinations reprogrammed the immunosuppressive microenvironment and sensitized otherwise refractory tumors to immunotherapy.