Novel targeted therapies in cancer to overcome drug resistance – Katja Pokrovskaja Tamm's Team

Our research

The aim of my research is to find novel therapeutic approaches to overcome primary and secondary resistance to anti-cancer therapy. Anti-cancer treatment often leads to the activation of cellular protective mechanisms and an acquired resistance. One of such mechanisms is induction of autophagy, a conserved cellular program devoted to protecting cells from a variety of stresses, including stress created upon cytotoxic chemotherapy. Indeed, using a phenotypic screen-based assay we found earlier that at least one third of all anti-cancer drugs induce autophagy (Dyczynski M PMID: 30055290). In that study, we also demonstrated in a few examples of targeted drugs that inhibition of autophagy using experimental drugs against a lipid kinase Vps34 is a promising strategy to enhance their cytotoxic effects.  

We therefore focused on targeting autophagy for anti-cancer therapy using Vps34 inhibitors developed by several companies including Sprint Bioscience (SB02024). In mouse studies, such compounds were shown to inhibit tumor growth; notably, they can reprogram so-called cold into hot tumors with an accumulation of immune cells in the tumor xenograft microenvironment as well as could improve the anti-PD-1/PD-L1 immunotherapy in mouse models (PMID: 32494661). More recently, we found that Vps34 inhibitor treatment of cancer cells induced cGAS-STING pathway leading to the induction of IFN-beta and pro-inflammatory cytokines CCL5 and CXCL10 (Yu Y, PMID: 38506049), providing a mechanistic insight into immune cell infiltration upon Vps34 inhibition. 

Our goal is now to identify the molecular mechanisms behind cGAS-STING activation by Vps34 and other inhibitors of autophagy and to demonstrate whether cancer cells treated with Vps34- or lysosomal inhibitors can activate immune cells (such as NK cells) for tumor-cell killing. 

I collaborate with Andreas Lundqvist, OnkPat, Bioclinicum, Aljona Maljukova and Olle Sangfelt, CMB, Biomedicum and Rozbeh Jafari at OnkPat, SciLifeLab Solna.

• Swedish Cancer Society
  • STAT3 and autophagy as targets for therapy in pediatric acute leukemia
• Stiftelsen för Internationellt Onkologiskt Samarbete
  • Targeting Autophagy as a therapeutic strategy in pediatric acute lymphoblastic leukemia
• The Cancer Society in Stockholm

Affiliated

Angelo de Milito, PhD, Associate Professor (docent), Director Tumor Biology and Therapeutics, Sprint Bioscience, Huddinge

Alumni

Linda Vidarsdottir, PhD, University of Iceland
Yasmin Yu, PhD, Senior scientist, Sprint Bioscience, Huddinge

Targeting autophagy in pediatric leukemia 

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Yearly about 70-90 new ALL cases are diagnosed in Sweden. It is characterized by an expansion of immature B or T lymphocytes. The disease is heterogeneous and the subtypes are further divided into more than 10 different genetic subgroups characterized by recurring genetic abnormalities that include chromosomal translocations, gene amplifications, and mutations.

One of the key drugs in the treatment of pediatric ALL are glucocorticoids (GC). High doses of Dexamethasone (Dex) are included in all treatment protocols as it efficiently eliminates leukemic blasts. However, such treatment also results in devastating and long-lasting side effects. Dex induces apoptotic cell death of ALL blasts (Laane E, PMID: 18024393); notably, as we found earlier, it also leads to an extensive autophagy prior to apoptosis (Laane E, PMID: 19390558). Dex profoundly affects leukemic cell energy metabolism by inhibiting glucose uptake and utilization (Buentke E, PMID: 22829187). By assessing the global metabolic and protein changes induced by Dex, we found several pathways to be largely affected including glutamine synthesis and lysosomal function (Dyczynski M, PMID: 30154400). More recently, we demonstrated that combination of Dex and autophagy inhibition by either the lysosomal or the Vps34 inhibitors has strong synergistic pro-apoptotic cytotoxic effects on leukemic blasts, both in cell lines and in ex vivo cultured leukemic cells from patients (Bwanika HC, PMID: 38369625).

These results suggest that combining Dex with autophagy inhibitors can be a rational for (1) potentiating pro-apoptotic effects and thus lowing the doses of Dex to limit the resistance and side effects, and (2) for eradicating minimal residual disease, MRD, under ALL treatment. MRD is believed to be a source for relapse when a pre-existing at the diagnosis clone(s) start proliferating again when the intensive treatment is stopped.  Relapsed ALL is commonly associated with a highly resistant disease and a poor prognosis, and therefore novel targeted therapies are required to overcome both the relapse and the resistance. As we demonstrated before on other types of tumors, inhibition of autophagy also leads to the activation of cGAS/STING pathway and consequently to the attraction of immune cells to the tumor site. Our goal now is to demonstrate as a proof-of-principle that autophagy inhibition can be such a tool for eradicating MRD in the bone marrow of patients with ALL through attraction and activation of immune cells (such as NK cells). 

We support a large sample collection of live-frozen cells purified from bone marrow and peripheral blood of pediatric patients at diagnosis with acute leukemia in collaboration with Mats Heyman, Anna Nilsson at KBH and Vasilios Zachariadis, Martin Enge at OnkPat, Bioclinicum. The required ethical permissions to use the leukemic cells from patients in the ex vivo experimental models for the project have been obtained.