Wennerberg Group

For most cancers, therapeutic approaches have been identified that initially can eradicate most of the cancer cells, but very commonly, some cells with capacity to reform the cancer persist, and eventually cause the cancer to relapse. In some cancer types, such acute myeloid leukemia (AML), these relapse-driving cells have clear cancer stem cell features. In other cancers, these cells are more likely “fit” cancer cells that can take on cancer stem cell-like properties through intrinsic or extrinsic cues. Our goal is to understand mechanisms of drug sensitivity and resistance in individual cancers and in particular the subsets of cells that persist current therapies and drive cancer recurrence. Through this knowledge, we aim to identify new effective cancer precision medicine strategies that can be explored in clinical trials. Our overarching research questions are therefore:

• Can we identify and understand the drug resistant cells in a cancer, including the cells with cancer stem cell properties that have the capacity to regrow new tumors?
• Can we identify “druggable” vulnerabilities in these cells?
• Can we predict drug resistance mechanisms and therapeutic approaches to overcome them from molecular and phenotypic profiles of an individual cancer?
• Can these discoveries be translated to clinical efficacy?

Establishment of cancer cell ex vivo drug response profiling methods to identify personalized cancer therapies.

• Development of drug response profiling platforms for real-time discoveries of personalized therapies.
• Establishment of analytical methods for optimal analyses of high throughput drug response profiling.
• Primary culturing methods allowing for identification and repurposing drugs that can eradicate cancer stem cells and overcome treatment resistance.

Combining in vitro drug screens with drug target information and molecular profiles to identify molecular vulnerabilities and effective drug combinations.

• Collaborative establishment of the largest available curated drug-molecular target interaction resource (Drug target commons).
• Combining drug response profiling, drug target information and molecular profiling has allowed us computationally predict and validate new drug combination strategies for individual cancers and cancer cell subtypes.

Targeting RAF kinases in acute myeloid leukemia.

• RAF kinase inhibition is selectively inducing apoptosis in a subset of AMLs. This is different than inhibition of the downstream kinases MEK and ERK, which only cause temporary cytostasis.
• RAF inhibition leads to loss of translation of the anti-apoptotic protein MCL-1, thereby inducing apoptosis.
• RAF inhibition can overcome BCL-2 inhibitor resistance in AML and together with BCL-2 inhibitors target the phenotype of the leukemic stem cells.

Discoveries of selective drug combinations overcoming drug resistance development in mature NK cell cancers.

• Mature NK cell cancers are rare cancers but very aggressive cancers with a poor prognosis
• These cancers are driven by JAK/STAT signaling, but blocking this signal only slows down the cancer cells and is insufficient to eradicate them.
• Through series of short- to long-term drug response profiling assays, several clinically relevant JAK inhibitor containing combinations with capacity to completely eradicate mature NK cell cancer models were identified, including combinations targeting TP53-mutant disease.

Program for Translational Hematology

Precision drugs Against Resistance In Subpopulations ERA PerMed project